بسم الله الرحمن الرحيم
Bacterial virulence factors
1-Adherence Factors:
When bacteria enter the body of the host, they must adhere to cells of a tissue surface. If they did not adhere, they would be swept away by mucus and other fluids that bathe the tissue surface. Adherence, which is only one step in the infectious process, is followed by development of micro-colonies and subsequent steps in the pathogenesis of infection.
The interactions between bacteria and tissue cell surfaces in the adhesion process are complex. Several factors play important roles: surface hydrophobicity and net surface charge, binding molecules on bacteria (ligands), and host cell receptor interactions. Bacteria and host cells commonly have net negative surface charges and, therefore, repulsive electrostatic forces. These forces are overcome by hydrophobic and other more specific interactions between bacteria and host cells.
Bacteria also have specific surface molecules that interact with host cells. Many bacteria have pili, hair-like appendages that extend from the bacterial cell surface and help mediate adherence of the bacteria to host cell surfaces. For example, some E coli strains have type 1 pili, which adhere to epithelial cell receptors containing D-mannose; adherence can be blocked in vitro by addition of D-mannose to the medium. E coli organisms that cause urinary tract infections commonly do not have D-mannose-mediated adherence but have P-pili, which attach to a portion of the P blood group antigen.
Antibodies that act against the specific bacterial ligands that promote adherence (eg, pili and lipoteichoic acid) can block adherence to host cells and protect the host from infection.
After adherence occurs, conformational changes in the host cell follow that can lead to cytoskeletal changes allowing organism uptake by the cell.
Sometimes, changes in the adhesin molecule after attachment may trigger activation of virulence genes that promote invasion or that result in other pathogenic changes.
Invasion of Host Cells & Tissues:
Invasion is the term commonly used to describe the entry of bacteria into host cells and for many disease-causing bacteria, invasion of the host’s epithelium is central to the infectious process. Some bacteria (eg, Salmonella species) invadetissues through the junctions between epithelial cells. Other bacteria (eg, Yersinia species, N gonorrhoeae, and Chlamydia trachomatis) invade specific types of the host’s epithelial cells and may subsequently enter the tissue. In many infections,
the bacteria produce virulence factors that cause the host cells to engulf (ingest) the bacteria.
The host cells play a very active role in the process. When inside the host cell, bacteria may remain enclosed in a vacuole composed of the host cell membrane, or the vacuole membrane may be dissolved and bacteria may be dispersed in the cytoplasm. Some bacteria (eg, Shigella species) multiply within host cells, but other bacteria do not.
Toxin production and other virulence properties are generally independent of the ability of bacteria to invade cells and tissues. For example, Corynebacterium diphtheriae is able to invade the epithelium of the nasopharynx and cause symptomatic sore throat even when the C diphtheriae strains are nontoxigenic.
Toxins:
ExotoxinsMany gram-positive and gram-negative bacteria produce exotoxins of considerable medical importance. Some of these toxins have had major roles in world history. For example, tetanus caused by the toxin of C tetani killed as many as 50,000 soldiers of the Axis powers in World War II. Many exotoxins consist of A and B subunits. The B subunit generally mediates adherence of the toxin complex to a host cell and aids entrance of the exotoxin into the host cell. The A subunit provides the toxic activity.
C botulinum causes botulism. It is found in soil or water and may grow in foods (canned, vacuum-packed, etc) if the environment is suitably anaerobic. An remarkably potent toxin (the most potent toxin known) is produced. It is heat-labile and is destroyed by sufficient heating.
Some S aureus strains growing on mucous membranes or in wounds, elaborate toxic shock syndrome toxin-1 (TSST-1), which causes toxic shock syndrome. The illness is characterized by shock, high fever, and a diffuse red rash that later desquamates; multiple other organ systems are involved as well.
TSST-1 is a super antigen and stimulates lymphocytes to produce large amounts of IL-1 and TNF. The major clinical manifestations of the disease appear to be secondary to the effects of the cytokines. TSST-1 may act synergistically with low levels of lipopolysaccharide to yield the toxic effect.
Exotoxins associated with diarrheal diseases are frequently called enterotoxins and many belong to the type III toxin family; such as V cholerae has produced epidemic diarrheal disease.
Some strains of S aureus produce enterotoxins while growing in meat, dairy products, or other foods.
Lipopolysaccharides of Gram-Negative Bacteria:
The lipopolysaccharides (LPS, endotoxin) of gram-negative bacteria are derived from cell walls and are often liberated when the bacteria lyse. The substances are heat-stable, have molecular weights between 3000 and 5000 (lipo-oligosaccharides, LOS) and several million (lipopolysaccharides).The pathophysiologic effects of LPS are similar regardless of their bacterial origin except for those of Bacteroides species, which have a different structure and are less toxic. LPS in the bloodstream is initially bound to circulating proteins which then interact with receptors on macrophages and monocytes and other cells of the reticulo-endothelial system. Proinflammatory cytokines such as IL-1, IL-6, IL-8, TNF-a and other cytokines are released, and the complement and coagulation cascades are activated..
