Virulence factor

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Virulence factors (preferably known as pathogenicity factors or effectors in plant science) are cellular structures, molecules and regulatory systems that enable microbial pathogens (bacteria, viruses, fungi, and protozoa) to achieve the following: [1] [2]

Contents

Specific pathogens possess a wide array of virulence factors. Some are chromosomally encoded and intrinsic to the bacteria (e.g. capsules and endotoxin), whereas others are obtained from mobile genetic elements like plasmids and bacteriophages (e.g. some exotoxins). Virulence factors encoded on mobile genetic elements spread through horizontal gene transfer, and can convert harmless bacteria into dangerous pathogens. Bacteria like Escherichia coli O157:H7 gain the majority of their virulence from mobile genetic elements. Gram-negative bacteria secrete a variety of virulence factors at host–pathogen interface, via membrane vesicle trafficking as bacterial outer membrane vesicles for invasion, nutrition and other cell-cell communications. It has been found that many pathogens have converged on similar virulence factors to battle against eukaryotic host defenses. These obtained bacterial virulence factors have two different routes used to help them survive and grow:

Attachment, immunoevasion, and immunosuppression

Bacteria produce various adhesins including lipoteichoic acid, trimeric autotransporter adhesins and a wide variety of other surface proteins to attach to host tissue.

Capsules, made of carbohydrate, form part of the outer structure of many bacterial cells including Neisseria meningitidis . Capsules play important roles in immune evasion, as they inhibit phagocytosis, as well as protecting the bacteria while outside the host.

Another group of virulence factors possessed by bacteria are immunoglobulin (Ig) proteases. Immunoglobulins are antibodies expressed and secreted by hosts in response to an infection. These immunoglobulins play a major role in destruction of the pathogen through mechanisms such as opsonization. Some bacteria, such as Streptococcus pyogenes , are able to break down the host's immunoglobulins using proteases.

Viruses also have notable virulence factors. Experimental research, for example, often focuses on creating environments that isolate and identify the role of "niche-specific virulence genes". These are genes that perform specific tasks within specific tissues/places at specific times; the sum total of niche-specific genes is the virus' virulence. Genes characteristic of this concept are those that control latency in some viruses like herpes. Murine gamma herpesvirus 68 (γHV68) and human herpesviruses depend on a subset of genes that allow them to maintain a chronic infection by reactivating when specific environmental conditions are met. Even though they are not essential for lytic phases of the virus, these latency genes are important for promoting chronic infection and continued replication within infected individuals. [6]

Destructive enzymes

Some bacteria, such as Streptococcus pyogenes , Staphylococcus aureus and Pseudomonas aeruginosa , produce a variety of enzymes which cause damage to host tissues. Enzymes include hyaluronidase, which breaks down the connective tissue component hyaluronic acid; a range of proteases and lipases; DNases, which break down DNA, and hemolysins which break down a variety of host cells, including red blood cells.

GTPases

A major group of virulence factors are proteins that can control the activation levels of GTPases. There are two ways in which they act. One is by acting as a GEF or GAP, and proceeding to look like a normally eukaryotic cellular protein. The other is covalently modifying the GTPase itself. The first way is reversible; many bacteria like Salmonella have two proteins to turn the GTPases on and off. The other process is irreversible, using toxins to completely change the target GTPase and shut down or override gene expression.

One example of a bacterial virulence factor acting like a eukaryotic protein is Salmonella protein SopE it acts as a GEF, turning the GTPase on to create more GTP. It does not modify anything, but overdrives normal cellular internalization process, making it easier for the Bacteria to be colonized within a host cell.

YopT (Yersinia outer protein T) from Yersinia is an example of modification of the host. It modifies the proteolytic cleavage of carboxyl terminus of RhoA, releasing RhoA from the membrane. The mislocalization of RhoA causes downstream effectors to not work.

