Elucidating mechanisms of host-pathogen interactions in chickens

本计划研究宿主-病原体之间的相互作用，特别是对马立克氏病病毒(MDV)的免疫反应。马立克氏病病毒是一种致癌的疱疹病毒，可导致马立克氏病(MD)。*对MD的免疫依赖于先天和后天免疫机制之间的相互作用。在获得性免疫机制中，T细胞在免疫中起着重要作用。MDV感染过程中可诱导产生α-βCD8+T细胞。然而，伽马-德尔塔T细胞的作用在很大程度上仍然没有得到充分的研究。与人类和小鼠血液中的伽马-德尔塔T细胞数量非常少不同，在鸡血和组织中发现了大量的伽马-德尔塔T细胞。然而，关于鸡的伽马-德尔塔T细胞的功能的信息很少。伽马-德尔塔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。我们的小组还发现，感染MDV的鸡在感染后10天和21天(Dpi)其脾中的Gamma-Delta T细胞数量显著增加，21dpi时几乎100%的这些Gamma-Delta T细胞是CD8+。此外，在感染早期，脾γ-Delta T细胞上调了干扰素-α的表达。γ-Delta T细胞识别和应答病原体的机制可能依赖于先天受体和其他机制。在先天受体中，包括TLR2、3、4和21在内的TLRs参与了对疱疹病毒感染的感知。我们的小组已经展示了其中一些TLR的配体在提高对MDV的免疫力方面的效用。我们还证明了鸡的Gamma-Delta T细胞表达TLR3和TLR21，并且在MDV感染后TLR3显著上调。然而，鸡的Gamma-Delta T细胞表达TLRs或其他天然受体与MDV免疫的生物学相关性尚未确定。更好地了解淋巴组织以及受感染鸡的肺和羽毛中发生的免疫事件，应为更好地了解对病毒的免疫、开发有效的病毒预防平台铺平道路。*该计划的长期目标是加强对宿主对病原体的反应的了解，强调对MD的免疫力。本提案的总体目标是描述伽马-德尔塔T细胞在马立克氏病免疫中的作用。短期目标是：1-在分子水平上表征不同组织中的伽马-德尔塔T细胞对MDV的反应；2-描述伽马-德尔塔T细胞通过其固有受体识别MDV的方式；3-揭示伽马-德尔塔T细胞识别MDV的先天途径以及在这些细胞中诱导先天抗病毒反应；4-检查体内天然病毒识别途径下调对伽马-德尔塔T细胞对MDV的反应的影响。

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.**