What is the rate of bacterial cell death due to viruses on land?

"The rate of viral infection in the oceans stands at 1 × 10^23 infections per second, and these infections remove 20-40% of all bacterial cells each day." -

What are the equivalent figures on land?

The Microbiome and Cancer

From left to right: A transmission electron micrograph of a bacterial virus (bacteriophage), scanning electron micrograph of E. coli bacteria (artificially colored), bacteria (white) growing after being spread on a dish, edible mushrooms.

Below is a list of information found within this section:

Deep-Sea Viruses Destroy Archaea

Ruth Williams
Oct 12, 2016

WIKIMEDIA, LARS LENTZ In the microbial populations of deep-sea sediments, archaea suffer viral infections about twice as often as bacteria, despite the latter being more abundant, according to a study published in Science Advances today (October 12). Given the enormous scale of deep-sea ecosystems, the results indicate that archaea-virus relationships could be a major contributor to global biogeochemical cycles.

&ldquo[This] appears to be a careful and thorough study that has significant implications for microbial communities across all oceanic basins,&rdquo microbiologist Steven Wilhelm of the University of Tennessee, Knoxville, who was not involved in the work, wrote in an email to The Scientist. &ldquo[It] implies that certain microbial populations are much more susceptible to virus activity in these deep ocean regions,&rdquo he added.

Deep-sea ecosystems cover more than 65 percent of the world&rsquos surface and comprise more than 90 percent of the global biosphere, but how they work is still.

The main hosts for these viruses are prokaryotes (bacteria and archaea), explained Danovaro. Indeed, he and his colleagues have previously shown that nearly all prokaryotic death in deep-sea sediments is due to viral infection. And, because of the scale of these ecosystems, the team has estimated that this viral killing of prokaryotes is responsible for the global release of between 0.37 and 0.63 gigatons of carbon per year.

On land and in the shallows, in general bacteria are considerably more abundant than archaea, explained Danovaro, “But in the deep, [archaea] become much more abundant,” he said. In the deep-sea samples analyzed in the present study, for example, Danovaro’s team showed that archaea comprised up to 32 percent (average 12 percent) of the prokaryotes. Given that archaea likely have a larger influence on these ecosystems than others, Danovaro’s team examined viral killing of archaea in particular.

Using nearly 500 sediment samples from deep-sea regions across the globe, the team analyzed extracellular DNA—as a proxy for virus-induced cell lysis—and determined that while between 1 percent and 2.2 percent of bacteria were lysed by viral infection per day, for archaea the lysis rate was double (2.3 percent to 4.3 percent). Thus, although archaea are less abundant than bacteria in these ecosystems, they are considerably more susceptible to viral infection, the researchers reported.

“If there is a lot of mortality due to viruses, then the growth rates of the cells have to offset this,” explained Wilhelm.

Sure enough, the team calculated that the turnover times of archaea in their samples were 12 to 22 days, compared with 31 to 52 days for the bacteria. Extrapolating from their results, the team estimated that viral lysis of archaea alone could contribute between 15 percent and 30 percent of the total carbon released from virus-killed prokaryotes in this ecosystem.

The authors concluded that viruses play a crucial role in the lifecycle of deep-sea archaea and, in turn, the global cycling of carbon as well as other chemicals and nutrients.

The results are “an important contribution to our understanding of marine archaea and their viruses with respect to both biogeochemical cycling and ecological interactions,” ecologist and evolutionary biologist Julie Huber of the Marine Biological Laboratory at Woods Hole, Massachusetts, who did not participate in the research, wrote in an email to The Scientist. “While marine sediments remain more well-studied then many other subseafloor habitats, this is essential data that will serve as an important comparison point as more studies are done on archaea-virus interactions in a variety of marine habitats,” she added.

R. Danovaro et al., “Virus-mediated archaeal hecatomb in the deep seafloor,” Science Advances, doi:10.1126/sciadv.1600492, 2016.

Materials and methods

Effects of UVA light on common opportunistic microbes in culture

Bacterial and yeast preparations.

Bacteria and yeast were grown in appropriate liquid culture media and conditions (detailed in S1 Table). Primary cultures were used to inoculate solid microbial agar and isolate single colony forming units (CFU). Liquid cultures were prepared from a single CFU of each microbe to guarantee purity. Cultures were incubated (S1 Table) until they reached the McFarland standard of 0.5 [12] and 1000 μL of the liquid culture was transferred into each of two 1.7 mL micro-centrifuge sterile tubes. A 100 μL aliquot from each tube was serially diluted and plated on solid microbial medium to determine baseline CFU/mL (S1 Table), and UVA light was applied to the remainder.

UVA light against bacteria and yeast.

UVA effects were assessed using both broad band (BB) and narrow band (NB) wavelength spectra. For BB assessments (peak wavelength

345nm), a mercury vapor lamp (Asahi Max 303, Asahi Spectra Co., Tokyo, Japan) was used to transmit light via a borosilicate rod etched with diluted sulfuric acid, sodium bifluoride, barium sulfate and ammonium bifluoride (Armour, NJ). For NB experiments, an array of LEDs (peak wavelength 343±3nm, with full width at half maximum of 5nm) mounted on an aluminum heatsink (Seoul Viosys, Gyeonggi-Do, South Korea) (S1 Fig) was used. Wavelengths were confirmed by spectrometry (Flame UV-VIS, Ocean Optics, FL) and UV meters (SDL470 and UV510 UV, Extech, NH) (S1 Fig).

For the BB-UVA experiments, the sterilized rod was placed through the caps of 1.7mL tubes. An identical unlit rod was placed into control tubes. After incubation, CFU/mL were determined by serial dilutions of aliquots and measured using a Scan 300 Automatic Colony Counter (Interscience, Woburn, MA). This process was repeated at 20 and 40 minutes.

For the NB-UVA experiments, the LED array was placed 1cm from the surface of a culture plated with E. coli GFP, and illuminated (2000 μW/cm 2 at the plate). In separate experiments, we exposed liquid cultures of 10 6 CFU/mL of E. coli and P. aeruginosa to NB-UVA at intensities of 500, 1000, 2000 and 3000 μW/cm 2 for 20 and 40 minutes.

Safety of NB-UVA on human cells

HeLa cells (ATCC® CCL-2™) were added to DMEM cell culture medium (Gibco, Waltham, MA) plus 10% Bovine serum (Omega Scientific, Tarzana, CA) and 1x Antibiotic-Antimycotic (100x, Gibco) in 60x15mm standard tissue culture dishes (Corning, NY) and incubated at 37ºC (5% CO2) for 24 hours to achieve 1,000,000 to 1,800,000 cells per plate. Cells were exposed to NB-UVA (2000 μW/cm 2 ) for 0 (control), 10, or 20min. After 24hr of further incubation at 37°C (5% CO2), cells were removed using 0.05% Trypsin-EDTA (1x) (Gibco), stained with Trypan Blue 0.4% (1:1) (Gibco) to define live/dead cells [13, 14] and quantitated using an automated cell counter (Biorad T20, Hercules, CA). HeLa cells were also exposed to higher NB-UVA at 5000 μW/cm 2 for 20 minutes and quantitated after 24hr of incubation at 37ºC (5% CO2).

Effects of UVA were also tested on human alveolar (ATCC A549) and primary ciliated tracheal epithelial cells (HTEpC, Lot 446Z036.8, Male, age 50, Caucasian) (PromoCell, Heidelberg, Germany). Cells were plated and grown for 48h in DMEM (Alveolar cell) and Airway Growth Medium (HTEpC) (PromoCell) at 37ºC (5% CO2). Subsequently, cells were exposed to UVA (2000 μW/cm 2 ) for 0 (control) or 20 minutes (treated), and cell counts were obtained after 24hr at 37ºC (5% CO2) by automated cell counter (Biorad T20).

Levels of 8-hydroxy-2’-deoxyguanosineis (8-OHdG), a sensitive marker of oxidative DNA damage and oxidative stress [15, 16], were analyzed in the DNA of NB-UVA-treated cells. DNA was extracted using AllPrep DNA/RNA/Protein Mini Kits (Qiagen). 8-OHdG levels were detected using EpiQuik™ 8-OHdG DNA Damage Quantification Direct Kits (Epigentek, Farmingdale, NY). For optimal quantification, the input DNA amount was 300 ng, as the basal 8-OHdG is generally less than 0.01% of total DNA (Epigentek). A standard curve of 8-OHdG ranging from 5 to 200 pg was used to determine the concentration of 8-OHdG in the samples.

Effects of NB-UVA light on human cells transfected with group B coxsackievirus

NB-UVA exposure of HeLa cells transfected with group B coxsackievirus.

HeLa cells were cultured (12 plates, mean 253,000 cells/plate) for 24hr at 37ºC (5% CO2). Recombinant coxsackievirus B (pMKS1) expressing an enhanced green fluorescent protein (EGFP-CVB) was prepared as previously described [17] half were exposed to NB-UVA (2000 μW/cm 2 ) for 20min while the other half were not exposed. HeLa cells were then transfected with NB-UVA-exposed or NB-UVA-unexposed virus (multiplicity of infection (MOI) = 0.1). Coxsackievirus is considered highly lytic [18]. After 6hrs, supernatant was removed, and cells were washed twice with 1x sterile PBS (pH = 7.0). New DMEM media was added and cells were incubated at 37ºC (5% CO2). Dead cells in the supernatant (floating cells) were collected and quantified 24hrs later using an automated cell counter (Biorad T20). Six plates (3 NB-UVA-exposed and 3 unexposed) were assessed for live cells. Of the remaining six plates, the 3 plates transfected with NB-UVA-exposed virus were exposed to an additional 20min of NB-UVA (2000 μW/cm 2 ). After 24hrs at 37ºC (5% CO2), imaging was performed using a BZ-9000 BioRevo (Keyence Corp., Itasca, IL). Dead and live cells were determined by the Trypan Blue 0.4% (1:1)(Gibco) method and counts were obtained using an automated cell counter (Biorad T20).

HeLa cell pre-treatment with NB-UVA and group B coxsackievirus transfection.