Toxins

A major category of virulence factors are bacterial toxins. These are divided into two groups: endotoxins and exotoxins. [4]

Endotoxins

Endotoxin is a component (lipopolysaccharide (LPS)) of the cell wall of gram-negative bacteria. It is the lipid A part of this LPS which is toxic. [4] Lipid A is an endotoxin. Endotoxins trigger intense inflammation. They bind to receptors on monocytes causing the release of inflammatory mediators which induce degranulation. As part of this immune response cytokines are released; these can cause the fever and other symptoms seen during disease. If a high amount of LPS is present then septic shock (or endotoxic shock) may result which, in severe cases, can lead to death. As glycolipids (as opposed to peptides), endotoxins are not bound by B or T-cell receptors and do not elicit an adaptive immune response.

Exotoxins

Exotoxins are actively secreted by some bacteria and have a wide range of effects including inhibition of certain biochemical pathways in the host. The two most potent known exotoxins [4] are the tetanus toxin (tetanospasmin) secreted by Clostridium tetani and the botulinum toxin secreted by Clostridium botulinum . Exotoxins are also produced by a range of other bacteria including Escherichia coli ; Vibrio cholerae (causative agent of cholera); Clostridium perfringens (common causative agent of food poisoning as well as gas gangrene) and Clostridium difficile (causative agent of pseudomembranous colitis). A potent three-protein virulence factor produced by Bacillus anthracis , called anthrax toxin, plays a key role in anthrax pathogenesis. Exotoxins are extremely immunogenic meaning that they trigger the humoral response (antibodies target the toxin).

Exotoxins are also produced by some fungi as a competitive resource. The toxins, named mycotoxins, deter other organisms from consuming the food colonised by the fungi. As with bacterial toxins, there is a wide array of fungal toxins. Arguably one of the more dangerous mycotoxins is aflatoxin produced by certain species of the genus Aspergillus (notably A. flavus ). If ingested repeatedly, this toxin can cause serious liver damage.

Examples

Examples of virulence factors for Staphylococcus aureus are hyaluronidase, protease, coagulase, lipases, deoxyribonucleases and enterotoxins. Examples for Streptococcus pyogenes are M protein, lipoteichoic acid, hyaluronic acid capsule, destructive enzymes (including streptokinase, streptodornase, and hyaluronidase), and exotoxins (including streptolysin). Examples for Listeria monocytogenes include internalin A, internalin B, listeriolysin O, and actA, all of which are used to help colonize the host. Examples for Yersinia pestis are an altered form of lipopolysaccharide, type three secretion system, and YopE and YopJ pathogenicity. The cytolytic peptide Candidalysin is produced during hyphal formation by Candida albicans ; it is an example of a virulence factor from a fungus. Other virulence factors include factors required for biofilm formation (e.g. sortases) and integrins (e.g. beta-1 and 3). [7]

Inhibition and control

Strategies to target virulence factors and the genes encoding them have been proposed. [8] Small molecules being investigated for their ability to inhibit virulence factors and virulence factor expression include alkaloids, [9] flavonoids, [10] and peptides. [11] Experimental studies are done to characterize specific bacterial pathogens and to identify their specific virulence factors. Scientists are trying to better understand these virulence factors through identification and analysis to better understand the infectious process in hopes that new diagnostic techniques, specific antimicrobial compounds, and effective vaccines or toxoids may be eventually produced to treat and prevent infection. There are three general experimental ways for the virulence factors to be identified: biochemically, immunologically, and genetically. For the most part, the genetic approach is the most extensive way in identifying the bacterial virulence factors. Bacterial DNA can be altered from pathogenic to non-pathogenic, random mutations may be introduced to their genome, specific genes encoding for membrane or secretory products may be identified and mutated, and genes that regulate virulence genes maybe identified.

Experiments involving Yersinia pseudotuberculosis have been used to change the virulence phenotype of non-pathogenic bacteria to pathogenic. Because of horizontal gene transfer, it is possible to transfer the a clone of the DNA from Yersinia to a non-pathogenic E. coli and have them express the pathogenic virulence factor. Transposon, a DNA element inserted at random, mutagenesis of bacteria DNA is also a highly used experimental technique done by scientists. These transposons carry a marker that can be identified within the DNA. When placed at random, the transposon may be placed next to a virulence factor or placed in the middle of a virulence factor gene, which stops the expression of the virulence factor. By doing so, scientists can make a library of the genes using these markers and easily find the genes that cause the virulence factor.

See also

Related Research Articles

Virulence is a pathogen's or microorganism's ability to cause damage to a host.

