One of the main mechanisms by which bacteria cause disease is invasion of tissue followed by inflammation. (The inflammatory response is described in Chapter 8.) The other main mechanism, toxin production, and a third mechanism, immunopathogenesis, are described later in this chapter.
Several enzymes secreted by invasive bacteria play a role in pathogenesis. Among the most prominent are the following:
(1) Collagenase and hyaluronidase, which degrade collagen and hyaluronic acid, respectively, and allow bacteria to spread through subcutaneous tissue; they are especially important in cellulitis caused by Streptococcus pyogenes.
(2) Coagulase, which is produced by Staphylococcus aureus, accelerates the formation of a fibrin clot from fibrinogen (this clot may protect the bacteria from phagocytosis by walling off the infected area and by coating the organisms with a layer of fibrin).
(3) Immunoglobulin (Ig) proteases. Several organisms produce enzymes that degrade IgA and IgG. Neisseria gonorrhoeae, Haemophilus influenzae, and Streptococcus pneumoniae produce IgA proteases, which inactivate IgA at the mucosal surface. This leads to better adherence of these organisms to mucous mem branes. Streptococcus pyogenes produces an enzyme that specifically cleaves IgG heavy chains, which reduces opsonization and complement activation, enhancing the virulence of this organism.
In addition to these enzymes, several virulence factors con tribute to invasiveness by limiting the ability of the host defense mechanisms, especially phagocytosis, to operate effectively.
(1) The most important of these antiphagocytic factors is the capsule, which surrounds the cell wall of several important pathogens including S. pneumoniae, Neisseria meningitidis, and H. influenzae. Capsule prevents phagocytes from adhering to the bacteria. Note that anticapsular antibodies allow more effective phagocytosis to occur (a process called opsonization). Vaccines against S. pneumoniae, H. influenzae, and N. meningitidis contain the capsular polysaccharide of the organism as the antigen and induce production of protective anticapsular antibodies.
(2) A second group of antiphagocytic factors are the cell wall proteins of the gram-positive cocci, such as the M protein of the group A streptococci (S. pyogenes) and protein A of S. aureus. The M protein is antiphagocytic, and protein A binds to the Fc portion of IgG and prevents the activation of complement (see Table1).
(3) Leukocidins, such as the Panton-Valentine leukocidin produced by methicillin-resistant strains of S. aureus (MRSA), are pore-forming toxins that degrade the cell membrane of neutrophils and macrophages.
Table1. Surface Virulence Factors Important for Bacterial Pathogenesis
Bacteria cause two types of inflammation: pyogenic and granulomatous. In pyogenic (pus-producing) inflammation, neutrophils are the predominant cells. Some of the most important pyogenic bacteria are the gram-positive and gram-negative cocci listed in Table 1. In granulomatous inflammation, macrophages and helper T cells predominate. The most important organism in this category is Mycobacterium tuberculosis.
Many bacteria are capable of intracellular survival, which enhances their ability to cause disease because their intracellular location protects them from antibody and neutrophils that function extracellularly. The best known of these pathogens include bacterial species within Mycobacterium, Legionella, Brucella, and Listeria genera, and the fungal pathogen, Histoplasma. These organisms can be cultured on media in the laboratory and therefore are not obligate intracellular parasites, which distinguishes them from Chlamydia and Rickettsia.
Intracellular bacteria use several different mechanisms to allow them to survive and grow inside cells. These include (1) inhibiting phagolysosome fusion, which allows the organisms to avoid the degradative enzymes in the lysosome (Mycobacterium and Legionella utilize this mechanism); (2) inhibiting phagosome acidification, which reduces the activity of the lysosomal degradative enzymes; and (3) escaping from the phagosome into the cytoplasm, where there are no degradative enzymes (Listeria utilize this mechanism).
Bacterial cell invasion relies on specific bacterial surface proteins called invasins interacting with specific cellular receptors belonging to the integrin family of transmembrane adhesion proteins. Translocation of bacteria into the cell is a function of actin microfilaments. Once inside the cell, bacteria typically reside within cell vacuoles (i.e., phagosomes). Some remain there, others migrate into the cytoplasm, and some move from the cytoplasm into adjacent cells. Infection of the surrounding cells in this manner allows bacteria to evade host defenses. For example, Listeria monocytogenes aggregates actin filaments on its surface forming actin tails that propel the organism from one host cell to another.
The “Yops” (Yersinia outer-membrane proteins) produced by several Yersinia species are examples of bacterial virulence fac tors that act primarily after invasion of human cells by inhibiting phagocytosis by neutrophils and macrophages and cytokine production (e.g., tumor necrosis factor [TNF] production) by macrophages. For example, one of the Yops of Y. pestis (Yop J) is a protease that cleaves signal transduction proteins required for the induction of TNF synthesis. This inhibits the activation of our host defenses and contributes to the ability of the organism to cause bubonic plague.
The genes encoding many bacterial virulence factors are clustered in pathogenicity islands located on the bacterial chromosome or plasmids. For example, in many bacteria, genes encoding adhesins, invasins, and exotoxins are adjacent to each other on these islands. Nonpathogenic variants of these bacteria typically do not have these pathogenicity islands. It appears that these large regions of the bacterial genome were transferred as a block via conjugation or transduction. Pathogenicity islands are found in many gram-negative rods (i.e., E. coli, Salmonella, Shigella, Pseudomonas, and Vibrio cholerae), and in gram-positive cocci, such as S. pneumoniae.
After bacteria have colonized and multiplied at the portal of entry, they may invade the bloodstream and spread to other parts of the body. Receptors for the bacteria on the surface of cells determine, in large part, the organs affected. For example, certain bacteria or viruses infect the brain because receptors for these microbes are located on the surface of brain neurons.