HeLa cells were plated and incubated in DMEM for 24 hours at 37ºC (5% CO2). Plates were divided into unexposed controls (n = 3) and HeLa cells exposed to NB-UVA (2000 μW/cm 2 ) for 20min (n = 3). After 24hrs at 37ºC (5% CO2), all plates were transfected with EGFP-CVB (MOI = 0.1). At 24hrs post-transfection, cells were counted using an automated cell counter (Biorad T20).

Pre-treatment of group B coxsackievirus with NB-UVA and HeLa cell transfection.

HeLa cells were cultured for 24hrs at 37ºC (5% CO2) and transfected with EGFP-CVB (MOI = 0.1). Prior to transfection, half of the EGFP-CVB aliquots were exposed to NB-UVA (2000 μW/cm 2 ) and the other half remained unexposed. After 24hrs at 37ºC (5% CO2), imaging was performed and HeLa cell counts were using an automated cell counter (Biorad T20).

Effects of repeated exposure of NB-UVA on HeLa cells already transfected with group B coxsackievirus.

HeLa cells were plated and incubated at 37ºC (5% CO2) and at 24hrs, cells were divided into three groups: Group 1, cells transfected with EGFP-CVB (n = 3, MOI = 0.1), served as positive transfected controls. Group 2, HeLa cells transfected with EGFP-CVB (MOI = 0.1) exposed to NB-UVA (n = 3, 2000 μW/cm 2 for 20 min) and 6hrs later exposed again to NB-UVA (2000 μW/cm 2 ) for 20 minutes followed by 4 additional exposures (two 20-minute exposures on day 2, 8hrs apart, and two 20-minute exposures on day 3, 8hrs apart. Group 3, not transfected with EGFP-CVB but exposed to NB-UVA at the same time-points as Group 2 (n = 3) to assess UVA effects. In all experiments, imaging and cell counts were performed using an automated cell counter (Biorad T20).

NB-UVA exposure on alveolar (A549) cells already transfected with group B coxsackievirus.

Ideal timepoints of cell death from transfection were determined to be 24 hours in preliminary experiments with alveolar cells (results not shown). Alveolar cells were plated, incubated at 37ºC (5% CO2) and counted at 48hrs (n = 9, cell count of 754,000). Cells were then transfected with EGFP-CVB (n = 6, MOI = 0.1), and 24hrs later, plated cells were exposed to NB-UVA (2000 μW/cm 2 ) for 0 (control, n = 3) or 20 minutes (treated, n = 3). Exposure was repeated every 24hrs for three days, with imaging and cell counts performed at 96hrs post-transfection. Three control plates were not transfected and not exposed.

Preparation of coronavirus 229E.

Human coronavirus 229E (CoV-229E) (ATCC VR-740, ATCC) was overlain onto confluent MRC-5 human lung fibroblasts. CoV-229E is considered lytic [19]. Once cells exhibited

50% cytopathic effect, cells were trypsinized and the cell/media suspension was collected. The cell/media mixture underwent one rapid freeze/thaw cycle and was centrifuged at 1000x g for 10min to clarify the media. The virus in the supernatant was used for subsequent experiments. Equal volumes of the supernatant from the same culture containing the virus were used for transfection of primary human cells.

NB-UVA exposure of ciliated tracheal epithelial cells (HTEpC) transfected with CoV-229E.

HTEpC (135,000 cells) were plated into three groups. Group 1 was transfected with CoV-229E (n = 3, 50uL per plate). In group 2, prior to transfection, CoV-229E was exposed to NB-UVA (n = 3, 2000 μW/cm 2 ) for 20min. Group 3 was not exposed to NB-UVA or transfected (n = 3). After transfection, the cells were exposed to NB-UVA (4cm distance with 2000 μW/cm 2 at the plate surface) for 20min daily. Plates were imaged at 16, 36, 72, and 96hrs, cell viability (live/dead) counts were obtained at 72 and 96hrs post-transfection. Trypan Blue 0.4% (1:1) (Gibco) was used to determine live/dead cells and cell counts were obtained using an automated cell counter (Biorad T20, Hercules, CA). Cells were kept at 37ºC (5% CO2).

NB-UVA effects on CoV-229E and mitochondrial antiviral signaling protein (MAVS).

AllPrep DNA/RNA/Protein Mini Kits (Qiagen) were used to extract total protein from UVA-exposed and unexposed tracheal cells transfected with CoV-229E. Proteins were loaded into a Bolt 4–12% Bis-Tris gel (NW04122 Thermo Fisher) and transferred onto a Biotrace NT nitrocellulose membrane (27376–991, VWR). Total proteins were stained with Ponceau S solution (P7170, Sigma-Aldrich). The membrane was blocked in blocking solution (tris-buffered saline containing 3% bovine serum albumin (A7030, Sigma-Aldrich) and 0.1% Tween 20 (P1379, Sigma-Aldrich) (TBS-T) and incubated overnight at 4°C with either rabbit anti-coronavirus spike protein antibody (1:1000 PA5-81777, Thermo Fisher) or mouse anti-MAVS antibody (1:200 SC-166583, Santa Cruz Biotechnology) diluted in blocking solution. After washing in TBS-T, the membrane was then overlain with either horseradish peroxidase (HRP)-conjugated goat anti-rabbit IgG antibody (1:300 95058–734, VWR) or HRP-conjugated goat anti-mouse IgG antibody (1:300 5220–0286, SeraCare), washed in TBS-T, and exposed to enhanced chemiluminescence solution (RPN2235, GE Healthcare). Immunoreactive protein bands were imaged using a ChemiDoc Imaging System (Bio-Rad Laboratories, Hercules, CA).

In vivo effects of UVA

Animal preparation.

In vivo effects of UVA exposure on mammalian internal visceral cells were assessed using wildtype 129S6/SvEv mice (n = 20, female = 10) and BALB/cJ mice (n = 10, female = 5). Animals were anesthetized prior to UVA light treatment in a chamber containing isoflurane anesthetic gas (1–5%) mixed with oxygen, and maintained under sedation using a nose cone anesthesia (1–2% isoflurane) at one breath per second. Euthanasia was performed using C02 inhalation followed by cervical dislocation. All animal research was performed under a protocol approved by the Institutional Animal Care and Use Committee (IACUC) at Cedars-Sinai Medical Center, IACUC007304.

Exposure of colonic mucosa to UVA.

Under anesthesia, the borosilicate rod (OD = 4mm, length = 40mm) was introduced anally to the splenic flexure (S1C Fig). Five BALB/cJ mice underwent colonic BB-UVA exposure (2,000 μW/cm 2 ) for 30min, and 5 mice were treated with an unlit optic rod. In the second experiment, ten 129S6/SvEv mice underwent 20min daily colonic UVA exposure (3,000–3,500 μW/cm 2 ) for 2 two consecutive days, and 10 mice (male = 5) were treated with an unlit rod.

Endoscopic examination before and after UVA light therapy.

While anesthetized, a rigid pediatric cystoscope (Olympus A37027A) was used to assess the intestinal mucosa up to the splenic flexure before and after UVA exposure. All endoscopies were recorded and blindly interpreted by two gastroenterologists (JHP and SYK) with expertise in animal model endoscopies. Endoscopic appearances were analyzed based on perianal examination, transparency of the intestinal wall, mucosal bleeding, and focal lesions.

Tissue analysis.

At day 14, control and treated mice were euthanized, and swiss-roll preparations of the colon were performed as described [20]. The rolled colon was transferred to a tissue-processing/embedding cassette and placed in 10% buffered formalin overnight. Paraffin sections of the colon were cut, stained with hematoxylin and eosin (H&E), and assessed by a blinded pathologist (SS).

Statistical analysis

Descriptive statistics were calculated to describe the bacteria counts and colony sizes and UVA exposure with varying intensities. Each UVA group included 4 measurements and the mean of the measurements at each time point was reported. To assess the effect of UVA light on bacteria, yeast, and virus, the measurements of bacteria and human cells in UVA exposed and control groups were compared with t-test. Bivariate analyses were used to further determine the association between UVA exposure and viral effect on three human cell types. The continuous variables were compared with t-test. The statistical significance was defined as p < 0.05. Analyses were performed using GraphPAD Prism 7 (GraphPad, San Diego, CA).

Here's what scientists learn from studying dangerous pathogens in secure labs

Biosafety levels are defined by how much risk is involved in working with particular pathogens. Credit: The Conversation, CC BY-ND

There are about 1,400 known human pathogens—viruses, bacteria, fungi, protozoa and helminths that can cause a person's injury or death. But in a world with a trillion individual species of microorganisms, where scientists have counted only one one-thousandth of one percent, how likely is it researchers have discovered and characterized everything that might threaten people?

Not very likely at all. And there's a lot to be gained from knowing these microscopic enemies better.

So even though in day-to-day life it makes sense to avoid these dangerous microorganisms, scientists like me are motivated to study them up close and personal to learn how they work. Of course, we want to do it in as safe a way as possible.

I've worked in biocontainment laboratories and have published scientific articles on both bacteria and viruses, including influenza and the SARS-CoV-2 coronavirus. Here at Oklahoma State University, 10 research groups are currently studying pathogens in biosecure labs. They're identifying genetic variations of viruses and bacteria, studying how they operate within cells of their hosts. Some are untangling how the host immune system responds to these invaders and is affected by so-called comorbidities of obesity, diabetes or advanced age. Others are investigating how to detect and eliminate pathogens.

This kind of research, to understand how pathogens cause harm, is crucial to human and veterinary medicine, as well as the health of mammals, birds, fish, plants, insects and other species around the globe.

Forewarned is forearmed

Think about all scientists have learned in the past century about how to prevent diseases based on understanding which microorganism is responsible, where it is in the environment and how it overcomes humans' natural defenses.

Understanding what these organisms do, how they do it, and how they spread helps researchers develop measures to detect, mitigate and control their expansion. The goal is to be able to cure or prevent the disease they cause. The more dangerous the pathogen, the more urgently scientists need to understand it.

This is where lab research comes in.

Scientists have basic questions about how a pathogen conducts itself. What machinery does it use to enter a host cell and replicate? What genes does it activate, to make which proteins? This kind of information can be used to pinpoint strategies to eliminate the pathogen or lead to disease treatments or vaccines.

As the library of what is known about pathogens grows, there's more chance researchers can apply some of that knowledge when faced with an emerging pathogen.