<span class="mw-page-title-main">Lipopolysaccharide</span> Class of molecules found in the outer membrane of Gram-negative bacteria

Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by covalent bonds, and are found in the bacterial capsule, the outermost membrane of cell envelope of Gram-negative bacteria, such as E. coli and Salmonella. Today, the term endotoxin is often used synonymously with LPS, although there are a few endotoxins that are not related to LPS, such as the so-called delta endotoxin proteins produced by Bacillus thuringiensis.

<span class="mw-page-title-main">Exotoxin</span> Toxin from bacteria that destroys or disrupts cells

An exotoxin is a toxin secreted by bacteria. An exotoxin can cause damage to the host by destroying cells or disrupting normal cellular metabolism. They are highly potent and can cause major damage to the host. Exotoxins may be secreted, or, similar to endotoxins, may be released during lysis of the cell. Gram negative pathogens may secrete outer membrane vesicles containing lipopolysaccharide endotoxin and some virulence proteins in the bounding membrane along with some other toxins as intra-vesicular contents, thus adding a previously unforeseen dimension to the well-known eukaryote process of membrane vesicle trafficking, which is quite active at the host–pathogen interface.

<span class="mw-page-title-main">Secretion</span> Controlled release of substances by cells or tissues

Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classical mechanism of cell secretion is via secretory portals at the plasma membrane called porosomes. Porosomes are permanent cup-shaped lipoprotein structures embedded in the cell membrane, where secretory vesicles transiently dock and fuse to release intra-vesicular contents from the cell.

Pathogenicity islands (PAIs), as termed in 1990, are a distinct class of genomic islands acquired by microorganisms through horizontal gene transfer. Pathogenicity islands are found in both animal and plant pathogens. Additionally, PAIs are found in both gram-positive and gram-negative bacteria. They are transferred through horizontal gene transfer events such as transfer by a plasmid, phage, or conjugative transposon. Therefore, PAIs contribute to microorganisms' ability to evolve.

<span class="mw-page-title-main">Enterotoxin</span> Toxin from a microorganism affecting the intestines

An enterotoxin is a protein exotoxin released by a microorganism that targets the intestines. They can be chromosomally or plasmid encoded. They are heat labile (>60⁰), of low molecular weight and water-soluble. Enterotoxins are frequently cytotoxic and kill cells by altering the apical membrane permeability of the mucosal (epithelial) cells of the intestinal wall. They are mostly pore-forming toxins, secreted by bacteria, that assemble to form pores in cell membranes. This causes the cells to die.

Adhesins are cell-surface components or appendages of bacteria that facilitate adhesion or adherence to other cells or to surfaces, usually in the host they are infecting or living in. Adhesins are a type of virulence factor.

<span class="mw-page-title-main">Lysogenic cycle</span> Process of virus reproduction

Lysogeny, or the lysogenic cycle, is one of two cycles of viral reproduction. Lysogeny is characterized by integration of the bacteriophage nucleic acid into the host bacterium's genome or formation of a circular replicon in the bacterial cytoplasm. In this condition the bacterium continues to live and reproduce normally, while the bacteriophage lies in a dormant state in the host cell. The genetic material of the bacteriophage, called a prophage, can be transmitted to daughter cells at each subsequent cell division, and later events can release it, causing proliferation of new phages via the lytic cycle.

<i>Yersinia pseudotuberculosis</i> Species of bacterium

Yersinia pseudotuberculosis is a Gram-negative bacterium that causes Far East scarlet-like fever in humans, who occasionally get infected zoonotically, most often through the food-borne route. Animals are also infected by Y. pseudotuberculosis. The bacterium is urease positive.

Host tropism is the infection specificity of certain pathogens to particular hosts and host tissues. This explains why most pathogens are only capable of infecting a limited range of host organisms.

<i>Xanthomonas campestris</i> Species of bacterium

Xanthomonas campestris is a gram-negative, obligate aerobic bacterium that is a member of the Xanthomonas genus, which is a group of bacteria that are commonly known for their association with plant disease. This species includes Xanthomonas campestris pv. campestris the cause of black rot of brassicas, one of the most important diseases of brasicas worldwide.

