Defining a role for monocyte licensing in the regulation of Leishmania-specific T cell immunity following short- and long-term pre-exposure to sand fly blood feeding

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Project Summary Exposure to the bites of blood feeding arthropods elicits both innate and adaptive immune responses in the vertebrate host. These responses have largely been attributed to inoculation of arthropod-derived salivary proteins into the skin. In turn, immunity elicited by salivary proteins significantly influences the outcome of infection upon subsequent exposure to arthropod transmitted pathogens. However, the immunological events that occur following blood feeding, and more importantly, how these events change in the physiological setting of repeated exposure, are not well defined. In addition, if and how the adaptive immune response to salivary proteins directly influences the activation of pathogen-specific cells is not known. Without a clearer understanding of the interactions between salivary- and pathogen-specific immunity our ability to harness the power of the immune system to prevent or treat vector-transmitted diseases is likely to remain inadequate. In preliminary experiments, we have found that the murine adaptive and innate immune responses to the bites of uninfected Lutzomia longipalpus sand flies, a blood feeding arthropod and vector of leishmaniasis caused by the protozoan parasitic pathogen Leishmania, changes with repeated exposure to uninfected bites. During repeated exposure to blood feeding an initial homogenous phase of salivary protein-specific T helper (Th) 1 immunity gives way to a heterogenous response at the population level and alters the monocyte response. Both the impact of the diverse and likely cross-regulatory responses elicited by long-term pre-exposure to uninfected bites on Leishmania-specific immunity and the mechanism by which salivary-specific immunity influences Leishmania-specific immunity are unknown. In light of these observations, we HYPOTHESIZE that, following an initial Th1 dominated response to blood feeding, the immune system undergoes a diversification with ongoing chronic exposure resulting in a heterogenous response involving multiple CD4 T cell subsets. Given the intimate co-localization of sand fly- and parasite-derived antigens, including the microbiota, at a Leishmania-infected sand fly bite site in the skin, saliva- or bacteria- specific T cells will subsequently impact Leishmania-specific immunity via CCR2+ inflammatory monocyte licensing. These hypotheses will be tested experimentally within the following two aims: AIM 1: Determine how innate and adaptive immunity to sand fly bites and sand fly derived antigens changes with repeated exposure.; and AIM 2: Determine the impact of chronic exposure to sand fly bites on de novo generation of Leishmania-specific T cells and define a role for CCR2+ monocytes as the central antigen presenting cell in this process. Conducting these studies will provide a critical pre-clinical understanding of how the ‘host-vector- pathogen’ relationship may impact the success of prophylactic and therapeutic intervention strategies to treat arthropod transmitted diseases.