Chapter 114. Molecular Mechanisms of Microbial Pathogenesis (Part 9)

The AIDS epidemic has resoundingly illustrated this principle: the immunodeficiency of many HIV-infected patients permits the development of life-threatening fungal infections of the lung, blood, and brain. Other than the capsule of C. neoformans, specific fungal antigens involved in tissue invasion are not well characterized. Both fungal and protozoal pathogens undergo morphologic changes to spread within a host. Yeast-cell forms of C. albicans transform into hyphal forms when invading deeper tissues. Malarial parasites grow in liver cells as merozoites and are released into the blood to invade erythrocytes and become trophozoites. ...
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Chapter 114. Molecular Mechanisms of Microbial Pathogenesis (Part 9) Chapter 114. Molecular Mechanisms of Microbial Pathogenesis (Part 9) Fungal pathogens almost always take advantage of hostimmunocompromise to spread hematogenously to deeper tissues. The AIDSepidemic has resoundingly illustrated this principle: the immunodeficiency ofmany HIV-infected patients permits the development of life-threatening fungalinfections of the lung, blood, and brain. Other than the capsule of C. neoformans,specific fungal antigens involved in tissue invasion are not well characterized.Both fungal and protozoal pathogens undergo morphologic changes to spreadwithin a host. Yeast-cell forms of C. albicans transform into hyphal forms wheninvading deeper tissues. Malarial parasites grow in liver cells as merozoites andare released into the blood to invade erythrocytes and become trophozoites. E.histolytica is found as both a cyst and a trophozoite in the intestinal lumen,through which this pathogen enters the host, but only the trophozoite form canspread systemically to cause amebic liver abscesses. Other protozoal pathogens,such as T. gondii, Giardia lamblia, and Cryptosporidium, also undergo extensivemorphologic changes after initial infection to spread to other tissues. Tissue Damage and Disease Disease is a complex phenomenon resulting from tissue invasion anddestruction, toxin elaboration, and host response. Viruses cause much of theirdamage by exerting a cytopathic effect on host cells and inhibiting host defenses.The growth of bacterial, fungal, and protozoal parasites in tissue, which may ormay not be accompanied by toxin elaboration, can also compromise tissuefunction and lead to disease. For some bacterial and possibly some fungal pathogens, toxin productionis one of the best-characterized molecular mechanisms of pathogenesis, while hostfactors such as IL-1, TNF-α, kinins, inflammatory proteins, products ofcomplement activation, and mediators derived from arachidonic acid metabolites(leukotrienes) and cellular degranulation (histamines) readily contribute to theseverity of disease. Viral Disease See Chap. 170. Bacterial Toxins Among the first infectious diseases to be understood were those due totoxin-elaborating bacteria. Diphtheria, botulism, and tetanus toxins are responsiblefor the diseases associated with local infections due to Corynebacteriumdiphtheriae, Clostridium botulinum, and Clostridium tetani, respectively.Enterotoxins produced by E. coli, Salmonella, Shigella, Staphylococcus, and V.cholerae contribute to diarrheal disease caused by these organisms. Staphylococci,streptococci, P. aeruginosa, and Bordetella elaborate various toxins that cause orcontribute to disease, including toxic shock syndrome toxin 1 (TSST-1);erythrogenic toxin; exotoxins A, S, T, and U; and pertussis toxin. A number ofthese toxins (e.g., cholera toxin, diphtheria toxin, pertussis toxin, E. coli heat-labile toxin, and P. aeruginosa exotoxins A, S, and T) have adenosine diphosphate(ADP)-ribosyltransferase activity—i.e., the toxins enzymatically catalyze thetransfer of the ADP-ribosyl portion of nicotinamide adenine diphosphate to targetproteins and inactivate them. The staphylococcal enterotoxins, TSST-1, and thestreptococcal pyogenic exotoxins behave as superantigens, stimulating certain Tcells to proliferate without processing of the protein toxin by antigen-presentingcells. Part of this process involves stimulation of the antigen-presenting cells toproduce IL-1 and TNF-α, which have been implicated in many of the clinicalfeatures of diseases like toxic shock syndrome and scarlet fever. A number ofgram-negative pathogens (Salmonella, Yersinia, and P. aeruginosa) can injecttoxins directly into host target cells by means of a complex set of proteins referredto as the type III secretion system. Loss or inactivation of this virulence systemusually greatly reduces the capacity of a bacterial pathogen to cause disease. Endotoxin The lipid A portion of gram-negative LPS has potent biologic activities thatcause many of the clinical manifestations of gram-negative bacterial sepsis,including fever, muscle proteolysis, uncontrolled intravascular coagulation, andshock. The effects of lipid A appear to be mediated by the production of potentcytokines due to LPS binding to CD14 and signal transduction via TLRs,particularly TLR4. Cytokines exhibit potent hypothermic activity through effectson the hypothalamus; they also increase vascular permeability, alter the activity ofendothelial cells, and induce endothelial-cell procoagulant activity. Numerous therapeutic strategies aimed at neutralizing the effects of ...