<span class="mw-page-title-main">Intimin</span>

Intimin is a virulence factor (adhesin) of EPEC and EHEC E. coli strains. It is an attaching and effacing (A/E) protein, which with other virulence factors is necessary and responsible for enteropathogenic and enterohaemorrhagic diarrhoea.

Listeriolysin O (LLO) is a hemolysin produced by the bacterium Listeria monocytogenes, the pathogen responsible for causing listeriosis. The toxin may be considered a virulence factor, since it is crucial for the virulence of L. monocytogenes.

<span class="mw-page-title-main">Clostridium difficile toxin A</span>

Clostridium difficile toxin A (TcdA) is a toxin generated by Clostridioides difficile, formerly known as Clostridium difficile. It is similar to Clostridium difficile Toxin B. The toxins are the main virulence factors produced by the gram positive, anaerobic, Clostridioides difficile bacteria. The toxins function by damaging the intestinal mucosa and cause the symptoms of C. difficile infection, including pseudomembranous colitis.

<span class="mw-page-title-main">AB toxin</span>

The AB toxins are two-component protein complexes secreted by a number of pathogenic bacteria, though there is a pore-forming AB toxin found in the eggs of a snail. They can be classified as Type III toxins because they interfere with internal cell function. They are named AB toxins due to their components: the "A" component is usually the "active" portion, and the "B" component is usually the "binding" portion. The "A" subunit possesses enzyme activity, and is transferred to the host cell following a conformational change in the membrane-bound transport "B" subunit. These proteins consist of two independent polypeptides, which correspond to the A/B subunit moieties. The enzyme component (A) enters the cell through endosomes produced by the oligomeric binding/translocation protein (B), and prevents actin polymerisation through ADP-ribosylation of monomeric G-actin.

Microbial toxins are toxins produced by micro-organisms, including bacteria, fungi, protozoa, dinoflagellates, and viruses. Many microbial toxins promote infection and disease by directly damaging host tissues and by disabling the immune system. Endotoxins most commonly refer to the lipopolysaccharide (LPS) or lipooligosaccharide (LOS) that are in the outer plasma membrane of Gram-negative bacteria. The botulinum toxin, which is primarily produced by Clostridium botulinum and less frequently by other Clostridium species, is the most toxic substance known in the world. However, microbial toxins also have important uses in medical science and research. Currently, new methods of detecting bacterial toxins are being developed to better isolate and understand these toxins. Potential applications of toxin research include combating microbial virulence, the development of novel anticancer drugs and other medicines, and the use of toxins as tools in neurobiology and cellular biology.

Pathogenomics is a field which uses high-throughput screening technology and bioinformatics to study encoded microbe resistance, as well as virulence factors (VFs), which enable a microorganism to infect a host and possibly cause disease. This includes studying genomes of pathogens which cannot be cultured outside of a host. In the past, researchers and medical professionals found it difficult to study and understand pathogenic traits of infectious organisms. With newer technology, pathogen genomes can be identified and sequenced in a much shorter time and at a lower cost, thus improving the ability to diagnose, treat, and even predict and prevent pathogenic infections and disease. It has also allowed researchers to better understand genome evolution events - gene loss, gain, duplication, rearrangement - and how those events impact pathogen resistance and ability to cause disease. This influx of information has created a need for bioinformatics tools and databases to analyze and make the vast amounts of data accessible to researchers, and it has raised ethical questions about the wisdom of reconstructing previously extinct and deadly pathogens in order to better understand virulence.

<span class="mw-page-title-main">Streptococcal pyrogenic exotoxin</span>

Streptococcal pyrogenic exotoxins also known as erythrogenic toxins, are exotoxins secreted by strains of the bacterial species Streptococcus pyogenes. SpeA and speC are superantigens, which induce inflammation by nonspecifically activating T cells and stimulating the production of inflammatory cytokines. SpeB, the most abundant streptococcal extracellular protein, is a cysteine protease. Pyrogenic exotoxins are implicated as the causative agent of scarlet fever and streptococcal toxic shock syndrome. There is no consensus on the exact number of pyrogenic exotoxins. Serotypes A-C are the most extensively studied and recognized by all sources, but others note up to thirteen distinct types, categorizing speF through speM as additional superantigens. Erythrogenic toxins are known to damage the plasma membranes of blood capillaries under the skin and produce a red skin rash. Past studies have shown that multiple variants of erythrogenic toxins may be produced, depending on the strain of S. pyogenes in question. Some strains may not produce a detectable toxin at all. Bacteriophage T12 infection of S. pyogenes enables the production of speA, and increases virulence.

