Whitmarsh, Ryan J

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  • Publication
    Innate Signals in the Macrophage Determine the Severity of Toxoplasma Gondii infection
    (2011-12-21) Whitmarsh, Ryan J
    Toxoplasma gondii is an obligate intracellular pathogen that is a cause of significant morbidity and mortality in humans and animals. The immune response necessary to control this infection requires successful coordination of strong innate and adaptive responses. Recognition of the pathogen by innate accessory cells such as macrophages, neutrophils, and dendritic cells induces the release of IL-12 that activates NK and T cells to produce protective IFN-g, the major mediator of immunity to T. gondii. T. gondii has many mechanisms to limit the activation of innate cells and to reduce the production of IL-12. One of the ways T. gondii achieves this is by inducing the phosphorylation of the transcription factor Signal Transducer of Activation 3 (STAT3) that leads to repressed pro-inflammatory responses such as diminished IL-12 production. How STAT3 antagonizes inflammatory responses is poorly understood but the Suppressors of Cytokine Signaling (SOCS) proteins are downstream candidate molecules that antagonize cytokine signaling. Recent studies have identified SOCS proteins as being important during infection with a number of pathogens and have provided insights into how intracellular pathogens affect STAT signaling to promote their replication and survival. In particular, SOCS1 is thought to inhibit IFN-g signals whereas SOCS3 antagonizes IL-6 signals. Studies have shown that both of these proteins are upregulated in other models but little is known about how they contribute to the outcome of infection. This thesis provides evidence that the IL-6 signaling in macrophages reduces the cell’s ability to produce IL-12 that is enhanced in the absence of SOCS3. Furthermore, infection of SOCS3 conditional knockouts leads to acute susceptibility with high parasite burdens associated with impaired IL-12 production. Blocking anti-bodies to IL-6 as well as addition of exogenous IL-12 rescues the lethality in these mice suggesting that IL-6 is a natural antagonist of IL-12 production during infection with T. gondii. This thesis will discuss the roles that IL-6, STAT3, and SOCS3 play during infection with T. gondii and how these molecules affect cytokine regulation, cellular recruitment, and microbicidal activity and also how these studies enhance our understanding of inflammation and resistance to infection.