People might encounter new pathogens as they move into different parts of the world, or alter ecosystems. Sometimes a pathogen adapts to a new vector—meaning it can be carried by a different organism—allowing it to spread into new areas and infect new populations. Roughly 70% of emerging infectious diseases around the world are transmitted through animals to people these are called zoonotic diseases. It is critical to understand how these pathways work in order to have even a modest ability to predict what could happen.

While there are patterns in nature that can provide clues, the tremendous diversity of the microbial world and the rate at which these organisms evolve new strategies for their own defense and survival makes it imperative to study and understand each one as it's discovered.

Can this research be done safely?

There is no such thing as zero risk in any endeavor, but over many years, researchers have developed safe laboratory methods for working with dangerous pathogens.

Each study must document in advance what is to be done, how, where and by whom. These descriptions are reviewed by independent committees to make sure the plans outline the safest way to do the work. There's independent follow-up by trained professionals within the institution and, in some cases, by the U.S. Centers for Disease Control and Prevention, the U.S. Department of Agriculture, or both, to ensure researchers are following the approved procedures and regulations.

Those who work with dangerous pathogens adhere to two sets of principles. There's biosafety, which refers to containment. It includes all the engineering controls that keep the scientists and their surroundings safe: enclosed, ventilated workspaces called biosafety cabinets, directional airflows and anterooms to control air movement inside the lab. Special high-efficiency particulate air filters (HEPA) clean the air moving in and out of the laboratory.

We stick to good laboratory work practices, and everyone suits up in personal protective equipment including gowns, masks and gloves. Sometimes we use special respirators to filter the air we breathe while in the lab. Additionally we often inactivate the pathogen we're studying—essentially taking it apart so it is not functional—and work on the pieces one or a few at a time.

Then there's biosecurity, meaning the measures designed to prevent loss, theft, release or misuse of a pathogen. They include access controls, inventory controls and certified methods for decontaminating and disposing of waste. Part of these security measures is keeping the details close.

The research community recognizes four levels of biosafety practices. Biosafety level-1 (BSL-1) and BSL-2 are applied to general laboratory spaces where there is low to no risk. They would not work with microorganisms that pose a serious threat to people or animals.

BSL-3 refers to laboratories where there is high individual risk but low community risk, meaning there is a pathogen that can cause human disease but is not transmitted from person to person and the disease is readily treatable. This is the kind of work my colleagues and I, and many medical and veterinary schools, will do.

BSL-4 refers to work with pathogens that pose a high risk of significant disease in people, animals or both that is transmitted among individuals and for which an effective treatment may not be available. BSL-4 laboratories are relatively rare, by one estimate only about 50 exist in the world.

At each level the increased risk requires increasingly stringent precautions to keep workers safe and prevent any accidental or malicious misuse.

What's at risk if science ignores these microbes?

In recent years, the world has seen outbreaks of severe disease caused by several types of pathogens. Even for the pathogens scientists do know about, much remains unknown. It is reasonable to expect there are more threats out there yet to be discovered.

It is critical for scientists to study new disease pathogens in the lab as they're discovered and to understand how they move from host to host and are affected by conditions what variations develop over time and what effective control measures can be developed. In addition to more well-known viruses such as rabies, West Nile virus and Ebola, there are several critically important pathogens circulating in the world today that pose a serious threat. Hantaviruses, dengue, Zika virus and the Nipah virus are all under investigation in various labs, where researchers are working to understand more about how they're transmitted, develop rapid diagnostics and produce vaccines and therapeutics.

Microorganisms are the most abundant form of life on the planet and extremely important to human health and the health of plants and animals. In general, people have adapted to their presence, and vice versa. For those microbes with the capacity to do real harm, it makes sense to study as many as scientists can now, before the next pandemic hits.

This article is republished from The Conversation under a Creative Commons license. Read the original article.

Chapter 43 - The Immune System

  • An invading microbe must penetrate the external barrier formed by the skin and mucous membranes, which cover the surface and line the openings of an animal’s body.
  • If it succeeds, the pathogen encounters the second line of nonspecific defense, innate cellular and chemical mechanisms that defend against the attacking foreign cell.

The skin and mucous membrane provide first-line barriers to infection.

  • Intact skin is a barrier that cannot normally be penetrated by bacteria or viruses, although even minute abrasions may allow their passage.
  • Likewise, the mucous membranes that line the digestive, respiratory, and genitourinary tracts bar the entry of potentially harmful microbes.
    • Cells of these mucous membranes produce mucus, a viscous fluid that traps microbes and other particles.
    • In the trachea, ciliated epithelial cells sweep out mucus with its trapped microbes, preventing them from entering the lungs.
    • In humans, for example, secretions from sebaceous and sweat glands give the skin a pH ranging from 3 to 5, which is acidic enough to prevent colonization by many microbes.
    • Microbial colonization is also inhibited by the washing action of saliva, tears, and mucous secretions that continually bathe the exposed epithelium.
      • All these secretions contain antimicrobial proteins.
      • One of these, the enzyme lysozyme, digests the cell walls of many bacteria, destroying them.
      • The acid destroys many microbes before they can enter the intestinal tract.
      • One exception, the virus hepatitis A, can survive gastric acidity and gain access to the body via the digestive tract.

      Phagocytic cells and antimicrobial proteins function early in infection.

      • Microbes that penetrate the first line of defense face the second line of defense, which depends mainly on phagocytosis, the ingestion of invading organisms by certain types of white cells.
      • Phagocyte function is intimately associated with an effective inflammatory response and also with certain antimicrobial proteins.
      • Phagocytes attach to their prey via surface receptors found on microbes but not normal body cells.
      • After attaching to the microbe, a phagocyte engulfs it, forming a vacuole that fuses with a lysosome.
        • Microbes are destroyed within lysosomes in two ways.
          • Lysosomes contain nitric oxide and other toxic forms of oxygen, which act as potent antimicrobial agents.
          • Lysozymes and other enzymes degrade mitochondrial components.
          • The outer capsule of some bacterial cells hides their surface polysaccharides and prevents phagocytes from attaching to them.
          • Other bacteria are engulfed by phagocytes but resist digestion, growing and reproducing within the cells.
          • Cells damaged by invading microbes release chemical signals that attract neutrophils from the blood.
          • The neutrophils enter the infected tissue, engulfing and destroying microbes there.
          • Neutrophils tend to self-destruct as they destroy foreign invaders, and their average life span is only a few days.
          • After a few hours in the blood, they migrate into tissues and develop into macrophages, which are large, long-lived phagocytes.
          • Some macrophages migrate throughout the body, while others reside permanently in certain tissues, including the lungs, liver, kidneys, connective tissues, brain, and especially in lymph nodes and the spleen.
          • Microbes that enter the blood become trapped in the spleen, while microbes in interstitial fluid flow into lymph and are trapped in lymph nodes.
          • In either location, microbes soon encounter resident macrophages.
          • Eosinophils position themselves against the external wall of a parasite and discharge destructive enzymes from cytoplasmic granules.
          • In addition to lysozyme, other antimicrobial agents include about 30 serum proteins, known collectively as the complement system.
            • Substances on the surface of many microbes can trigger a cascade of steps that activate the complement system, leading to lysis of microbes.
            • These proteins are secreted by virus-infected body cells and induce uninfected neighboring cells to produce substances that inhibit viral reproduction.
            • Interferon limits cell-to-cell spread of viruses, helping to control viral infection.
            • Because they are nonspecific, interferons produced in response to one virus may confer short-term resistance to unrelated viruses.
            • One type of interferon activates phagocytes.
            • Interferons can be produced by recombinant DNA technology and are being tested for the treatment of viral infections and cancer.
            • When injured, mast cells release their histamine.
            • Histamine triggers both dilation and increased permeability of nearby capillaries.
            • Leukocytes and damaged tissue cells also discharge prostaglandins and other substances that promote blood flow to the site of injury.
            • Increased local blood supply leads to the characteristic swelling, redness, and heat of inflammation.
            • Blood-engorged leak fluid into neighboring tissue, causing swelling.
            • First, they aid in delivering clotting elements to the injured area.
              • Clotting marks the beginning of the repair process and helps block the spread of microbes elsewhere.
              • Phagocyte migration usually begins within an hour after injury.
              • Injured cells secrete chemicals that stimulate the release of additional neutrophils from the bone marrow.
              • In a severe infection, the number of white blood cells may increase significantly within hours of the initial inflammation.
              • Another systemic response to infection is fever, which may occur when substances released by activated macrophages set the body’s thermostat at a higher temperature.
                • Moderate fever may facilitate phagocytosis and hasten tissue repair.
                • Characterized by high fever and low blood pressure, septic shock is the most common cause of death in U.S. critical care units.
                • Clearly, while local inflammation is an essential step toward healing, widespread inflammation can be devastating.
                • They also attack abnormal body cells that could become cancerous.
                • NK cells attach to a target cell and release chemicals that bring about apoptosis, or programmed cell death.

                Invertebrates also have highly effective innate defenses.

                • Insect hemolymph contains circulating cells called hemocytes.
                  • Some hemocytes can phagocytose microbes, while others can form a cellular capsule around large parasites.
                  • Other hemocytes secrete antimicrobial peptides that bind to and destroy pathogens.
                  • Sponge cells can distinguish self from nonself cells.
                  • Phagocytic cells of earthworms show immunological memory, responding more quickly to a particular foreign tissue the second time it is encountered.

                  Concept 43.2 In acquired immunity, lymphocytes provide specific defenses against infection

                  • While microorganisms are under assault by phagocytic cells, the inflammatory response, and antimicrobial proteins, they inevitably encounter lymphocytes, the key cells of acquired immunity, the body’s second major kind of defense.
                  • As macrophages and dendritic cells phagocytose microbes, they secrete certain cytokines that help activate lymphocytes and other cells of the immune system.
                    • Thus the innate and acquired defenses interact and cooperate with each other.
                    • Most antigens are large molecules such as proteins or polysaccharides.
                    • Most are cell-associated molecules that protrude from the surface of pathogens or transplanted cells.
                    • A lymphocyte actually recognizes and binds to a small portion of an antigen called an epitope.

                    Lymphocytes provide the specificity and diversity of the immune system.