Omptins are a family of bacterial proteases. They are aspartate proteases, which cleave peptides with the use of a water molecule. Found in the outer membrane of gram-negative enterobacteria such as Shigella flexneri, Yersinia pestis, Escherichia coli, and Salmonella enterica. Omptins consist of a widely conserved beta barrel spanning the membrane with 5 extracellular loops. These loops are responsible for the various substrate specificities. These proteases rely upon binding of lipopolysaccharide for activity.

Antivirulence is the concept of blocking virulence factors. In regards to bacteria, the idea is to design agents that block virulence rather than kill bacteria en masse, as the current regime results in much more selective pressure.

References

  1. 1 2 3 4 5 Casadevall A, Pirofski LA (2009). "Virulence factors and their mechanisms of action: the view from a damage –response framework". Journal of Water and Health. 7 (Supplement 1): S2–S18. doi:10.2166/wh.2009.036. PMID   19717929.
  2. 1 2 3 Ryding S (2021). "What are Virulence Factors?". News-Medical.Net. Retrieved 3 June 2021.
  3. Cross, Alan S (2008). "What is a virulence factor?". Critical Care. 12 (6): 197. doi: 10.1186/cc7127 . PMC   2646308 . PMID   19090973.
  4. 1 2 3 4 Levinson, W. (2010). Review of Medical Microbiology and Immunology (11th ed.). McGraw-Hill.
  5. Duan, Q; Zhou, M; Zhu, L; Zhu, G (January 2013). "Flagella and bacterial pathogenicity". Journal of basic microbiology. 53 (1): 1–8. doi:10.1002/jobm.201100335. PMID   22359233.
  6. Knipe, Howley, David, Peter (2013). Fields Virology, 6th Edition. Philadelphia, PA, USA: LIPPINCOTT WILLIAMS & WILKINS. p. 254. ISBN   978-1-4511-0563-6.{{cite book}}: CS1 maint: multiple names: authors list (link)
  7. Bien, Justyna; Sokolova, Olga; Bozko, Przemyslaw (21 May 2018). "Characterization of Virulence Factors of Staphylococcus aureus: Novel Function of Known Virulence Factors That Are Implicated in Activation of Airway Epithelial Proinflammatory Response". Journal of Pathogens. 2011: 601905. doi: 10.4061/2011/601905 . PMC   3335658 . PMID   22567334.
  8. Keen, E. C. (December 2012). "Paradigms of pathogenesis: Targeting the mobile genetic elements of disease". Frontiers in Cellular and Infection Microbiology. 2: 161. doi: 10.3389/fcimb.2012.00161 . PMC   3522046 . PMID   23248780.
  9. Deborah T. Hung; Elizabeth A. Shakhnovich; Emily Pierson; John J. Mekalanos (2005). "Small-molecule inhibitor of Vibrio cholerae virulence and intestinal colonization". Science. 310 (5748): 670–674. Bibcode:2005Sci...310..670H. doi: 10.1126/science.1116739 . PMID   16223984. S2CID   30557147.
  10. T.P. Tim Cushnie; Andrew J. Lamb (2011). "Recent advances in understanding the antibacterial properties of flavonoids". International Journal of Antimicrobial Agents. 38 (2): 99–107. doi:10.1016/j.ijantimicag.2011.02.014. PMID   21514796.
  11. Oscar Cirioni; Roberto Ghiselli; Daniele Minardi; Fiorenza Orlando; Federico Mocchegiani; Carmela Silvestri; Giovanni Muzzonigro; Vittorio Saba; Giorgio Scalise; Naomi Balaban & Andrea Giacometti (2007). "RNAIII-inhibiting peptide affects biofilm formation in a rat model of staphylococcal ureteral stent infection". Antimicrobial Agents and Chemotherapy. 51 (12): 4518–4520. doi:10.1128/AAC.00808-07. PMC   2167994 . PMID   17875996.