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Tag words: pathogenic bacteria, bacterial pathogenicity, invasiveness, toxigenesis, colonization, specific adherence, adhesin, receptor, invasion, invasin, coagulase, leucocidin, hemolysin, streptokinase, phagocytosis, phagosome, lysosome, phagolysosome, immunological tolerance, antigenic disguise, immunosuppression, antigenic variation, protein toxins, botulinum toxin, diphtheria toxin, anthrax toxin, tetanus toxin, pertussis toxin, cholera enterotoxin, adenylate cyclase, staph enterotoxin, TSST, pyrogenic exotoxin, superantigen, shiga toxin, E. coli LT toxin, ST toxin, endotoxin, lipopolysaccharide, LPS, Lipid A, O antigen, O polysaccharide, toxoid, pathogenicity island.









Kenneth Todar currently teaches Microbiology 100 at the University of Wisconsin-Madison.  His main teaching interest include general microbiology, bacterial diversity, microbial ecology and pathogenic bacteriology.

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Mechanisms of Bacterial Pathogenicity (page 5)

(This chapter has 8 pages)

© Kenneth Todar, PhD

EVASION OF HOST DEFENSES

Some pathogenic bacteria are inherently able to resist the bactericidal components of host tissues. For example, the poly-D-glutamate capsule of Bacillus anthracis protects the organisms against cell lysis by cationic proteins in sera or in phagocytes. The outer membrane of Gram-negative bacteria is a formidable permeability barrier that is not easily penetrated by hydrophobic compounds such as bile salts which are harmful to the bacteria. Pathogenic mycobacteria have a waxy cell wall that resists attack or digestion by most tissue bactericides. And intact lipopolysaccharides (LPS) of Gram-negative pathogens may protect the cells from complement-mediated lysis or the action of lysozyme.

Most successful pathogens, however, possess additional structural or biochemical features which allow them to resist the main lines of host internal defense against them, i.e., the phagocytic and immune responses of the host.

Overcoming Host Phagocytic Defenses

Microorganisms invading tissues are first and foremost exposed to phagocytes. Bacteria that readily attract phagocytes, and that are easily ingested and killed, are generally unsuccessful as parasites. In contrast, most bacteria that are successful as parasites interfere to some extent with the activities of phagocytes or in some way avoid their attention.

Microbial strategies to avoid phagocytic killing are numerous and diverse, but are usually aimed at blocking one or of more steps in the phagocytic process. Recall the steps in phagocytosis:

1. Contact between phagocyte and microbial cell

2. Engulfment

3. Phagosome formation

4. Phagosome-lysosome fusion

5. Killing and digestion

Avoiding Contact with Phagocytes

Bacteria can avoid the attention of phagocytes in a number of ways.

1. Invade or remain confined in regions inaccessible to phagocytes. Certain internal tissues (e.g. the lumen of glands) and surface tissues (e.g. the skin) are not patrolled by phagocytes.

2. Avoid provoking an overwhelming inflammatory response. Some pathogens induce minimal or no inflammation required to focus the phagocytic defenses.

3. Inhibit phagocyte chemotaxis. e.g. Streptococcal streptolysin (which also kills phagocytes) suppresses neutrophil chemotaxis, even in very low concentrations. Fractions of Mycobacterium tuberculosis are known to inhibit leukocyte migration. Clostridium ø toxin inhibits neutrophil chemotaxis.

4. Hide the antigenic surface of the bacterial cell. Some pathogens can cover the surface of the bacterial cell with a component which is seen as "self" by the host phagocytes and immune system. Phagocytes cannot recognize bacteria upon contact and the possibility of opsonization by antibodies to enhance phagocytosis is minimized. For example, pathogenic Staphylococcus aureus produces cell-bound coagulase which clots fibrin on the bacterial surface. Treponema pallidum binds fibronectin to its surface. Group A streptococci are able to synthesize a capsule composed of hyaluronic acid.

Inhibition of Phagocytic Engulfment

Some bacteria employ strategies to avoid engulfment (ingestion) if phagocytes do make contact with them. Many important pathogenic bacteria bear on their surfaces substances that inhibit phagocytic adsorption or engulfment. Clearly it is the bacterial surface that matters. Resistance to phagocytic ingestion is usually due to a component of the bacterial cell wall, or fimbriae, or a capsule enclosing the bacterial wall. Classical examples of antiphagocytic substances on the bacterial surface include:

Polysaccharide capsules of S. pneumoniae, Haemophilus influenzae, Treponema pallidum and Klebsiella pneumoniae

M protein and fimbriae of Group A streptococci

Surface slime (polysaccharide) produced by Pseudomonas aeruginosa

O antigen associated with LPS of E. coli

K antigen of E. coli or the analogous Vi antigen of Salmonella typhi

Cell-bound or soluble Protein A produced by Staphylococcus aureus


Streptococcus pneumoniae, FA stain showing its antphagocytic capsule (CDC). S. pneumoniae cells that possess a capsule are virulent; nonencapsulated strains are avirulent. Although S. pneumoniae strains possess a variety of determinants of virulence, this illustrates the essential role of their capsule in ability to resist phagocytosis by alveolar macrophages in order to initiate disease.

Survival Inside of Phagocytes

Some bacteria survive inside of phagocytic cells, in either neutrophils or macrophages. Bacteria that can resist killing and survive or multiply inside of phagocytes are considered intracellular parasites. The environment of the phagocyte may be a protective one, protecting the bacteria during the early stages of infection or until they develop a full complement of virulence factors. The intracellular environment guards the bacteria against the activities of extracellular bactericides, antibodies, drugs, etc.

