Previous studies have shown that T. gondii infected mice undergo thymic atrophy, a process that in other systems has been linked with glucocorticoid (GC) production. In work completed and accepted for publication during the report period (see Scientific Advance below) we showed that GC are induced during acute Toxoplasma gondii infection and directly control the CD4+ T cell response to the parasite. Thus, when infected with toxoplasma, GRlck-Cre mice that selectively lack GC receptor expression in T cells undergo excessive immunopathology and mortality associated with hyperactive Th1 cell function. Using this genetic mouse tool we decided to analyze the role of GC in the thymic atrophy induced by T. gondii. In initial work we showed that that atrophy requires infection with actively replicating parasites, is induced rapidly during the first week of infection and persists for months into the chronic phase. Experiments employing infection of the GRlck-Cre mice described above indicate that this atrophy is only in part mediated by GR signaling at the T cell level and instead is closely associated with infection induced destruction of the thymic epithelium. Interestingly the process of thymic atrophy is accompanied by a persistent and marked reduction in the number of nave CD4+ T cells in the periphery. These experiments reveal a previously unappreciated mechanism by which T.gondii modifies the immune competence of its intermediate rodent hosts. While innate recognition of T. gondii has been extensively characterized in the mouse, it is still unclear how human innate cells, which do not express the major murine sensors TLR11 and TLR12 respond to the parasite. For this reason, as outlined in our last years report, we initiated a new project aimed at both characterizing the cytokine/chemokine response elicited in human peripheral blood myeloid cells upon exposure to T. gondii tachyzoites and identifying the signaling pathways involved. We found that purified elutriated CD14+ monocytes (but not in vitro differentiated dendritic cells or macrophages) produce proinflammatory cytokines (e.g. TNF and p40 IL-12) and chemokines when exposed to live tachyzoites. During the report period we established that this response occurs selectively in the CD16high ("patrolling") and CD16 intermediate but not CD16low ("classical") monocyte subsets. In addition, we determined that induction of cytokine/chemokine production requires live but not replicating parasites and direct contact with host cells since no response was observed when tachyzoites and monocytes are separated in a transwell. These findings clearly distinguish recognition of T. gondii by human cells from the pathway occuring in mouse cells which is contact independent and can be mediated by a soluble parasite extract. The NOD receptors are cytoplasmic pattern recognition receptors previously characterized as recognizing bacterial cell wall peptidoglycans. Recent data have suggested a role for NOD2 in murine host resistance to T. gondii, although this finding was disputed in a later publication by a different group.To clarify the role of the NOD receptors in T. gondii infection, we infected NOD1-, NOD2- or NOD1/2-deficient mice. Surprisingly, we found that NOD1- and NOD1/2- but not NOD2-deficient mice rapidly succumb to T. gondii infection and display enhanced parasite burdens. This correlated with decreased production of IFNγfrom NOD1-deficient CD4 T cells in the peritoneal infection site. Taken together, these results demonstrate that NOD1 plays an essential role in host resistance to the parasite. Our initial data suggest that the increased susceptibility of NOD1 deficient mice is the consequence of impaired T cell infiltration/retention at the site of infection or alternatively to an intrinsic defect in T cells that compromises their survival and/or ability to become Th1 effectors.

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