Source: http://www.asmscience.org/content/book/10.1128/9781555816650.ch30
Timestamp: 2019-04-24 18:05:18+00:00

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The intracellular protozoan Toxoplasma gondii is a pathogen of humans and an important zoonotic infection in domestic animals. The resultant toxoplasmic encephalitis, most dramatically highlighted in chronically infected AIDS patients, is lethal if not appropriately controlled by drug therapy. This chapter describes the multiple facets of early encounters between T. gondii and the professional phagocytes, considering how these phagocytes lead to resistance or disease as the ultimate outcome of infection. Originally defined for their role in detection of bacterial, fungal, and viral molecules, it is now known that toll-like receptor (TLR) also possess protozoan recognition properties. The first indication for TLR-based recognition of Toxoplasma came from the observation that MyD88-deficient mice were hypersusceptible to infection, and death was associated with defective IFN- γ and IL-12 responses. As MyD88-deficient mice uniformly succumb to T. gondii during acute infection, the implication is that additional TLRs are likely important in Toxoplasma recognition. Importantly, experiments using STAT3−/− macrophages show that T. gondii requires this host molecule to suppress responses to LPS. For the host, it is essential to control the parasite to prevent death from infection. In the future, we can expect a major drive to determine at the molecular level how this complex balance is achieved, and indeed, this research effort is already well under way.
Multiple pathways lead to IL-12 production during T. gondii infection. A parasite profilin molecule triggers proinflammatory cytokine production through TLR11/MyD88 signaling. In addition, GPI molecules from the parasite surface activate both TLR2 and TLR4 for cytokine production. The TLR signaling pathways are likely to also involve p38 MAPK. The cyclophilin-18 molecule expressed by tachyzoites appears to act through the seven-transmembrane chemokine receptor CCR5 to induce dendritic cell IL-12. Finally, another pathway that does not involve MyD88, CCR5, or G-protein-mediated signaling also leads to IL-12 induction. Little is known about this last pathway except that p38 MAPK is an essential component.
Major phagocytic killing mechanisms operating against Toxoplasma. (1) IFN-γ signaling through STAT1 is a major mechanism for inducing microbicidal activity. Among STAT1-inducible proteins are the IRG family members. (2) Some IRG proteins (Irgm1, Irgm3, Irga6) act to induce parasitophorous vacuole membrane breakdown and parasite elimination involving, in some cases, autophagy. (3) Independently of the IFN-γ pathway, CD40 ligation transmits signals for parasite killing that also involve autophagy. (4) Other IRG proteins (Irgd) as well as iNOS are induced by STAT1 signaling, but are only required for survival during chronic infection. How these molecules function is enigmatic.
T. gondii mechanisms of subverting phagocyte immune function. Once inside the cell, Toxoplasma renders cells nonresponsive to IFN-γ. This appears to occur at several levels. (1) The parasite may induce the negative regulator SOCS-1 that blocks STAT1 phosphorylation and induces its degradation. (2) There is evidence that the parasite also prevents nuclear translocation of phosphorylated STAT1, although this is less certain. (3) Some studies also suggest that Toxoplasma may dephosphorylate STAT1 that has translocated into the nucleus in response to IFN-γ. (4) Rhoptry protein discharge during invasion; in particular, the putative serine-threonine kinase ROP16 induces STAT3 activation that downregulates proinflammatory signaling. (5) The parasite also interferes with TLR-mediated NF-κB activity in a process that may involve accelerated export from the nucleus. (6) Toxoplasma also deactivates proinflammatory MAPK signaling cascades initiated through TLR, in a process that may involve either parasite or host phosphatase activity.
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