Chapter 114. Molecular Mechanisms of Microbial Pathogenesis (Part 8)

GPI-anchored receptors do not have intracellular signaling domains. Instead, the mammalian Toll-like receptors (TLRs) transduce signals for cellular activation due to LPS binding. It has recently been shown that binding of microbial factors to TLRs to activate signal transduction occurs not on the cell surface, but rather in the phagosome of cells that have internalized the microbe. This interaction is probably due to the release of the microbial surface factor from the cell in the environment of the phagosome, where the liberated factor can bind to its cognate TLRs. TLRs initiate cellular activation through a series of signaltransducing molecules...
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Chapter 114. Molecular Mechanisms of Microbial Pathogenesis (Part 8) Chapter 114. Molecular Mechanisms of Microbial Pathogenesis (Part 8) GPI-anchored receptors do not have intracellular signaling domains.Instead, the mammalian Toll-like receptors (TLRs) transduce signals for cellularactivation due to LPS binding. It has recently been shown that binding ofmicrobial factors to TLRs to activate signal transduction occurs not on the cellsurface, but rather in the phagosome of cells that have internalized the microbe.This interaction is probably due to the release of the microbial surface factor fromthe cell in the environment of the phagosome, where the liberated factor can bindto its cognate TLRs. TLRs initiate cellular activation through a series of signal-transducing molecules (Fig. 114-3) that lead to nuclear translocation of thetranscription factor nuclear factor κB (NF-κB), a master-switch for production ofimportant inflammatory cytokines such as tumor necrosis factor α (TNF-α) andinterleukin (IL) 1. Inflammation can be initiated not only with LPS and peptidoglycan but alsowith viral particles and other microbial products such as polysaccharides,enzymes, and toxins. Bacterial flagella activate inflammation by binding of aconserved sequence to TLR5. Some pathogens, including Campylobacter jejuni,Helicobacter pylori, and Bartonella bacilliformis, make flagella that lack thissequence and thus do not bind to TLR5. The result is a lack of efficient hostresponse to infection. Bacteria also produce a high proportion of DNA moleculeswith unmethylated CpG residues that activate inflammation through TLR9. TLR3recognizes double-strand RNA, a pattern-recognition molecule produced by manyviruses during their replicative cycle. TLR1 and TLR6 associate with TLR2 topromote recognition of acylated microbial proteins and peptides. The myeloid differentiation factor 88 (MyD88) molecule is a generalizedadaptor protein that binds to the cytoplasmic domains of all known TLRs and alsoto receptors that are part of the IL-1 receptor (IL-1Rc) family. Numerous studieshave shown that MyD88-mediated transduction of signals from TLRs and IL-1Rcis critical for innate resistance to infection. Mice lacking MyD88 are moresusceptible than normal mice to infection with group B Streptococcus, Listeriamonocytogenes, and Mycobacterium tuberculosis . However, it is now appreciatedthat some of the TLRs (e.g., TLR3 and TLR4) can activate signal transduction viaan MyD88-independent pathway. Additional Interactions of Microbial Pathogens and Phagocytes Other ways that microbial pathogens avoid destruction by phagocytesinclude production of factors that are toxic to phagocytes or that interfere with thechemotactic and ingestion function of phagocytes. Hemolysins, leukocidins, andthe like are microbial proteins that can kill phagocytes that are attempting to ingestorganisms elaborating these substances. For example, staphylococcal hemolysinsinhibit macrophage chemotaxis and kill these phagocytes. Streptolysin O made byS. pyogenes binds to cholesterol in phagocyte membranes and initiates a process ofinternal degranulation, with the release of normally granule-sequestered toxiccomponents into the phagocytes cytoplasm. E. histolytica, an intestinal protozoanthat causes amebic dysentery, can disrupt phagocyte membranes after directcontact via the release of protozoal phospholipase A and pore-forming peptides. Microbial Survival Inside Phagocytes Many important microbial pathogens use a variety of strategies to surviveinside phagocytes (particularly macrophages) after ingestion. Inhibition of fusionof the phagocytic vacuole (the phagosome) containing the ingested microbe withthe lysosomal granules containing antimicrobial substances (the lysosome) allowsM. tuberculosis , S. enterica serovar typhi, and Toxoplasma gondii to surviveinside macrophages. Some organisms, such as L. monocytogenes, escape into thephagocytes cytoplasm to grow and eventually spread to other cells. Resistance tokilling within the macrophage and subsequent growth are critical to successfulinfection by herpes-type viruses, measles virus, poxviruses, Salmonella, Yersinia,Legionella, Mycobacterium, Trypanosoma, Nocardia, Histoplasma, Toxoplasma,and Rickettsia. Salmonella spp. use a master regulatory system, in which thePhoP/PhoQ genes control other genes, to enter and survive within cells;intracellular survival entails structural changes in the cell envelope LPS. Tissue Invasion and Tissue Tropism Tissue Invasion Most viral pathogens cause disease by growth at skin or mucosal entrysites, but some pathogens spread from the initial site to deeper tissues. Virus canspread via the nerves (rabies virus) o ...