17.2: Bacterial Virulence Factors- Adhesins and Exoenzymes

Learning Objectives

• Explain how virulence factors contribute to signs and symptoms of infectious disease
• Describe the importance of adhesion and how it contributes to colonization
• Differentiate between various bacterial exoenzymes 
• Evaluate how exoenzymes enhance pathogenicity

In the previous section, we explained that some pathogens are more virulent than others. This is due to the unique virulence factors produced by individual pathogens, which determine the extent and severity of disease they may cause. A pathogen’s virulence factors are encoded by genes that can be identified using molecular Koch’s postulates. When genes encoding virulence factors are inactivated, virulence in the pathogen is diminished. In this section, we examine various types and specific examples of virulence factors and how they contribute to each step of pathogenesis.

Virulence Factors for Adhesion

As discussed in the previous section, the first two steps in pathogenesis are exposure and adhesion. Recall that an adhesin is a protein or glycoprotein found on the surface of a pathogen that attaches to receptors on the host cell. Adhesins are found on bacterial, viral, fungal, and protozoan pathogens. One example of a bacterial adhesin is type 1 fimbrial adhesin, a molecule found on the tips of fimbriae of enterotoxigenic E. coli (ETEC). Recall that fimbriae are hairlike protein bristles on the cell surface. Type 1 fimbrial adhesin allows the fimbriae of ETEC cells to attach to the mannose glycans expressed on intestinal epithelial cells. Table \(\PageIndex{1}\) lists common adhesins found in some of the pathogens we have discussed or will be seeing later in this chapter.

Table \(\PageIndex{1}\): Some Bacterial Adhesins and Their Host Attachment Sites

Pathogen	Disease	Adhesin	Attachment Site
Streptococcus pyogenes	Strep throat	Protein F	Respiratory epithelial cells
Streptococcus mutans	Dental caries	Adhesin P1	Teeth
Neisseria gonorrhoeae	Gonorrhea	Type IV pili	Urethral epithelial cells
Enterotoxigenic E. coli (ETEC)	Traveler’s diarrhea	Type 1 fimbriae	Intestinal epithelial cells
Vibrio cholerae	Cholera	N-methylphenylalanine pili	Intestinal epithelial cells

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Bacterial Exoenzymes and Toxins as Virulence Factors

After exposure and adhesion, the next step in pathogenesis is invasion, which can involve enzymes and toxins. Many pathogens achieve invasion by entering the bloodstream, an effective means of dissemination because blood vessels pass close to every cell in the body. The downside of this mechanism of dispersal is that the blood also includes numerous elements of the immune system. Various terms ending in –emia are used to describe the presence of pathogens in the bloodstream. The presence of bacteria in blood is called bacteremia. Bacteremia involving pyogens(pus-forming bacteria) is called pyemia. When viruses are found in the blood, it is called viremia. The term toxemiadescribes the condition when toxins are found in the blood. If bacteria are both present and multiplying in the blood, this condition is called septicemia.

Patients with septicemia are described as septic, which can lead to shock, a life-threatening decrease in blood pressure (systolic pressure <90 mm Hg) that prevents cells and organs from receiving enough oxygen and nutrients. Some bacteria can cause shock through the release of toxins (virulence factors that can cause tissue damage) and lead to low blood pressure. Gram-negative bacteria are engulfed by immune system phagocytes, which then release tumor necrosis factor, a molecule involved in inflammation and fever. Tumor necrosis factor binds to blood capillaries to increase their permeability, allowing fluids to pass out of blood vessels and into tissues, causing swelling, or edema(Figure \(\PageIndex{1}\)). With high concentrations of tumor necrosis factor, the inflammatory reaction is severe and enough fluid is lost from the circulatory system that blood pressure decreases to dangerously low levels. This can have dire consequences because the heart, lungs, and kidneys rely on normal blood pressure for proper function; thus, multi-organ failure, shock, and death can occur.

Figure \(\PageIndex{1}\): This patient has edema in the tissue of the right hand. Such swelling can occur when bacteria cause the release of pro-inflammatory molecules from immune cells and these molecules cause an increased permeability of blood vessels, allowing fluid to escape the bloodstream and enter tissue.

Exoenzymes

Some pathogens produce extracellular enzymes, or exoenzymes, that enable them to invade host cells and deeper tissues. Exoenzymes have a wide variety of targets. Some general classes of exoenzymes and associated pathogens are listed in Table \(\PageIndex{2}\). Each of these exoenzymes functions in the context of a particular tissue structure to facilitate invasion or support its own growth and defend against the immune system. For example, hyaluronidase S, an enzyme produced by pathogens like Staphylococcus aureus, Streptococcus pyogenes, and Clostridium perfringens, degrades the glycoside hylauronan (hyaluronic acid), which acts as an intercellular cement between adjacent cells in connective tissue (Figure \(\PageIndex{2}\)). This allows the pathogen to pass through the tissue layers at the portal of entry and disseminate elsewhere in the body (Figure \(\PageIndex{2}\)).