                    • The vertebrate body is populated by two main types of lymphocytes: B lymphocytes (B cells) and T lymphocytes (T cells).
                      • Both types of lymphocytes circulate throughout the blood and lymph and are concentrated in the spleen, lymph nodes, and other lymphatic tissue.
                      • A single B or T cell bears about 100,000 identical antigen receptors.
                      • A region in the tail portion of the molecule, the transmembrane region, anchors the receptor in the cell’s plasma membrane.
                      • A short region at the end of the tail extends into the cytoplasm.
                      • B cell receptors are often called membrane antibodies or membrane immunoglobulins.
                      • Depending on their source, peptide antigens are handled by a different class of MHC molecule and recognized by a particular subgroup of T cells.
                        • Class I MHC molecules, found on almost all nucleated cells of the body, bind peptides derived from foreign antigens that have been synthesized within the cell.
                          • ? Any body cell that becomes infected or cancerous can display such peptide antigens by virtue of its class I MHC molecules.
                          • ? Class I MHC molecules displaying bound peptide antigens are recognized by a subgroup of T cells called cytotoxic T cells.
                          • In these cells, class II MHC molecules bind peptides derived from foreign materials that have been internalized and fragmented by phagocytosis.
                          • As a result of the large number of different alleles in the human population, most of us are heterozygous for every one of our MHC genes.
                          • Moreover, it is unlikely that any two people, except identical twins, will have exactly the same set of MHC molecules.
                          • The MHC provides a biochemical fingerprint virtually unique to each individual that marks body cells as “self.”

                          Lymphocyte development gives rise to an immune system that distinguishes self from nonself.

                          • Lymphocytes, like all blood cells, originate from pluripotent stem cells in the bone marrow or liver of a developing fetus.
                          • Early lymphocytes are all alike, but they later develop into T cells or B cells, depending on where they continue their maturation.
                          • Lymphocytes that migrate from the bone marrow to the thymus develop into T cells.
                          • Lymphocytes that remain in the bone marrow and continue their maturation there become B cells.
                          • There are three key events in the life of a lymphocyte.
                            • The first two events take place as a lymphocyte matures, before it has contact with any antigen.
                            • The third event occurs when a mature lymphocyte encounters and binds a specific antigen, leading to its activation, proliferation, and differentiation—a process called clonal selection.
                            • The variability of these regions is enormous.
                            • Each person has as many as a million different B cells and 10 million different T cells, each with a specific antigen-binding ability.
                            • These genes consist of numerous coding gene segments that undergo random, permanent rearrangement, forming functional genes that can be expressed as receptor chains.
                            • Genes for the light chain of the B cell receptor and for the alpha and beta chains of the T cell receptor undergo similar rearrangements, but we will consider only the gene coding for the light chain of the B cell receptor.
                            • The immunoglobulin light-chain gene contains a series of 40 variable (V) gene segments separated by a long stretch of DNA from 5 joining (J) gene segments.
                            • Beyond the J gene segments is an intron, followed by a single exon that codes for the constant region of the light chain.
                            • In this state, the light-chain gene is not functional.
                            • However, early in B cell development, a set of enzymes called recombinase link one V gene segment to one J gene segment, forming a single exon that is part V and part J.
                              • Recombinase acts randomly and can link any one of 40 V gene segments to any one of 5 J gene segments.
                              • For the light-chain gene, there are 200 possible gene products (20 V × 5 J).
                              • Once V-J rearrangement has occurred, the gene is transcribed and translated into a light chain with a variable and constant region. The light chains combine randomly with the heavy chains that are similarly produced.
                              • Failure to do this can lead to autoimmune diseases such as multiple sclerosis.

                              Antigens interact with specific lymphocytes, inducing immune responses and immunological memory.

                              • Although it encounters a large repertoire of B cells and T cells, a microorganism interacts only with lymphocytes bearing receptors specific for its various antigenic molecules.
                              • A lymphocyte is “selected” when it encounters a microbe with epitopes matching its receptors.
                                • Selection activates the lymphocyte, stimulating it to divide and differentiate, and eventually to produce two clones of cells.
                                • One clone consists of a large number of effector cells, short-lived cells that combat the same antigen.
                                • The other clone consists of memory cells, long-lived cells bearing receptors for the same antigen.
                                • Each antigen, by binding selectively to specific receptors, activates a tiny fraction of cells from the body’s diverse pool of lymphocytes.
                                • This relatively small number of selected cells gives rise to clones of thousands of cells, all specific for and dedicated to eliminating that antigen.
                                • About 10 to 17 days are required from the initial exposure for the maximum effector cell response.
                                • During this period, selected B cells and T cells generate antibody-producing effector B cells called plasma cells, and effector T cells, respectively.
                                • While this response is developing, a stricken individual may become ill, but symptoms of the illness diminish and disappear as antibodies and effector T cells clear the antigen from the body.
                                • This response is faster (only 2 to 7 days), of greater magnitude, and more prolonged.
                                • In addition, the antibodies produced in the secondary response tend to have greater affinity for the antigen than those secreted in the primary response.
                                • The immune system’s capacity to generate secondary immune responses is called immunological memory, based not only on effector cells, but also on clones of long-lived T and B memory cells.
                                  • These memory cells proliferate and differentiate rapidly when they later contact the same antigen.

                                  Concept 43.3 Humoral and cell-mediated immunity defend against different types of threats

                                  • The immune system can mount two types of responses to antigens: a humoral response and a cell-mediated response.
                                    • Humoral immunity involves B cell activation and clonal selection and results in the production of antibodies that circulate in the blood plasma and lymph.
                                      • Circulating antibodies defend mainly against free bacteria, toxins, and viruses in the body fluids.

                                      Helper T lymphocytes function in both humoral and cell-mediated immunity.

                                      • When a helper T cell recognizes a class II MHC molecule-antigen complex on an antigen-presenting cell, the helper T cell proliferates and differentiates into a clone of activated helper T cells and memory helper T cells.
                                      • A surface protein called CD4 binds the side of the class II MHC molecule.
                                      • This interaction helps keep the helper T cell and the antigen-presenting cell joined while activation of the helper T cell proceeds.
                                      • Activated helper T cells secrete several different cytokines that stimulate other lymphocytes, thereby promoting cell-mediated and humoral responses.
                                      • Dendritic cells are important in triggering a primary immune response.
                                        • They capture antigens, migrate to the lymphoid tissues, and present antigens, via class II MHC molecules, to helper T cells.

                                        In the cell-mediated response, cytotoxic T cells counter intracellular pathogens.

                                        • Antigen-activated cytotoxic T lymphocytes kill cancer cells and cells infected by viruses and other intracellular pathogens.
                                        • Fragments of nonself proteins synthesized in such target cells associate with class I MHC molecules and are displayed on the cell surface, where they can be recognized by cytotoxic T cells.
                                          • This interaction is greatly enhanced by the T surface protein CD8 that helps keep the cells together while the cytotoxic T cell is activated.
                                          • The death of the infected cell not only deprives the pathogen of a place to reproduce, but also exposes it to circulating antibodies, which mark it for disposal.
                                          • Once activated, cytotoxic T cells kill other cells infected with the same pathogen.
                                          • Because tumor cells carry distinctive molecules not found on normal cells, they are identified as foreign by the immune system.
                                          • Class I MHC molecules on a tumor cell present fragments of tumor antigens to cytotoxic T cells.
                                          • Interestingly, certain cancers and viruses actively reduce the amount of class I MHC protein on affected cells so that they escape detection by cytotoxic T cells.
                                          • The body has a backup defense in the form of natural killer cells, part of the nonspecific defenses, which lyse virus-infected and cancer cells.

                                          In the humoral response, B cells make antibodies against extracellular pathogens.

                                          • Antigens that elicit a humoral immune response are typically proteins and polysaccharides present on the surface of bacteria or transplanted tissue.
                                          • The activation of B cells is aided by cytokines secreted by helper T cells activated by the same antigen.
                                            • These B cells proliferate and differentiate into a clone of antibody-secreting plasma cells and a clone of memory B cells.
                                            • These include the polysaccharides of many bacterial capsules and the proteins of the bacterial flagella.
                                            • These antigens bind simultaneously to a number of membrane antibodies on the B cell surface.
                                            • This stimulates the B cell to generate antibody-secreting plasma cells without the help of cytokines.
                                            • While this response is an important defense against many bacteria, it generates a weaker response than T-dependent antigens and generates no memory cells.
                                            • Each plasma cell is estimated to secrete about 2,000 antibody molecules per second over the cell’s 4- to 5-day life span.
                                            • A secreted antibody has the same general Y-shaped structure as a B cell receptor, but lacks a transmembrane region that would anchor it to a plasma membrane.
                                            • In addition, for some humans, the proteins of foreign substances such as pollen or bee venom act as antigens that induce an allergic, or hypersensitive, humoral response.
                                            • Two classes exist primarily as polymers of the basic antibody molecule: IgM as a pentamer and IgA as a dimmer.
                                            • The other three classes—IgG, IgE, and IgD—exist exclusively as monomers,
                                            • Some antibody tools are polyclonal, the products of many different clones of B cells, each specific for a different epitope.
                                            • Others are monoclonal, prepared from a single clone of B cells grown in culture.
                                              • These cells produce monoclonal antibodies, specific for the same epitope on an antigen.
                                              • These have been used to tag specific molecules.
                                              • For example, toxin-linked antibodies search and destroy tumor cells.
                                              • In viral neutralization, antibodies bind to proteins on the surface of a virus, blocking the virus’s ability to infect a host cell.
                                              • In opsonization, the bound antibodies enhance macrophage attachment to and phagocytosis of the microbes. Neither the B cell receptor for an antigen nor the secreted antibody actually binds to an entire antigen molecule.
                                              • Agglutination is possible because each antibody molecule has at least two antigen-binding sites.
                                              • IgM can link together five or more viruses or bacteria.
                                              • These large complexes are readily phagocytosed by macrophages.
                                              • The first complement component links two bound antibodies and is activated, initiating the cascade.
                                                • Ultimately, complement proteins generate a membrane attack complex (MAC), which forms a pore in the bacterial membrane, resulting in cell lysis.

                                                Immunity can be achieved naturally or artificially.

