INVASION

The invasion of a host by a pathogen may be aided by the production of bacterial extracellular substances which act against the host by breaking down primary or secondary defenses of the body. Medical microbiologists have long referred to these substances as invasins. Most invasins are proteins (enzymes) that act locally to damage host cells and/or have the immediate effect of facilitating the growth and spread of the pathogen. The damage to the host as a result of this invasive activity may become part of the pathology of an infectious disease.

The extracellular proteins produced by bacteria which promote their invasion are not clearly distinguished from some extracellular protein toxins ("exotoxins") which also damage the host. Invasins usually act at a short range (in the immediate vicinity of bacterial growth) and may not actually kill cells as part of their range of activity; exotoxins are often cytotoxic and may act at remote sites (removed from the site of bacterial growth). Also, exotoxins typically are more specific and more potent in their activity than invasins. Even so, some classic exotoxins (e.g. diphtheria toxin, anthrax toxin) may play some role in colonization or invasion in the early stages of an infection, and some invasins (e.g. staphylococcal leukocidin) have a relatively specific cytopathic effect.

A Survey of Bacterial Invasins

Hyaluronidase. is the original spreading factor. It is produced by streptococci. staphylococci, and clostridia. The enzyme attacks the interstitial cement ("ground substance") of connective tissue by depolymerizing hyaluronic acid.

Collagenase is produced by Clostridium histolyticum and Clostridium perfringens. It breaks down collagen, the framework of muscles, which facilitates gas gangrene due to these organisms.

Neuraminidase is produced by intestinal pathogens such as Vibrio cholerae and Shigella dysenteriae. It degrades neuraminic acid (also called sialic acid), an intercellular cement of the epithelial cells of the intestinal mucosa.

Streptokinase and staphylokinase are produced by streptococci and staphylococci, respectively. Kinase enzymes convert inactive plasminogen to plasmin which digests fibrin and prevents clotting of the blood. The relative absence of fibrin in spreading bacterial lesions allows more rapid diffusion of the infectious bacteria.

Enzymes that Cause Hemolysis and/or Leucolysis

These enzymes usually act on the animal cell membrane by insertion into the membrane (forming a pore that results in cell lysis), or by enzymatic attack on phospholipids, which destabilizes the membrane. They may be referred to as lecithinases or phospholipases, and if they lyse red blood cells they are sometimes called hemolysins. Leukocidins, produced by staphylococci and streptolysin produced by streptococci specifically lyse phagocytes and their granules. These latter two enzymes are also considered to be bacterial exotoxins.

Phospholipases, produced by Clostridium perfringens (i.e., alpha toxin), hydrolyze phospholipids in cell membranes by removal of  polar head groups.

Lecithinases, also produced by Clostridium perfringens,  destroy lecithin (phosphatidylcholine) in cell membranes.

Hemolysins,  notably produced by staphylococci (i.e., alpha toxin), streptococci (i.e., streptolysin) and various clostridia, may be channel-forming proteins or phospholipases or lecithinases that destroy red blood cells and other cells (i.e., phagocytes) by lysis.

Beta-hemolytic Streptococcus. This is the characteristic appearance of a blood agar plate culture of the bacterium. Note the translucency around the bacterial colonies, representing hemolysis of the red cells in the culture medium due to production of a diffusible hemolysin (streptolysin).

Staphylococcal coagulase

Coagulase, formed by Staphylococcus aureus, is a cell-associated and diffusible enzyme that converts fibrinogen to fibrin which causes clotting. Coagulase activity is almost always associated with pathogenic S. aureus and almost never associated with nonpathogenic S. epidermidis, which has led to much speculation as to its role as a determinant of virulence. Possibly, cell bound coagulase could provide an antigenic disguise if it clotted fibrin on the cell surface. Or a staphylococcal lesion encased in fibrin (e.g. a boil or pimple) could make the bacterial cells resistant to phagocytes or tissue bactericides or even drugs which might be unable to diffuse to their bacterial target.

Extracellular Digestive Enzymes

Heterotrophic bacteria, in general, produce a wide variety of extracellular enzymes including proteases, lipases, glycohydrolases, nucleases, etc., which are not clearly shown to have a direct role in invasion or pathogenesis. These enzymes presumably have other functions related to bacterial nutrition or metabolism, but may aid in invasion either directly or indirectly.

Toxins With Short-Range Effects Related to Invasion

Bacterial protein toxins which have adenylate cyclase activity, are thought to have immediate effects on host cells that promote bacterial invasion. One component of the anthrax toxin (EF or Edema Factor) is an adenylate cyclase that acts on nearby cells to cause increased levels of cyclic AMP and disruption of cell permeability. One of the toxins of Bordetella pertussis, the agent of whooping cough,  has a similar effect. These toxins may contribute to invasion through their effects on macrophages or lymphocytes in the vicinity which are playing an essential role to contain the infection. For example, since they use ATP as a substrate, they may deplete phagocyte reserves of energy needed for ingestion. Edema is seen as a pathology because the increase in cAMP in affected cells disrupts equilibrium.

Gelatinous edema seen in a cutaneous anthrax lesion. CDC.

The following table summarizes the activities of many bacterial proteins that are noted for their contribution to bacterial invasion of tissues.
 

TABLE 3. SOME EXTRACELLULAR BACTERIAL PROTEINS THAT ARE CONSIDERED INVASINS

Invasin	Bacteria Involved	Activity
Hyaluronidase	Streptococci, staphylococci and clostridia	Degrades hyaluronic of connective tissue
Collagenase	Clostridium species	Dissolves collagen framework of muscles
Neuraminidase	Vibrio cholerae and Shigella dysenteriae	Degrades neuraminic acid of intestinal mucosa
Coagulase	Staphylococcus aureus	Converts fibrinogen to fibrin which causes clotting
Kinases	Staphylococci and streptococci	Converts plasminogen to plasmin which digests fibrin
Leukocidin	Staphylococcus aureus	Disrupts neutrophil membranes and causes discharge of lysosomal granules
Streptolysin	Streptococcus pyogenes	Repels phagocytes and disrupts phagocyte membrane and causes discharge of lysosomal granules
Hemolysins	Streptococci, staphylococci and clostridia	Phospholipases or lecithinases that destroy red blood cells (and other cells) by lysis
Lecithinases	Clostridium perfringens	Destroy lecithin in cell membranes
Phospholipases	Clostridium perfringens	Destroy phospholipids in cell membrane
Anthrax EF	Bacillus anthracis	One component (EF) is an adenylate cyclase which causes increased levels of intracellular cyclic AMP
Pertussis AC	Bordetella pertussis	One toxin component is an adenylate cyclase that acts locally producing an increase in intracellular cyclic AMP