The following can be observed clinically or experimentally: fever, leukopenia, and hypoglycemia; hypotension and shock resulting in impaired perfusion of essential organs (eg, brain, heart, kidney); intravascular coagulation; and death from massive organ dysfunction
• Property
• Exotoxin
• Endotoxin
• Gene location
• Extra-chromosomal genes (Plasmid or bacteriophage)
• Bacterial chromosome
• composition
• proteins
• LPS
• Heat stability
• Labile destroyed at 60C°
• Stable at 100 C° for 1 hr
• Action
• Strong
• Weak
• Diffusibility
• Yes
• No
• Antigenicity
• Strong
• Weak
• Toxicity
• Strong
• Weak
• Convertibility to toxoid
• Yes
• No
• Produced by
• G+ve, and G-
• Mainly G-ve
Enzymes:
Tissue-Degrading Enzymes
Many bacteria produce tissue-degrading enzymes. The best-characterized are enzymes from C perfringens), S aureus , group A streptococci , and, to a lesser extent, anaerobic bacteria. The roles of tissue-degrading enzymes in the pathogenesis of infections appear clear but have been difficult to prove, especially those of individual enzymes. For example, antibodies against the tissue-degrading enzymes of streptococci do not modify the features of streptococcal disease.
In addition to lecithinase, C perfringens produces the proteolytic enzyme collagenase, which degrades collagen, the major protein of fibrous connective tissue, and promotes spread of infection in tissue.
S aureus produces coagulase, which works in conjunction with serum factors to coagulate plasma. Coagulase contributes to the formation of fibrin walls around staphylococcal lesions, which helps them persist in tissues. Coagulase also causes deposition of fibrin on the surfaces of individual staphylococci, which may help protect them from phagocytosis or from destruction within phagocytic cells.
Hyaluronidases are enzymes that hydrolyze hyalouronic acid, a essential of the ground substance of connective tissue. They are produced by many bacteria (eg, staphylococci, streptococci, and anaerobes) and aid in their spread through tissues.
Many hemolytic streptococci produce streptokinase (fibrinolysin), a substance that activates a proteolytic enzyme of plasma. This enzyme is then able to dissolve coagulated plasma and probably aids in the rapid spread of streptococci through tissues. Streptokinase has been used in treatment of acute myocardial infarction to dissolve fibrin clots.
Many bacteria produce substances that are cytolysins that is, they dissolve red blood cells (hemolysins) or kill tissue cells or leukocytes (leukocidins).
IgA1 Proteases:
Immunoglobulin A is the secretory antibody on mucosal surfaces. It has two primary forms, IgA1 and IgA2, that differ near the center, or hinge, region of the heavy chains of the molecules. IgA1 has a series of amino acid in the hinge region that are not present in IgA2. Some bacteria that cause disease produce enzymes, IgA1 proteases, that split IgA1 at specific proline-threonine or proline-serine bonds in the hinge region and inactivate its antibody activity. IgA1 protease is an important virulence factor of the pathogens N gonorrhoeae, N meningitidis, H influenzae, and S pneumoniae.Antiphagocytic Factors:
Many bacterial pathogens are rapidly killed once they are ingested by polymorphonuclear cells or macrophages. Some pathogens evade phagocytosis or leukocyte microbicidal mechanisms by adsorbing normal host components to their surfaces. For example, S aureus has surface protein A, which binds to the Fc portion of IgG. Other pathogens have surface factors that impede phagocytosis—eg, S pneumoniae, N meningitidis; many other bacteria have polysaccharide capsules. S pyogenes (group A streptococci) has M protein.N gonorrhoeae (gonococci) has pili. Most of these antiphagocytic surface structures show much antigenic heterogeneity. For example, there are more than 90 pneumococcal capsular polysaccharide types and more than 80 M protein types of group A streptococci. Antibodies against one type of the antiphagocytic factor (eg, capsular polysaccharide, M protein) protect the host from disease caused by bacteria of that type but not from those with other antigenic types of the same factor.
A few bacteria (eg: Bordetella) produce soluble factors or toxins that inhibit chemotaxis by leukocytes and thus evade phagocytosis by a different mechanism.
Consequently, the main antiphagostic factors include:
• 1- protein A as in S. aureus
• 2-polysaccharide capsule
• 3-pili as in Neisseria spp
• 4-soluble factors or toxins
• 5- enzymes as coagulase