                                                • Immunity conferred by recovering from an infectious disease such as chicken pox is called active immunity because it depends on the response of the infected person’s own immune system.
                                                  • Active immunity can be acquired naturally or artificially, by immunization, also known as vaccination.
                                                  • Vaccines include inactivated bacterial toxins, killed microbes, parts of microbes, viable but weakened microbes, and even genes encoding microbial proteins.
                                                  • These agents can act as antigens, stimulating an immune response and, more important, producing immunological memory.
                                                  • Routine immunization of infants and children has dramatically reduced the incidence of infectious diseases such as measles and whooping cough, and has led to the eradication of smallpox, a viral disease.
                                                  • Unfortunately, not all infectious agents are easily managed by vaccination.
                                                    • For example, the emergence of new strains of pathogens with slightly altered surface antigens complicates development of vaccines against some microbes, such as the parasite that causes malaria.
                                                    • This occurs naturally when IgG antibodies of a pregnant woman cross the placenta to her fetus.
                                                    • In addition, IgA antibodies are passed from mother to nursing infant in breast milk.
                                                    • Passive immunity persists as long as these antibodies last, a few weeks to a few months.
                                                      • This protects the infant from infections until the baby’s own immune system has matured.
                                                      • This confers short-term, but immediate, protection against that disease.
                                                      • For example, a person bitten by a rabid animal may be injected with antibodies against rabies virus because rabies may progress rapidly, and the response to an active immunization could take too long to save the life of the victim.
                                                        • Most people infected with rabies virus are given both passive immunizations (the immediate defense) and active immunizations (a longer-term defense).

                                                        Concept 43.4 The immune system’s ability to distinguish self from nonself limits tissue transplantation

                                                        • In addition to attacking pathogens, the immune system will also attack cells from other individuals.
                                                          • For example, a skin graft from one person to a nonidentical individual will look healthy for a day or two, but it will then be destroyed by immune responses.
                                                          • Interestingly, a pregnant woman does not reject the fetus as a foreign body. Apparently, the structure of the placenta is the key to this acceptance.
                                                          • In the ABO blood groups, an individual with type A blood has A antigens on the surface of red blood cells.
                                                            • This is not recognized as an antigen by the “owner,” but it can be identified as foreign if placed in the body of another individual.
                                                            • These antibodies arise in response to bacteria (normal flora) that have epitopes very similar to blood group antigens.
                                                            • Thus, an individual with type A blood does not make antibodies to A-like bacterial epitopes—these are considered self—but that person does make antibodies to B-like bacterial epitopes.
                                                            • If a person with type A blood receives a transfusion of type B blood, the preexisting anti-B antibodies will induce an immediate and devastating transfusion reaction.
                                                            • Each response is like a primary response, and it generates IgM anti-blood-group antibodies, not IgG.
                                                            • This is fortunate, because IgM antibodies do not cross the placenta, where they may harm a developing fetus with a blood type different from its mother’s.
                                                            • This situation arises when a mother that is Rh-negative (lacks the Rh factor) has a fetus that is Rh-positive, having inherited the factor from the father.
                                                            • If small amounts of fetal blood cross the placenta late in pregnancy or during delivery, the mother mounts a humoral response against the Rh factor.
                                                            • The danger occurs in subsequent Rh-positive pregnancies, when the mother’s Rh-specific memory B cells produce IgG antibodies that can cross the placenta and destroy the red blood cells of the fetus.
                                                            • She is, in effect, passively immunized (artificially) to eliminate the Rh antigen before her own immune system responds and generates immunological memory against the Rh factor, endangering her future Rh-positive babies.
                                                            • Because MHC creates a unique protein fingerprint for each individual, foreign MHC molecules are antigenic, inducing immune responses against the donated tissue or organ.
                                                            • To minimize rejection, attempts are made to match MHC of tissue donor and recipient as closely as possible.
                                                              • In the absence of identical twins, siblings usually provide the closest tissue-type match.
                                                              • However, this strategy leaves the recipient more susceptible to infection and cancer during the course of treatment.
                                                              • More selective drugs, which suppress helper T cell activation without crippling nonspecific defense or T-independent humoral responses, have greatly improved the success of organ transplants.
                                                              • Bone marrow transplants are used to treat leukemia and other cancers as well as various hematological diseases.
                                                              • Prior to the transplant, the recipient is typically treated with irradiation to eliminate the recipient’s immune system, eliminating all abnormal cells and leaving little chance of graft rejection.
                                                              • However, the donated marrow, containing lymphocytes, may react against the recipient, producing graft versus host reaction, unless well matched.

                                                              Concept 43.5 Exaggerated, self-directed, or diminished immune responses can cause disease

                                                              • Malfunctions of the immune system can produce effects ranging from the minor inconvenience of some allergies to the serious and often fatal consequences of certain autoimmune and immunodeficiency diseases.
                                                              • Allergies are hypersensitive (exaggerated) responses to certain environmental antigens, called allergens.
                                                                • One hypothesis to explain the origin of allergies is that they are evolutionary remnants of the immune system’s response to parasitic worms.
                                                                • The humoral mechanism that combats worms is similar to the allergic response that causes such disorders as hay fever and allergic asthma.
                                                                • Hay fever, for example, occurs when plasma cells secrete IgE specific for pollen allergens.
                                                                • Some IgE antibodies attach by their tails to mast cells present in connective tissue, without binding to the pollen.
                                                                • Later, when pollen grains enter the body, they attach to the antigen-binding sites of mast cell-associated IgE, cross-linking adjacent antibody molecules.
                                                                • These inflammatory events lead to typical allergy symptoms: sneezing, runny nose, tearing eyes, and smooth muscle contractions that can result in breathing difficulty.
                                                                • Antihistamines diminish allergy symptoms by blocking receptors for histamine.
                                                                • Anaphylactic shock results when widespread mast cell degranulation triggers abrupt dilation of peripheral blood vessels, causing a precipitous drop in blood pressure.
                                                                  • Death may occur within minutes.
                                                                  • In systemic lupus erythematosus (lupus), the immune system generates antibodies against various self-molecules, including histones and DNA released by the normal breakdown of body cells.
                                                                    • Lupus is characterized by skin rashes, fever, arthritis, and kidney dysfunction.
                                                                    • In MS, T cells reactive against myelin infiltrate the central nervous system and destroy the myelin sheath that surrounds some neurons.
                                                                    • People with MS experience a number of serious neurological abnormalities.
                                                                    • It was thought that people with autoimmune diseases had self-reactive lymphocytes that escaped elimination during their development.
                                                                    • We now know that healthy people also have lymphocytes with the capacity to react against self, but these cells are inhibited from inducing an autoimmune reaction by several regulatory mechanisms.
                                                                    • Autoimmune disease likely arises from some failure in immune regulation, perhaps linked with particular MHC alleles.
                                                                    • For individuals with this disease, long-term survival requires a bone marrow transplant that will continue to supply functional lymphocytes.
                                                                    • Several gene therapy approaches are in clinical trials to attempt to reverse SCID.
                                                                    • Recent successes include a child with SCID who received gene therapy in 2002 when she was 2 years old. In 2004, her T cells and B cells were still functioning normally.
                                                                    • For example, certain cancers suppress the immune system. An example is Hodgkin’s disease, which damages the lymphatic system.
                                                                    • For example, hormones secreted by the adrenal glands during stress affect the number of white blood cells and may suppress the immune system in other ways.
                                                                    • Similarly, some neurotransmitters secreted when we are relaxed and happy may enhance immunity.
                                                                    • Physiological evidence also points to an immune system–nervous system link based on the presence of neurotransmitter receptors on the surfaces of lymphocytes and a network of nerve fibers that penetrates deep into the thymus.

                                                                    AIDS is an immunodeficiency disease caused by a virus.

                                                                    • In 1981, increased rates of two rare diseases, Kaposi’s sarcoma, a cancer of the skin and blood vessels, and pneumonia caused by the protozoan Pneumocystis carinii, were the first signals to the medical community of a new threat to humans, later known as acquired immunodeficiency syndrome, or AIDS.
                                                                      • Both conditions were previously known to occur mainly in severely immunosuppressed individuals.
                                                                      • People with AIDS are susceptible to opportunistic diseases.
                                                                      • Because AIDS arises from the loss of helper T cells, both humoral and cell-mediated immune responses are impaired.
                                                                      • The main receptor for HIV on helper T cells is the cell’s CD4 molecule.
                                                                      • In addition to CD4, HIV requires a second cell-surface protein, a coreceptor.
                                                                      • However, these drugs are very expensive and not available to all infected people, especially in developing countries.
                                                                      • In addition, the mutational changes that occur with each round of virus reproduction can generate drug-resistant strains of HIV.
                                                                      • Transmission of HIV requires the transfer of body fluids containing infected cells, such as semen or blood, from person to person.
                                                                      • In December 2003, the Joint UN Program on AIDS estimated that 40 million people worldwide are living with HIV/AIDS. The best approach for slowing the spread of HIV is to educate people about the practices that lead to transmission, such as using dirty needles or having unprotected intercourse.

                                                                      Lecture Outline for Campbell/Reece Biology, 7th Edition, © Pearson Education, Inc. 43-9

                                                                      What is the rate of bacterial cell death due to viruses on land? - Biology

                                                                      Antibiotic resistance: delaying the inevitable

                                                                      Only a few decades ago, antibiotics were considered to be wonder drugs because they worked so well to cure deadly diseases. Ironically, though, many antibiotics have become less effective, precisely because they have worked so well and have been used so often.

                                                                      Making inroads against infectious disease
                                                                      The antibiotic era began in 1929 with Alexander Fleming's observation that bacteria would not grow near colonies of the mold Penicillium. In the decades that followed this breakthrough discovery, molecules produced by fungi and bacteria have been successfully used to combat bacterial diseases such as tuberculosis and pneumonia. Antibiotics drastically reduced death rates associated with many infectious diseases.

                                                                      Infectious diseases strike back
                                                                      The golden age of antibiotics proved to be a short-lived one. During the past few decades, many strains of bacteria have evolved resistance to antibiotics. An example of this is Neisseria gonorrhoeae, the bacteria that causes gonorrhea, shown at right. In the 1960s penicillin and ampicillin were able to control most cases of gonorrhea. Today, more than 24 percent of gonorrheal bacteria in the U.S. are resistant to at least one antibiotic, and 98 percent of gonorrheal bacteria in Southeast Asia are resistant to penicillin. 1 Infectious bacteria are much harder to control than their predecessors were ten or twenty years ago.

