Fig. 9.8 Mechanism of anthrax exotoxin action. The B subunit, also called protective antigen, binds a cell-surface receptor, is cleaved by a host protease, and forms a heptamer. Three A subunits of edema factor (EF) or lethal factor (LF) bind to the B heptamer, enter the cell, and are released into the cytoplasm. EF binds calcium and calmodulin to form an adenylate cyclase that increases intracellular cAMP, which causes efflux of water and interstitial edema. LF is a protease that destroys mitogen-activated protein kinase kinases (MAPKKs), leading to cell death. cAMP, cyclic adenosine monophosphate. Note that each B subunit binds either EF or LF, but not both (as shown for simplicity). (Adapted from Mourez M, Lacy DB, Cunningham, K, et al: 2011: A year of major advances in anthrax toxin research. Trends Microbiol 10:287, 2002.)
As mentioned earlier, the host immune response to microbes can sometimes be the cause of tissue injury. A few examples of types and mechanisms of injury are as follows:
Granulomatous inflammation. Infection with M. tuberculosis results in a delayed hypersensitivity response and the formation of granulomas, which sequester the bacilli and prevent its spread, but also produce tissue damage (caseous necrosis) and fibrosis.
T-cell–mediated inflammation. Damage from HBV and HCV infection of hepatocytes is due mainly to the immune response to the infected liver cells and not to cytopathic effects of the virus.
Innate immune inflammation. Pattern recognition receptors bind to pathogen-associated molecular patterns (PAMPS) and to damage-associated molecular patterns (DAMPS) released from damaged host cells, activating the immune system and leading to inflammation (discussed in Chapter 5).
Humoral immunity. Poststreptococcal glomerulonephritis can develop after infection with S. pyogenes. It is caused by antibodies that bind to streptococcal antigens and form immune complexes, which deposit in renal glomeruli and produce nephritis.
Chronic inflammatory diseases. In the development of inflammatory bowel disease (Chapter 15), an important early event may be compromise of the intestinal epithelial barrier, which enables the entry of both pathogenic and commensal microbes and their interactions with local immune cells, resulting in inflammation. The cycle of inflammation and epithelial injury may be an important component of the disease, with microbes playing the central role.
Cancer. Viruses, such as HBV and HCV, and bacteria, such as H. pylori, that are not known to carry or to activate oncogenes are associated with cancers, presumably because these microbes trigger chronic inflammation with subsequent tissue regeneration, which provides fertile ground for the development of cancer (Chapter 6).
Diseases caused by microbes involve an interplay of microbialvirulence and host responses.
Infectious agents can cause cell death or dysfunction by directlyinteracting with the cell.