Bacterial virulence factors help bacteria replicate and spread within a host, partly by subverting or evading host defenses. Bacteria use several different types of virulence factors. The sections below summarize the major categories.
Adherence factors help bacteria attach to host tissues. In most infections and colonization, attachment is the first step in pathogenesis. Common adherence factors include:
Pili: In E. coli and Neisseria gonorrhoeae, pili mediate adherence to urinary tract epithelium.
Glycocalyx: In S. epidermidis and S. viridans, it helps bacteria attach to heart valves.
Curli: Amyloid protein, fiber-like extensions projecting from the cell wall of some bacteria. In E. coli and Salmonella, curli mediate binding to endothelium and extracellular proteins such as fibronectin. Curli also bind Factor XII, facilitating thrombus formation in DIC associated with sepsis.
These bacterial enzymes help break down tissue barriers and host defenses, allowing the infection to spread. Important examples include:
Collagenase and Hyaluronidase: Important in the pathogenesis of cellulitis in Streptococcus pyogenes and in necrotizing fasciitis, giving them the nickname “flesh eating bacteria”.
Coagulase: Walls off the infected area with fibrin, protecting bacteria from phagocytes. Seen commonly in Staphylococcus aureus.
IgA Protease: Breaks down mucosal immunoglobulin IgA, allowing bacteria to adhere to mucosa. Seen in Neisseria gonorrhoeae, Haemophilus influenzae, and Streptococcus pneumoniae.
Leukocidins: Enzymes that destroy neutrophils and macrophages.
The capsule prevents phagocytes from adhering to bacteria and protects bacteria from phagocytosis and opsonization. Examples include Streptococcus pneumoniae and Neisseria meningitidis.
A biofilm is an assemblage of microbial cells that is irreversibly associated (not removed by gentle rinsing) with a surface and enclosed in a matrix of primarily polysaccharide material. Biofilms protect bacteria from antibiotics and host defenses such as neutrophils and antibodies.
They are often seen in device-associated infections, including indwelling urinary catheters, central lines, and intraperitoneal catheters; native and prosthetic valve infections; and dental plaques. Pseudomonas aeruginosa biofilms are seen in patients with Cystic Fibrosis.
M protein of group A Streptococcus is antiphagocytic, and protein A of Staphylococcus aureus binds IgG and prevents activation of complement.
Some bacteria evade the immune system by hiding and surviving within host cells (e.g., Mycobacteria, Listeria, Brucella, and Legionella).
Mycobacteria and Legionella inhibit fusion of the phagosome with the lysosome, escaping degradation. They also inhibit acidification of the phagosome, which is essential for digestion of internalized bacteria.
Listeria escapes from the phagosome into the cytoplasm, avoiding degradation by lysosomal enzymes.
Endotoxins are produced by Gram negative bacteria. They are lipopolysaccharides (LPS) normally present in the cell wall of Gram negative bacteria. The toxic portion of the molecule is called Lipid A. Endotoxin is encoded by genes on the bacterial chromosome.
Endotoxins cause fever, septic shock, and DIC, leading to SIRS (systemic inflammatory response syndrome).
| Effect | Mediator |
|---|---|
| Fever | Endotoxin indirectly stimulates macrophages to release IL 1 and TNF-α |
| Septic Shock | Nitric Oxide is released causing vasodilation; TNF increases vascular permeability and Bradykinins do both |
| DIC | Activation of the coagulation system by tissue factors |
Endotoxin binds to LPS-binding protein in the serum, which then binds to CD 14 on the surface of the macrophage. CD 14 interacts with Toll Like Receptor or TLR (a transmembrane protein), which stimulates an intracellular signaling cascade. This leads to activation of genes coding for various cytokines such as Interleukins and TNF.
Exotoxins are polypeptides secreted by both gram positive and gram negative bacteria. The genes coding for exotoxins are located on plasmids or lysogenic bacteriophages.
When treated with formaldehyde, acid, or heat, exotoxins are converted to toxoids. This property is used in the development of toxoid vaccines.
Exotoxins are secreted by bacteria through specialized secretion systems. The Type III secretion system is most important and is called an injectosome. It is important for the virulence of Pseudomonas aeruginosa, Shigella spp., E. coli, Salmonella spp., and Yersinis pestis.
| Exotoxin | Important Features |
|---|---|
| Diphtheria Toxin, Pseudomonas exotoxin A | ADP ribosylate Elongation Factor 2 (EF 2) and inactivate it hence inhibiting protein synthesis |
| Cholera Toxin, Enterotoxin of Bacillus cereus and E.coli heat labile enterotoxin | ADP ribosylation and activation of Gs, thus activate adenylate cyclase, increase in cAMP. Presents as diarrhea. |
| Pertussis Toxin | ADP ribosylation and inactivation of Gi , thus activating adenylate cyclase causing an increase in cAMP. Also inhibits signal transduction pathway used by chemokine receptors blocking lymphocytes from transmigrating into tissues causing lymphocytosis. |
| Edema Factor of Bacillus anthracis | The toxin itself has adenylate cyclase activity and increases cAMP. |
| Exotoxins with protease activity | Tetanus Toxin, Botulinum Toxin, Lethal Factor of Anthrax toxin and Scalded Skin toxin/ Exfoliatin or Epidermolytic Toxin of Staphylococcus aureus. |
| Heat stable Enterotoxin of E coli | It is a polypeptide not inactivated by boiling for 30 minutes. It stimulates guanylate cyclase to increase cGMP, inhibiting the reabsorption of sodium and causing diarrhea. |
| Shiga Toxin or Verotoxin | Produced by strains of E coli O 157:H7. Causes bloody diarrhoea. It inactivates protein synthesis by removing adenine from 28 S rRNA. It binds to receptors on the kidney and endothelium of small vessels causing HUS. |
| Alpha Toxin of Clostridium perfringens | It has lecithinase activity |
| Tetanus Toxin | It is a Neurotoxin, prevents release of inhibitory neurotransmitter Glycine causing muscle spasm and spastic paralysis. It has a heavy chain that binds to gangliosides on the neuron cell membrane. The light chain of tetanus toxin has protease activity. Neurons in the anterior horn and interstitial neurons of the spinal cord are affected. |
| Botulinum Toxin | Neurotoxin that blocks the release of acetylcholine at the synapse causing flaccid paralysis. |
| Exotoxin A of Clostridium difficile | It is an Enterotoxin causing watery diarrhoea. Glycosylates and inactivates signal transduction proteins Rho GTPases |
| Exotoxin B of Clostridium difficile | It is a Cytotoxin that causes the formation of pseudomembranes. Glycosylates and inactivates signal transduction proteins Rho GTPases. Causes disaggregation of actin filaments in the cytoskeleton leading to cell death and apoptosis. |
| (Toxic shock syndrome toxin) | A superantigen produced by certain strains of S.aureus and Step. pyogenes. TSST binds directly to Class II MHC on Antigen Presenting Cells which then binds to multiple Helper T cells. This causes massive release of cytokines like IL 1 and IL 2. It is also a T cell mitogen. |
| Staphylococcal Enterotoxin | It is a superantigen. Causes massive cytokine release from the intestinal lymphoid cells hence stimulating the enteric nervous system in the intestines causing diarrhea and vomiting. |
| Erythrogenic Toxin | A superantigen, produced by Step. pyogenes, causes the rash of scarlet fever. |
| PVL (Panton Valentine Leukocidin) | Is a pore forming exotoxin produced by MRSA. It destroys white blood cells, skin and subcutaneous tissue. |
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