Elucidating mechanisms of host-pathogen interactions in chickens

阐明鸡宿主与病原体相互作用的机制

• 批准号: RGPIN-2019-06110
• 负责人: Sharif, Shayan
• 金额: $ 5.03万
• 依托单位: University of Guelph
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=715932
• 关键词: Elucidating; mechanisms; host; pathogen; interactions

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.

本项目研究鸡体内宿主与病原体的相互作用，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性疱疹病毒，可引起鸡马立克氏病（MD）。 针对 MD 的免疫力取决于先天性免疫机制和获得性免疫机制之间的相互作用。在获得性机制中，T细胞在免疫中发挥着重要作用。 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得到充分探索。与人类和小鼠血液中 γ-δ T 细胞数量极少不同，鸡血和组织中含有丰富的 γ-δ T 细胞。然而，关于鸡的 γ-δ T 细胞功能的信息很少。 γ-δ T 细胞可能在应对鸡沙门氏菌等细菌感染中发挥作用。我们的小组还表明，感染 MDV 的鸡在感染后 10 天和 21 天 (dpi) 时，其脾脏中的 γ-δ T 细胞数量显着增加，并且这些 γ-δ T 细胞在 21 dpi 时几乎 100% 为 CD8+ 。此外，在感染早期，脾脏γ-δ T细胞的IFN-表达上调。 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。我们的小组已经展示了其中一些 TLR 的配体在增强对 MDV 免疫力方面的效用。我们还证明鸡 γ-δ T 细胞表达 TLR3 和 TLR21，并且 MDV 感染后 TLR3 显着上调。然而，在对抗 MDV 的免疫背景下，鸡 γ-δ T 细胞表达 TLR 或其他先天受体的生物学相关性尚未确定。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，应该为更好地了解病毒免疫、开发针对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了解，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 γ-δ T 细胞针对 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以及在这些细胞中诱导先天抗病毒反应所涉及的先天途径； 4-检查先天病毒识别途径下调对 MDV 的 γ-δ T 细胞反应的体内影响。