Most intracellular parasites have special (genetically-encoded) mechanisms to get themselves into their host cell as well as special mechanisms to survive once they are inside. Intracellular parasites usually survive by virtue of mechanisms which interfere with the bactericidal activities of the host cell. Some of these bacterial mechanisms include:

1. Inhibition of phagosome-lysosome fusion. The bacteria survive inside of phagosomes because they prevent the discharge of lysosomal contents into the phagosome environment. Specifically phagolysosome formation is inhibited in the phagocyte. This is the strategy employed by Salmonella, M. tuberculosis, Legionella and the Chlamydiae.


Intracellular Mycobacterium tuberculosis in lung. Ziehl-Neelsen acid fast stain (CDC).

2. Survival inside the phagolysosome. With some intracellular parasites, phagosome-lysosome fusion occurs but the bacteria are resistant to inhibition and killing by the lysosomal constituents. Also, some extracellular pathogens can resist killing in phagocytes utilizing similar resistance mechanisms. Little is known of how bacteria can resist phagocytic killing within the phagocytic vacuole, but it may be due to the surface components of the bacteria or due to extracellular substances that they produce which interfere with the mechanisms of phagocytic killing. Bacillus anthracis, Mycobacterium tuberculosis and Staphylococcus aureus all possess mechanisms to survive intracellular killing in macrophages.

3. Escape from the phagosome. Early escape from the phagosome vacuole is essential for growth and virulence of some intracellular pathogens. This is a very clever strategy employed by the Rickettsias which produce a phospholipase enzyme that lyses the phagosome membrane within thirty seconds of after ingestion.

Products of Bacteria that Kill or Damage Phagocytes

One obvious strategy in defense against phagocytosis is direct attack by the bacteria upon the professional phagocytes. Any of the substances that pathogens produce that cause damage to phagocytes have been referred to as "aggressins". Most of these are actually extracellular enzymes or toxins that kill phagocytes. Phagocytes may be killed by a pathogen before or after ingestion.

Killing phagocytes before ingestion. Many Gram-positive pathogens, particularly the pyogenic cocci, secrete extracellular enzymes which kill phagocytes. Many of these enzymes are called "hemolysins" because their activity in the presence of red blood cells results in the lysis of the rbcs.

Pathogenic streptococci produce streptolysin. Streptolysin O binds to cholesterol in membranes. The effect on neutrophils is to cause lysosomal granules to explode, releasing their contents into the cell cytoplasm.

Pathogenic staphylococci produce leukocidin, which also acts on the neutrophil membrane and causes discharge of lysosomal granules.

Other examples of bacterial extracellular proteins that inhibit phagocytosis include the Exotoxin A of Pseudomonas aeruginosa which kills macrophages, and the bacterial exotoxins that are adenylate cyclases (e.g. anthrax toxin EF and pertussis AC) which decrease phagocytic activity.


Gram stain of a pustular exudate from a mixed bacterial infection. Pus is the usual outcome of the battle between phagocytes and bacterial strategies to kill them.

Killing phagocytes after ingestion. Some bacteria exert their toxic action on the phagocyte after ingestion has taken place. They may grow in the phagosome and release substances which can pass through the phagosome membrane and cause discharge of lysosomal granules, or they may grow in the phagolysosome and release toxic substances which pass through the phagolysosome membrane to other target sites in the cell. Many bacteria which are the intracellular parasites of macrophages (e.g. Mycobacteria, Brucella, Listeria) usually destroy macrophages in the end, but the mechanisms are not understood.

Evading Complement

Antibodies that are bound to bacterial surfaces will activate complement by the classical pathway and bacterial polysaccharides activate complement by the alternative pathway. Bacteria in serum and other tissues, especially Gram-negative bacteria, need protection from the antimicrobial effects of complement before and during an immunological response.

One role of capsules in bacterial virulence is to protect the bacteria from complement activation and the ensuing inflammatory response. Polysaccharide capsules can hide bacterial components such as LPS or peptidoglycan which can induce the alternate complement pathway. Some bacterial capsules are able to inhibit formation of the C3b complex on their surfaces, thus avoiding C3b opsonization and subsequent formation of C5b and the membrane attack complex (MAC) on the bacterial cell surface. Capsules that contain sialic acid (a common component of host cell glycoproteins), such as found in Neisseria meningitidis, have this effect.

One of the principal targets of complement on Gram-negative bacteria is LPS. It serves as the attachment site for C3b and triggers the alternative pathway of activation. It also binds C5b.

LPS can be modified by pathogens in two ways that affects its interaction with complement. First, by attachment of sialic acid residues to the LPS O antigen, a bacterium can prevent the formation of C3 convertase just as capsules that contain sialic acid can do so. Both Neisseria meningitidis and Haemophilus influenzae, which cause bacterial meningitis, are able to covalently attach sialic acid residues to their O antigens resulting in resistance to MAC. Second, LPS with long, intact O antigen side-chains can prevent effective MAC killing. Apparently the MAC complex is held too far from the vulnerable outer membrane to be effective.

Bacteria that are not killed and lysed in serum by the complement MAC are said to be serum resistant. As might be expected many of the Gram-negative bacteria that cause systemic infections, (bacteremia or septicemia) are serum resistant. Gram-positive bacteria are naturally serum-resistant since their cells are not enclosed in an outer membrane.

Other ways that pathogens are able to inhibit the activity of complement is to destroy one or more of the components of complement.  Pseudomonas aeruginosa produces an extracellular elastase enzyme that inactivates components of complement.




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Kenneth Todar has taught microbiology to undergraduate students at The University of Texas, University of Alaska and University of Wisconsin since 1969.

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