                                                                      Doctors miss the "good old days," when the antibiotics they prescribed consistently cured their patients. However, evolutionary theory suggests some specific tactics to help slow the rate at which bacteria become resistant to our drugs.

                                                                      Applying our knowledge of evolution
                                                                      Evolutionary theory predicted that bacterial resistance would happen. Given time, heredity, and variation, any living organisms (including bacteria) will evolve when a selective pressure (like an antibiotic) is introduced. But evolutionary theory also gives doctors and patients some specific strategies for delaying even more widespread evolution of antibiotic resistance. These strategies include:

                                                                      Don't use antibiotics to treat viral infections.
                                                                      Antibiotics kill bacteria, not viruses. If you take antibiotics for a viral infection (like a cold or the flu), you will not kill the viruses, but you will introduce a selective pressure on bacteria in your body, inadvertently selecting for antibiotic-resistant bacteria. Basically, you want your bacteria to be "antibiotic virgins," so that if they someday get out of hand and cause an infection that your immune system can't handle, they can be killed by a readily available antibiotic.

                                                                      Avoid mild doses of antibiotics over long time periods.
                                                                      If an infection needs to be controlled with antibiotics, a short-term, high-dosage prescription is preferable. This is because you want to kill all of the illness-causing bacteria, leaving no bacterial survivors. Any bacteria that survive a mild dose are likely to be somewhat resistant. Basically, if you are going to introduce a selective pressure (antibiotics), make it so strong that you cause the extinction of the illness-causing bacteria in the host and not their evolution into resistant forms.

                                                                      When treating a bacterial infection with antibiotics, take all your pills.
                                                                      Just as mild doses can breed resistance, an incomplete regimen of antibiotics can let bacteria survive and adapt. If you are going to introduce a selective pressure (antibiotics), make it a really strong one and a long enough one to cause the extinction of the illness-causing bacteria and not their evolution.

                                                                      Use a combination of drugs to treat a bacterial infection.
                                                                      If one particular drug doesn't help with a bacterial infection, you may be dealing with a resistant strain. Giving a stronger dose of the same antibiotic just increases the strength of the same selective pressure — and may even cause the evolution of a "super-resistant" strain. Instead, you might want to try an entirely different antibiotic that the bacteria have never encountered before. This new and different selective pressure might do a better job of causing their extinction, not their evolution.

                                                                      Reduce or eliminate the "preventive" use of antibiotics on livestock and crops.
                                                                      Unnecessary use of antibiotics for agricultural and livestock purposes may lead to the evolution of resistant strains. Later, these strains will not be able to be controlled by antibiotics when it really is necessary. Preventive use of antibiotics on livestock and crops can also introduce antibiotics into the bodies of the humans who eat them.

                                                                      Disease and Conditions

                                                                      Importance of Trends in Human Disease and Condition

                                                                      Tracking overall rates of disease in the United States, independent of exposure, enables the evaluation of disease patterns and emerging trends. It may identify diseases, conditions, and possible risk factors that warrant further study or intervention and can help identify where policies or interventions have been successful.

                                                                      Because the United States has a diverse population, an important component of such an analysis is identifying disparities among people of differing races and ethnicities, genders, education and income levels, and geographic locations.

                                                                      Measures of Human Disease and Condition

                                                                      • Both morbidity and mortality can be measured using occurrences or rates:
                                                                        • Occurrences represent frequency counts.
                                                                        • Rates enable a comparison across populations. Rates are ratios that calculate the frequency of cases (of disease, condition, outcome) divided by the size of the defined population for a specified time period. Usually some constant (generally a multiplier of the power 10) is applied to convert the rate to a whole number.
                                                                        • Incidence refers to the number of new cases of a disease or condition in a population during a specified time period.
                                                                        • Prevalence refers to the total number of people with a given disease or condition in a population at a specified point in time.

                                                                        ROE Indicators

                                                                        The ROE presents nine indicators of health outcomes for which environmental exposures may be a risk factor and for which nationally representative data are available: Asthma, Birth Defects, Cancer, Cardiovascular Disease, Childhood Cancer, Chronic Obstructive Pulmonary Disease, Infectious Diseases, Low Birthweight, and Preterm Delivery. All indicators are based on vital statistics and surveillance data from the Centers for Disease Control and Prevention and the National Cancer Institute. The health outcomes covered by the ROE human disease and condition indicators fall into five broad categories:


                                                                        The term “cancer” refers to diseases in which abnormal cells divide without control, losing their ability to regulate their own growth, control cell division, and communicate with other cells. Cancer is the second leading cause of death in the United States (General Mortality indicator). More than one in three people will develop cancer and nearly one in four will die of it. 1

                                                                        In response, scientists continue to explore the role that the exposure to environmental contaminants may play, along with other possible risk factors, in the initiation and development of cancer. Some environmental contaminant exposures are known risk factors for certain types of cancers. Examples include radon and lung cancer and arsenic and skin cancer.

                                                                        Though many types of cancer are suspected of being related to ambient environmental exposures, associations are not always clear because the etiology of cancer is complex and influenced by a wide range of factors. Many factors can increase individual cancer risk, such as age, genetics, existence of infectious diseases, and socioeconomic factors that can affect exposure and susceptibility.

                                                                        Childhood cancers are dissimilar from cancers in adults and are therefore tracked separately. They affect different anatomic sites and may be of embryonic origin. Though overall cancer incidence rates are lower in children than in adults, childhood cancers are the leading cause of disease-related death in children age 1 to 19 years. 2,3

                                                                        Children may be particularly susceptible to exposures in utero or during early childhood because their systems are rapidly developing and affected by evolving hormonal systems. 4 As with many adult cancers, the causes of childhood cancers are unknown for the most part environmental influences may be a factor and have been the subject of extensive research. Environmental exposures are difficult to evaluate because cancer is rare in children and because of challenges in identifying past exposure levels, particularly during potentially important time periods such as in utero or maternal exposures prior to conception. 5

                                                                        Cardiovascular Disease

                                                                        More than one-third of the U.S. adult population lives with a cardiovascular disease, with more than 6 million hospitalizations each year. 6 Coronary heart disease and stroke, two of the major types of cardiovascular disease, rank as the first and fourth leading causes of death, respectively (General Mortality indicator), and are leading causes of premature and permanent disabilities.

                                                                        Known risk factors include smoking, high blood pressure, high blood cholesterol, diabetes, physical inactivity, and poor nutrition. Outdoor air pollution and environmental tobacco smoke are also known risk factors for cardiovascular disease. Particulate matter, for example, has been demonstrated to be a likely causal factor in both cardiovascular disease morbidity and mortality.

                                                                        Collective evidence from recent studies suggests excess risk associated with short-term exposures to particulate matter and hospital admissions or emergency department visits for cardiovascular effects. 7,8,9 Environmental tobacco smoke has been shown to be a risk factor for coronary heart disease morbidity and mortality and may contribute to stroke. 10,11

                                                                        Respiratory Disease

                                                                        Chronic obstructive pulmonary disease (COPD) and asthma are two prevalent chronic respiratory diseases. Chronic lower respiratory diseases represent the third leading cause of death in the United States (General Mortality indicator). Epidemiological and clinical studies have shown that ambient and indoor air pollution are risk factors in several respiratory health outcomes, including reported symptoms (nose and throat irritation), acute onset or exacerbation of existing disease (e.g., asthma), and deaths. 12,13,14

                                                                        The relationship between environmental tobacco smoke and diseases of the respiratory tract has been studied extensively in humans and in animals environmental tobacco smoke has been shown to produce a variety of upper and lower respiratory tract disorders. 15,16

                                                                        COPD is a group of diseases characterized by airflow obstruction, resulting in breathing-related symptoms it encompasses chronic obstructive bronchitis and emphysema. 17 COPD is the third leading cause of death in the United States and the leading cause of hospitalization in U.S. adults, particularly older adults. It represents a major cause of morbidity, mortality, and disability. 18 Air pollution may be an important contributor to COPD, though approximately 80 percent of COPD deaths is attributed to smoking. 19

                                                                        Asthma continues to receive attention in both children and adults. Asthma prevalence has increased over the past few decades. Asthma prevalence grew nearly 74 percent during 1980–1996, with more than 20 million people in the United States reporting asthma each year over the last decade. 20,21 Environmental exposures such as outdoor air pollution (e.g., particulate matter, ozone), environmental tobacco smoke, dust mites, pets, mold, and other allergens are considered important triggers for asthma. 22,23,24

                                                                        Infectious Disease

                                                                        Infectious diseases are acute illnesses caused by bacteria, protozoa, fungi, and viruses. Food and water contaminated with pathogenic microorganisms are the major environmental sources of gastrointestinal illness. Though well-established systems for reporting food- and waterborne cases exist, data reported through these largely voluntary programs must be interpreted with caution, because many factors can influence whether an infectious disease is recognized, investigated, and reported.

                                                                        Changes in the number of cases reported could reflect actual changes or simply changes in surveillance and reporting. In addition, many milder cases of gastrointestinal illnesses go unreported or are not diagnosed, making it difficult to estimate the number of people affected every year.

                                                                        The discovery of bacterial contamination of drinking water as the cause of many cases of gastrointestinal illness represents one of the great public health success stories of the 20th century.

                                                                        Waterborne diseases such as typhoid fever and cholera were major health threats across the United States at the beginning of the 20th century. Deaths due to diarrhea-like illnesses, including typhoid, cholera, and dysentery, represented the third largest cause of death in the nation at that time.

                                                                        These types of diarrheal deaths dropped dramatically once scientists identified the bacteria responsible, elucidated how these bacteria were transmitted to and among humans in contaminated water supplies, and developed effective water treatment methods to remove pathogens from water supplies.

                                                                        In addition to being of food- or waterborne origin, infectious disease can be airborne, arthropod-borne (spread by mosquitoes, ticks, fleas, etc.), or zoonotic (spread by rodents, dogs, cats, and other animals). Legionellosis can be contracted from naturally occurring bacteria found in water and spread through poorly maintained artificial water systems (e.g., air conditioning, ventilation systems). Arthropod-borne diseases, including Lyme disease, Rocky Mountain spotted fever, and West Nile virus, can be contracted from certain ticks and mosquitoes that acquire bacteria or viruses by biting infected mammals or birds.

