Elucidating mechanisms of host-pathogen interactions in chickens

本计划调查宿主-病原体相互作用，特别是免疫反应马立克氏病病毒（MDV），致癌疱疹病毒，导致马立克氏病（MD），在鸡。** 对MD的免疫力取决于先天性和获得性免疫机制之间的相互作用。在获得性机制中，T细胞在免疫中起重要作用。α-β CD 8 + T细胞在MDV感染过程中被诱导。然而，γ-δ T细胞的作用仍然在很大程度上未被探索。与人类和小鼠血液中γ-δ T细胞数量非常少不同，γ-δ T细胞在鸡的血液和组织中大量存在。然而，关于鸡中γ-δ T细胞功能的信息很少。γ-δ T细胞可能在鸡对沙门氏菌等细菌感染的反应中发挥作用。我们的研究小组还表明，MDV感染的鸡在感染后10天和21天（dpi）在其脾脏中具有显著更高数量的γ-δ T细胞，并且在21 dpi时这些γ-δ T细胞中几乎100%是CD 8+。此外，脾γ-δ T细胞在感染早期上调IFN-γ的表达。γ-δ T细胞识别和应答病原体的机制可能依赖于先天受体以及其他机制。在先天性受体中，TLR，包括TLR 2、3、4和21参与这种感测疱疹病毒感染。我们的小组已经显示了这些TLR中的一些TLR的配体的效用，以增强对MDV的免疫力。我们还证明，鸡γ-δ T细胞表达TLR 3和TLR 21，并且在MDV感染后TLR 3显著上调。然而，尚未确定鸡γ-δ T细胞表达TLR或其他先天性受体在抗MDV免疫背景下的生物学相关性。更好地了解受感染鸡的淋巴组织以及肺部和羽毛中发生的免疫事件，应为更好地了解针对该病毒的免疫力、开发针对该病毒的有效预防平台铺平道路。** 该计划的长期目标是加强对宿主对病原体反应的理解，强调对MD的免疫力。本提案的总体目标是描述γ-δ T细胞在抗马立克氏病免疫中的作用。短期目标是：1-在分子水平上表征γ-δ T细胞在各种组织中产生的针对MDV的应答; 2-描绘γ-δ T细胞通过其先天受体识别MDV的方式; 3-揭示γ-δ T细胞识别MDV和在这些细胞中诱导先天抗病毒应答所涉及的先天途径; 4-检查先天病毒识别途径的下调对γ-δ T细胞对MDV应答的体内影响。**

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.**