The long-term objective of this proposal is to understand how innate immunity recognizes and responds to microbial infection to drive emergence of adaptive immunity. The project focuses on mouse infection with the protozoan parasite Toxoplasma gondii, a pathogen triggering strong Th1 immunity that normally enables host survival and parasite encystment within the central nervous system. Previous work has established involvement of Toll-like receptor (TLR)-MyD88 signaling pathways driving dendritic cell IL-12 production that contributes to activation of protective T cells and control of infection. In this proposal the central hypothesis is that MyD88-independent recognition of Toxoplasma is an important alternative pathway leading to adaptive immunity to infection. This is supported by preliminary data in mice lacking MyD88 showing emergence of primed T cells and immunity to infection after vaccination with attenuated Toxoplasma. The hypothesis will be tested with two specific aims.
Aim 1 : Determine if TLR/IL-12 signaling is required for protective immunity in the absence of MyD88. A panel of knockout mice will be created by genetic crossing onto the Myd88-/- background that will enable us to determine involvement of MyD88-independent TLR signaling and MyD88- independent IL-12 in adaptive immunity to infection.
Aim 2 : Determine if inflammatory monocytes drive MyD88-independent protective immunity. We hypothesize that inflammatory monocytes, known for their microbicidal activity against T. gondii, are an unrecognized driver of MyD88-independent adaptive immunity. The hypothesis will be tested using in vivo mAb cell depletion and analysis of Myd88-/- IL-12-eYFP reporter mice that we will generate in this aim. The importance of the research is that we will generate data on uninvestigated MyD88-independent pathways driving adaptive immunity. This is likely to have an impact on understanding human immunity since populations deficient in MyD88 retain resistance to all but a narrow range of infections. Accordingly, the practical significance of this project is that we expect to identify new targets fr vaccine development and for immunotherapy during infection and inflammation.
of the project to public health is that it deals with host immune responses and inflammation during Toxoplasma gondii infection. This parasite is classified as a class B biodefense pathogen. Toxoplasma is a common opportunistic infection in humans that can cause life-threatening disease in immunocompromised populations and in congenital infection. Completing the project may ultimately identify new targets to treat inflammatory disease and to improve immunity to microbial infection.