                                                                        Birth Outcome

                                                                        Birth defects are structural or functional anomalies that present at birth or in early childhood. Birth defects cause physical or mental disability and can be fatal. They affect approximately one out of 33 babies born each year in the United States and remain the leading cause of infant mortality (Infant Mortality indicator). People with birth defects may experience serious, adverse effects on health, development, and functional ability. 25

                                                                        Birth defects have been linked with a variety of possible risk factors that can affect normal growth and development—genetic or chromosomal aberrations, as well as environmental factors such as exposure to chemicals exposure to viruses and bacteria and use of cigarettes, drugs, or alcohol by the mother.

                                                                        The causes of most birth defects are unknown, but research continues to show the possible influence of environmental exposures (e.g., prenatal exposure to high levels of contaminants such as mercury or PCBs). The relationship between exposure to lower concentrations of environmental contaminants and birth defects, however, is less clear.

                                                                        Low birthweight and preterm delivery are considered important risk factors for infant mortality and birth defects. Low birthweight and preterm infants have a significantly increased risk of infant death, and those who survive are more likely to experience long-term developmental disabilities. 26,27 Multiple birth babies have a low birthweight rate of more than 50 percent, compared to approximately 6 percent among singletons. 28 To eliminate the effect that multiple births may have on birth outcomes, this report presents data for singleton births only.

                                                                        Environmental exposures are being investigated for possible associations with birth outcomes such as low birthweight, preterm delivery, and infant mortality. Some of the risk factors for low birthweight infants born at term include maternal smoking, weight at conception, and nutrition and weight gain during pregnancy. 29

                                                                        Specific examples of known or suspected environmental contaminant influences on birth outcomes include environmental tobacco smoke, lead, and air pollution. Environmental tobacco smoke is associated with increased risk of low birthweight, preterm delivery, and sudden infant death syndrome. 30 Several studies have identified lead exposure as a risk factor for preterm delivery. 31 Growing evidence shows exposure-response relationships between maternal exposures to air pollutants (e.g., sulfur dioxide and particulates) and low birthweight and preterm delivery. 32,33,34

                                                                        Research continues, however, in establishing causal relationships between air pollution and low birthweight and preterm birth. Researchers also continue to examine possible associations between other contaminants as birth outcome risk factors, such as pesticides, polycyclic aromatic hydrocarbons, and others.

                                                                        EPA selected indicators for human diseases and conditions with well-established associations of exposures to environmental contaminants, recognizing that, in most cases, risk factors are multi-factorial and that the development of a particular disease or condition depends on the magnitude, duration, and timing of the exposure. The diseases and conditions addressed in this ROE question may be associated with, but cannot be tied directly to the contaminant levels or other environmental conditions reported by national-level ROE indicators in Air, Water, and Land.

                                                                        There are other diseases or conditions of potential interest for which no national-scale data are currently available, or for which the strength of associations with environmental contaminants is still being evaluated. Additional data are needed to enable EPA to track other diseases and conditions with potential environmental risk factors (direct or indirect), particularly those for which unexplained increases are being noted. Examples of diseases or conditions with suggestive or growing evidence that environmental contaminants may be a risk factor include behavioral and neurodevelopmental disorders in children, neurodegenerative disorders, diabetes, reproductive disorders, and renal disease.


                                                                        [2] National Center for Health Statistics. 2013. Deaths: Leading causes for 2010. National Vital Statistics Reports 62(6) (PDF) . (97 pp, 5.1MB).

                                                                        [4] Anderson, L.M., B.A. Diwan, N.T. Fear, and E. Roman. 2000. Critical windows of exposure for children's health: Cancer in human epidemiological studies and neoplasms in experimental animal models. Environ. Health. Perspect. 108(Suppl 3):573-594.

                                                                        [7] Brook, R.D., S. Rajagopalan, C.A. Pope, III, J.R. Brook, A. Bhatnagar, A.V. Diez-Roux, F. Holguin, Y. Hong, R.V. Luepker, M.A. Mittleman, A. Peters, D. Siscovick, S.C. Smith, Jr., L. Whitsel, and J.D. Kaufman, 2010. Particulate matter air pollution and cardiovascular disease: An update to the scientific statement from the American Heart Association. Circulation 121(21):2331-78.

                                                                        [8] U.S. Environmental Protection Agency. 2009. Integrated science assessment for particulate matter (final report). EPA/600/R-08/139F. Washington, DC.

                                                                        [9] U.S. Environmental Protection Agency. 2012. Provisional assessment of recent studies on health effects of particulate matter exposure. EPA/600/R-12/056F. Washington, DC.

                                                                        [10] U.S. Department of Health and Human Services. 2006. The health consequences of involuntary exposure to tobacco smoke: A report of the surgeon general (PDF) (727 pp, 19.8MB) . Atlanta, GA: Centers for Disease Control and Prevention, Coordinating Center for Health Promotion, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health.

                                                                        [11] U.S. Department of Health and Human Services. 2014. The health consequences of smoking — 50 years of progress: A report of the Surgeon General. Atlanta, GA: Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health.

                                                                        [12] U.S. Environmental Protection Agency. 2009. Integrated science assessment for particulate matter (final report). EPA/600/R-08/139F. Washington, DC.

                                                                        [13] U.S. Environmental Protection Agency. 2013. Integrated science assessment for ozone and related photochemical oxidants. EPA 600/R-10/076F. Washington, DC.

                                                                        [14] U.S. Institute of Medicine. 2000. Clearing the air. Asthma and indoor air exposures. Washington, DC: National Academies Press.

                                                                        [15] U.S. Department of Health and Human Services (HHS). 2006. The health consequences of involuntary exposure to tobacco smoke: A report of the surgeon general (PDF) (727 pp, 19.8MB) . Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, Coordinating Center for Health Promotion, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health. Accessed March 17, 2020.

                                                                        [16] U.S. Department of Health and Human Services. 2014. The health consequences of smoking — 50 years of progress: A report of the Surgeon General. Atlanta, GA: Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health.

                                                                        [17] Diaz-Guzman, E., and D.M. Mannino. 2014. Epidemiology and prevalence of chronic obstructive pulmonary disease. Clin. Chest Med. 35(1):7-16.

                                                                        [18] Akinbami, L.J., and X. Liu. 2011. Chronic obstructive pulmonary disease among adults aged 18 and over in the United States, 1998-2009 (PDF) (8 pp, 584K) . NCHS data brief, no. 63. Hyattsville, MD: National Center for Health Statistics.

                                                                        [20] Mannino, D.M., D.M. Homa, L.J. Akinbami, J.E. Moorman, C. Gwynn, and S.C. Redd. 2002. Surveillance for asthma—United States, 1980-1999. In: Surveillance Summaries. MMWR 51(SS-1):1-13.

                                                                        [21] Moorman J.E., L.J. Akinbami, C.M. Bailey, H.S. Zahran, M.E. King, C.A. Johnson, and X. Liu. 2012. National surveillance of asthma: United States, 2001-2010 (PDF) (67 pp, 910K) . Vital Health Stat 3(35). Hyattsville, MD: National Center for Health Statistics.

                                                                        [22] Vernon M.K., I. Wiklund, J.A. Bell, P. Dale, and K.R. Chapman. 2012. What do we know about asthma triggers? A review of the literature. J. Asthma 49(10):991-8.

                                                                        [23] U.S. Environmental Protection Agency. 2009. Integrated science assessment for particulate matter (final report). EPA/600/R-08/139F. Washington, DC.

                                                                        [24] U.S. Department of Health and Human Services. 2006. The health consequences of involuntary exposure to tobacco smoke: A report of the Surgeon General (PDF) (727 pp, 19.8MB) . Atlanta, GA: Centers for Disease Control and Prevention, Coordinating Center for Health Promotion, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health.

                                                                        [25] Centers for Disease Control and Prevention. 2006. Improved national prevalence estimates for 18 selected major birth defects—United States, 1999-2001. MMWR 54(51&52):1301-1305.

                                                                        [26] Mathews, T.J. and M.F. MacDorman. 2013. Infant mortality statistics from the 2009 period linked birth/infant death data set (PDF) (28 pp, 527K) . National Vital Statistics Reports 61(8). Hyattsville, MD: National Center for Health Statistics.

                                                                        [27] Behrman, R.E., and A. Stith Butler, eds. 2007. Preterm birth: Causes, consequences, and prevention. Committee on Understanding Premature Birth and Assuring Healthy Outcomes. Institute of Medicine of the National Academies. Washington, DC: National Academies Press.

                                                                        [28] National Center for Health Statistics. 2001. Healthy people 2000 final review (PDF) (382 pp, 7.2MB) . Hyattsville, MD: Public Health Service.

                                                                        [29] U.S. Department of Health and Human Services. Physical Activities Guidelines for Americans. 2nd edition. Washington, DC: U.S. Government Printing Office.

                                                                        [30] U.S. Department of Health and Human Services. 2006. The health consequences of involuntary exposure to tobacco smoke: A report of the Surgeon General (PDF) (727 pp, 19.8MB) . Atlanta, GA: Centers for Disease Control and Prevention, Coordinating Center for Health Promotion, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health.

                                                                        [31] Agency for Toxic Substances and Disease Registry. 2005. Toxicological profile for lead (update). Draft for public comment. Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service.

                                                                        [32] U.S. Environmental Protection Agency. 2009. Integrated science assessment for particulate matter (final report). EPA/600/R-08/139F. Washington, DC.

                                                                        [33] Sram, R.J., B. Binkova, J. Dejmek, and M. Bobak. 2005. Ambient air pollution and pregnancy outcomes: A review of the literature. Environ. Health Perspect. 113(4):375-382.

                                                                        [34] Proietti, E., M. Roosli, U. Frey, and P. Latzin. 2013. Air pollution during pregnancy and neonatal outcome: A review. J. Aerosol Med. Pulm. Drug Deliv. 26(1):9-23.

                                                                        Viruses hijack living host cells, and then replicate themselves

                                                                        You must all be tired of hearing about coronavirus disease Covid-19 (acronym for Co – corona, vi – virus, d – disease, 19 – 2019, the year the disease was first detected). Nevertheless, I thought readers would be interested in knowing more about viruses.

