Elucidating mechanisms of host-pathogen interactions in chickens

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The present program investigates host-pathogen interactions, particularly immune responses to Marek's disease virus (MDV), an oncogenic herpesvirus that causes Marek's disease (MD), in chickens. Immunity against MD is dependent on interactions between innate and acquired immune mechanisms. Among the acquired mechanisms, T cells play an important role in immunity. Alpha-beta CD8+ T cells are induced in the course of MDV infection. However, the role of gamma-delta T cells has remained largely underexplored. Unlike humans and mice which have very low number of gamma-delta T cells in their blood, gamma-delta T cells are found in abundance in the chicken blood and tissues. There is, however, paucity of information about the function of gamma-delta T cells in chickens. Gamma-delta T cells may play a role in response to bacterial infections such as Salmonella in chickens. Our group has also shown that MDV-infected chickens have significantly higher number of gamma-delta T cells in their spleens by 10 and 21 days post-infection (dpi) and nearly 100% of these gamma-delta T cells are CD8+ at 21 dpi. Moreover, splenic gamma-delta T cells had up-regulated expression of IFN-? early in infection. The mechanisms of pathogen recognition and response by gamma-delta T cells may be dependent on innate receptors as well as other mechanisms. Among innate receptors, TLRs, including TLR2, 3, 4 and 21 are involved in this sensing herpesvirus infection. Our group has shown the utility of ligands for some of these TLRs to boost immunity against MDV. We have also demonstrated that chicken gamma-delta T cells express TLR3 and TLR21 and TLR3 is significantly upregulated after MDV infection. However, biological relevance of expression of TLRs or other innate receptors by chicken gamma-delta T cells in the context of immunity against MDV has not been determined. Gaining a better understanding of the immunological events that occur in lymphoid tissues as well as in the lungs and feathers of infected chickens should pave the way to better understanding of immunity against the virus, development of efficacious prophylactic platforms against the virus. The long-term objective of this program is to enhance understanding of host response against pathogens, emphasizing immunity against MD. The overall goal of the present proposal is to delineate the role of gamma-delta T cells in immunity against Marek's disease. The short-term objectives are to: 1-characterize, at the molecular level, the responses generated by gamma-delta T cells against MDV in various tissues; 2- delineate the ways in which gamma-delta T cells recognize MDV through their innate receptors; 3- reveal the innate pathways involved in recognition of MDV by gamma-delta T cells and induction of innate antiviral responses in these cells; 4- examine the in vivo effects of down-regulation of innate viral recognition pathways on gamma-delta T cell responses to MDV.