Table \(\PageIndex{2}\): Some Classes of Exoenzymes and Their Targets

Class	Example	Function
Glycohydrolases	Hyaluronidase S in Staphylococcus aureus	Degrades hyaluronic acid that cements cells together to promote spreading through tissues
Nucleases	DNAse produced by S. aureus	Degrades DNA released by dying cells (bacteria and host cells) that can trap the bacteria, thus promoting spread
Phospholipases	Phospholipase C of Bacillus anthracis	Degrades phospholipid bilayer of host cells, causing cellular lysis, and degrade membrane of phagosomes to enable escape into the cytoplasm
Proteases	Collagenase in Clostridium perfringens	Degrades collagen in connective tissue to promote spread

Figure \(\PageIndex{2}\): (a) Hyaluronan is a polymer found in the layers of epidermis that connect adjacent cells. (b) Hyaluronidase produced by bacteria degrades this adhesive polymer in the extracellular matrix, allowing passage between cells that would otherwise be blocked.

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Pathogen-produced nucleases, such as DNAse produced by S. aureus, degrade extracellular DNA as a means of escape and spreading through tissue. As bacterial and host cells die at the site of infection, they lyse and release their intracellular contents. The DNA chromosome is the largest of the intracellular molecules, and masses of extracellular DNA can trap bacteria and prevent their spread. S. aureus produces a DNAse to degrade the mesh of extracellular DNA so it can escape and spread to adjacent tissues. This strategy is also used by S. aureus and other pathogens to degrade and escape webs of extracellular DNA produced by immune system phagocytes to trap the bacteria.

Enzymes that degrade the phospholipids of cell membranes are called phospholipases. Their actions are specific in regard to the type of phospholipids they act upon and where they enzymatically cleave the molecules. The pathogen responsible for anthrax, B. anthracis, produces phospholipase C. When B. anthracis is ingested by phagocytic cells of the immune system, phospholipase C degrades the membrane of the phagosome before it can fuse with the lysosome, allowing the pathogen to escape into the cytoplasm and multiply. Phospholipases can also target the membrane that encloses the phagosome within phagocytic cells. As described earlier in this chapter, this is the mechanism used by intracellular pathogens such as L. monocytogenes and Rickettsia to escape the phagosome and multiply within the cytoplasm of phagocytic cells. The role of phospholipases in bacterial virulence is not restricted to phagosomal escape. Many pathogens produce phospholipases that act to degrade cell membranes and cause lysis of target cells. These phospholipases are involved in lysis of red blood cells, white blood cells, and tissue cells.

Bacterial pathogens also produce various protein-digesting enzymes, or proteases. Proteases can be classified according to their substrate target (e.g., serine proteases target proteins with the amino acid serine) or if they contain metals in their active site (e.g., zinc metalloproteases contain a zinc ion, which is necessary for enzymatic activity).

One example of a protease that contains a metal ion is the exoenzyme collagenase. Collagenase digests collagen, the dominant protein in connective tissue. Collagen can be found in the extracellular matrix, especially near mucosal membranes, blood vessels, nerves, and in the layers of the skin. Similar to hyaluronidase, collagenase allows the pathogen to penetrate and spread through the host tissue by digesting this connective tissue protein. The collagenase produced by the gram-positive bacterium Clostridium perfringens, for example, allows the bacterium to make its way through the tissue layers and subsequently enter and multiply in the blood (septicemia). C. perfringens then uses toxins and a phospholipase to cause cellular lysis and necrosis. Once the host cells have died, the bacterium produces gas by fermenting the muscle carbohydrates. The widespread necrosis of tissue and accompanying gas are characteristic of the condition known as gas gangrene (Figure \(\PageIndex{3}\)).

Figure \(\PageIndex{3}\): The illustration depicts a blood vessel with a single layer of endothelial cells surrounding the lumen and dense connective tissue (shown in red) surrounding the endothelial cell layer. Collagenase produced by C. perfringens degrades the collagen between the endothelial cells, allowing the bacteria to enter the bloodstream. (credit illustration: modification of work by Bruce Blaus; credit micrograph: Micrograph provided by the Regents of University of Michigan Medical School © 2012)

Query \(\PageIndex{1}\)

 

Key Concepts and Summary

Virulence factors contribute to a pathogen’s ability to cause disease. Exoenzymes and toxins allow pathogens to invade host tissue and cause tissue damage. Exoenzymes are classified according to the macromolecule they target and exotoxins are classified based on their mechanism of action. 

Footnotes

1. 1 V. Meka. “Panton-Valentine Leukocidin.” http://www.antimicrobe.org/h04c.file...L-S-aureus.asp