                                                                        Life is divided into six kingdoms – animals, plants, bacteria, archaea (bacteria-like organisms living in extreme conditions), protists (eg amoebae) and fungi. The fundamental unit of each lifeform is the cell. Every cell is surrounded by a fatty membrane, and can grow and divide into two daughter cells.

                                                                        Viruses are not included in the six kingdoms of life because they are not cells. In a strict sense they are not alive, dependent on hijacking living host cells within which they replicate themselves.

                                                                        Viruses are unique. They are both the smallest and the most abundant biological organisms, outnumbering all other biological entities put together. They are found in almost every ecosystem on Earth. A typical virus is about one hundredth the size of a bacterium, which in turn is about one twentieth the size of an animal cell.

                                                                        Viruses have a simple structure composed of protein and genetic material (RNA or DNA). The genetic material carries coded information that allows the virus to replicate itself, and sits inside a protective coat of protein molecules called the nucleocapsid.

                                                                        Viruses fall into three structural categories – spherical, rod-shaped and complex (generally combining spherical and rod). Animal viruses are also enclosed in a membrane “envelope” derived from the host cell. .

                                                                        Viruses infect organisms in each of the six kingdoms of life, inserting their own genetic material into host cells’ genetic material and directing the cells to use this information to make many copies of the virus. These virus copies then escape from the host cell, often killing the cell in the process. Virus infections sicken us by killing cells or disrupting cell function.


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                                                                        Surface projections

                                                                        Coronaviruses are spherical enveloped viruses with surface projections giving each virus the appearance of a crown (“corona”). Four coronaviruses circulate in humans every year, mainly causing colds.

                                                                        The virus that causes Covid-19 is a new member of the coronavirus family called severe acute respiratory syndrome corona virus 2 (SARS-COV-2). Specific proteins on the virus envelope recognise and dock with receptors on the outside of the host cell. The virus then enters the host cell.

                                                                        Viruses cause many diseases in humans, including common colds, influenza and chickenpox, and more serious diseases like rabies, Ebola and Aids.

                                                                        Some viruses have a narrow host range, others a wider range –the smallpox virus only infects humans but the rabies virus can infect several species of mammals.

                                                                        Coronaviruses are zoonotic, ie can transfer to people from animals. It is thought SARS-COV-2 that causes Covid-19 originated in bats.

                                                                        We are advised to wash our hands in warm soapy water or alcohol-based sanitisers to protect ourselves from Covid-19. The basis for this protection is that soap and alcohol disrupt the fatty envelope around the virus, preventing it from docking with host cells.

                                                                        We are also told to protect ourselves by maintaining a distance of two metres between ourselves and the nearest person. Coronaviruses spread from person to person when someone with the virus coughs or sneezes. Respiratory droplets can land in your mouth or eye or nose. Studies show that influenza can spread up to 1.8 metres, and this is why we are asked to stay two metres apart.


                                                                        What about medicines to fight off viruses?

                                                                        Antibiotics don’t work because they are designed to fight bacteria. A bacterium is a cell with a complex biochemistry (metabolism). Antibiotics are designed to disrupt this metabolism, thereby inactivating the bacterium.

                                                                        A virus hijacks the metabolism of the host cell to replicate itself. It is not a cell itself, and has no target for an antibiotic to attack.

                                                                        A number of anti-viral drugs known to inhibit coronavirus replication in cells are now in trial. And, of course, we hope a vaccine will soon be available that will confer immunity against this virus.

                                                                        William Reville is an emeritus professor of biochemistry at University College Cork

                                                                        What is the rate of bacterial cell death due to viruses on land? - Biology

                                                                        Figure 1 – Geometry of bacteriophages. (A) Electron microscopy image of phi29 and T7 bacteriophages as revealed by electron microscopy. (B) Schematic of the structure of a bacteriophage. (A adapted from S. Grimes et al., Adv. Virus Res. 58:255, 2002.)

                                                                        In terms of their absolute numbers, viruses appear to be the most abundant biological entities on planet Earth. The best current estimate is that there are a whopping 10 31 virus particles in the biosphere. We can begin to come to terms with these astronomical numbers by realizing that this implies that for every human on the planet there are nearly Avogadro’s number worth of viruses. This corresponds to roughly 10 8 viruses to match every cell in our bodies. The number of viruses can also be contrasted with an estimate of 4-6 x 10 30 for the number of prokaryotes on Earth (BNID 104960). However, because of their extremely small size, the mass tied up in these viruses is only approximately 5% of the prokaryotic biomass. The assertion about the total number of viruses is supported by measurements using both electron and fluorescence microscopy. For example, if a sample is taken from the soil or the ocean, electron microscopy observations reveal an order of magnitude more viruses than bacteria (≈10/1 ratio, BNID 104962). These electron microscopy measurements are independently confirmed by light microscopy measurements. By staining viruses with fluorescent molecules, they can be counted directly under a microscope and their corresponding concentrations determined (e.g. 10 7 viruses/ml).

                                                                        Table 1: Sizes of representative key viruses. The viruses in the table are organized according to their size with the smallest viruses shown first and the largest viruses shown last. The organization by size gives a different perspective than typical biological classifications which use features such as the nature of the genome (RNA or DNA, single stranded (ss) or double stranded (ds)) and the nature of the host. Values are rounded to one or two significant digit.

                                                                        Organisms from all domains of life are subject to viral infection, whether tobacco plants, flying tropical insects or archaea in the hot springs of Yellowstone National Park. However, it appears that it is those viruses that attack bacteria (i.e. so called bacteriophages – literally, bacteria eater – see Figure 1) that are the most abundant of all with these viruses present in huge numbers (BNID 104839, 104962, 104960) in a host of different environments ranging from soils to the open ocean.

                                                                        Figure 2: Structures of viral capsids. The regularity of the structure of viruses has enabled detailed, atomic-level analysis of their construction patterns. This gallery shows a variety of the different geometries explored by the class of nearly spherical viruses. HIV and influenza figures are 3D renderings of virions from the tomogram..(Symmetric virus structures adapted from T. S. Baker et al., Microbiol. Mol. Biol. Rev. 63:862, 1999. HIV structure adapted from J. A. G. Briggs et al., Structure 14:15, 2006 and influenza virus structure adapted from A. Harris, Proceedings of the National Academy of Sciences, 103:19123, 2006.)

                                                                        As a result of their enormous presence on the biological scene, viruses play a role not only in the health of their hosts, but in global geochemical cycles affecting the availability of nutrients across the planet. For example, it has been estimated that as much as 20% of the bacterial mass in the ocean is subject to viral infection every day (BNID 106625). This can strongly decrease the flow of biomass to higher trophic levels that feed on prokaryotes (BNID 104965).

                                                                        Figure 3: The P30 protein dimer serves as a measure tape to help create the bacteriophage PRD1 capsid.

                                                                        Viruses are much smaller than the cells they infect. Indeed, it was their remarkable smallness that led to their discovery in the first place. Researchers were puzzled by remnant infectious elements that could pass through filters small enough to remove pathogenic bacterial cells. This led to the hypothesis of a new form of biological entity. These entities were subsequently identified as viruses.

                                                                        Viruses are among the most symmetric and beautiful of biological objects as shown in Figure 2. The figure shows that many viruses are characterized by an icosahedral shape with all of its characteristic symmetries (i.e. 2-fold symmetries along the edges, 3-fold symmetries on the faces and 5-fold rotational symmetries on the vertices, figure 2). The outer protein shell, known as the capsid, is often relatively simple since it consists of many repeats of the same protein unit. The genomic material is contained within the capsid. These genomes can be DNA or RNA, single stranded or double stranded (ssDNA, dsDNA, ssRNA or dsRNA) with characteristic sizes ranging from 10 3 -10 6 bases (BNID 103246, 104073. With some interesting exceptions, a useful rule of thumb is that the radii of viral capsids themselves are all within a factor of ten of each other, with the smaller viruses having a diameter of several tens of nanometers and the larger ones reaching diameters several hundreds of nanometers which is on par with the smallest bacteria (BNID 103114, 103115, 104073). Representative examples of the sizes of viruses are given in Table 1. The structures of many viruses such as HIV have an external envelope (resulting in the label “enveloped virus”) made up of a lipid bilayer. The interplay between the virus size and the genome length can be captured via the packing ratio which is the percent fraction of the capsid volume taken by viral DNA. For phage lambda it can be calculated to be about 40% whereas for HIV it is more than 10 times lower (BNID 111591).

                                                                        Some of the most interesting viruses have structures with less symmetry than those described above. Indeed, two of the biggest viral newsmakers, HIV and influenza, sometimes have irregular shapes and even the structure from one influenza or HIV virus particle to the next can be different. Examples of these structures are shown in Figure 2. Why should so many viruses have a characteristic length scale of roughly 100 nanometers? If one considers the density of genetic material inside the capsid, a useful exercise for the motivated reader, it is found that the genomic material in bacterial viruses can take up nearly as much as 50% of the volume. Further, the viral DNA often adopts a structure which is close packed and nearly crystalline to enable such high densities. Thus, in these cases if one takes as a given the length of DNA which is tied in turn to the number of genes that viruses must harbor, the viruses show strong economy of size, minimizing the required volume to carry their genetic material.

                                                                        To make a virus, the monomers making up the capsid can self assemble one mechanism is to start from some vertex and extend in a symmetric manner. But what governs the length of a facet, i.e. the distance between two adjacent vertices that dictates the overall size of a viron? In one case, a nearly linear 83 residue protein serves as a molecular tape measure helping the virus to build itself to the right size. The molecular players making this mechanism possible are shown in Figure 3. A dimer of two 15 nm long proteins defines distances in a bacteriophage which has a diameter of about 70 nm.

                                                                        The recently discovered gigantic mimivirus and pandoravirus are about an order of magnitude larger (BNID 109554, 111143). The mechanism that serves to set the size of remains an open question. These viruses are larger than some bacteria and even rival some eukaryotes. They also contain genomes larger than 2 Mbp long (BNID 109556) and challenge our understanding of both viral evolution and diversity.

                                                                        Watch the video: Ο Κ. Χατζής για τη δουλειά του Αλέξανδρου στη Γερμανία. 1010. ΕΡΤ (January 2022).