Elucidating mechanisms of host-pathogen interactions in chickens

本项目研究宿主-病原体相互作用，特别是鸡对马立克氏病病毒（MDV）的免疫反应，MDV是一种引起马立克氏病（MD）的致癌疱疹病毒。对MD的免疫依赖于先天和获得性免疫机制之间的相互作用。在获得性机制中，T细胞在免疫中起着重要作用。α - β CD8+ T细胞在MDV感染过程中被诱导。然而，γ - δ T细胞的作用在很大程度上仍未被充分探索。人类和老鼠的血液中γ - δ T细胞的数量很少，而鸡的血液和组织中γ - δ T细胞的数量却很多。然而，关于γ - δ T细胞在鸡体内的功能的信息缺乏。γ - δ T细胞可能在鸡的沙门氏菌等细菌感染反应中发挥作用。我们的研究小组还发现，感染埃博拉病毒的鸡在感染后10天和21天脾脏中的γ - δ T细胞数量显著增加，在感染后21天，这些γ - δ T细胞几乎100%是CD8+。此外，脾脏γ - δ T细胞上调IFN-？感染早期。γ - δ T细胞对病原体的识别和应答机制可能依赖于先天受体以及其他机制。在先天受体中，tlr，包括TLR2、3、4和21参与了这种感知疱疹病毒感染的过程。我们的研究小组已经证明了一些tlr的配体可以增强对MDV的免疫力。我们也证明了鸡γ - δ T细胞表达TLR3和TLR21，并且TLR3在MDV感染后显著上调。然而，在免疫MDV的情况下，鸡γ - δ T细胞表达TLRs或其他先天受体的生物学相关性尚未确定。更好地了解在感染鸡的淋巴组织以及肺和羽毛中发生的免疫事件，将为更好地了解对病毒的免疫，开发有效的预防平台铺平道路。该项目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。本提案的总体目标是描述γ - δ T细胞在马立克病免疫中的作用。短期目标是：1 .在分子水平上表征γ - δ T细胞在不同组织中对MDV产生的反应；2-描述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和诱导这些细胞的先天抗病毒反应的先天途径；4-研究先天病毒识别途径下调对γ - δ T细胞对MDV反应的体内影响。

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.