Roles of Pteropine Bat and Human TRIMs in Regulating Henipavirus Infection

项目摘要 蝙蝠是几种新出现和重新出现的病毒的自然宿主，包括海尼帕病毒(HNV)。 尽管感染这些病毒会导致人类的高病死率，但蝙蝠表现出耐受性。旧世界 翼蝙科果蝠是HNV的天然宿主，包括亨达(HEV)和尼帕(Nipah)。 HNV-翼蝙蝠的生态相互作用已经得到了很好的研究，但其背后的机制有限 翼状蝙蝠感染HNV后的免疫病理学尚不清楚。 在人类感染HNV期间，抗病毒I型干扰素(IFN-I)途径受到抑制，部分原因是通过 三方基序蛋白(TRIMS)的拮抗作用。TRIMs参与调节抗病毒免疫反应 包括干扰素-I的产生和信号转导途径。TRIM E3泛素连接酶家族的一些成员 刺激干扰素-I和促炎性抗病毒途径以促进病毒清除，而其他途径则拮抗 这些途径限制了免疫相关的病理。我们已经生成了初步数据，证明了 新城疫病毒在感染后期激活干扰素-I信号通路，但干扰素-I信号仍处于拮抗状态 在整个感染期间有效地在蝙蝠细胞中。基于这一观察，我们预测蝙蝠有 进化为表达TRIM以响应NiV感染，负面调节细胞质RNA识别 防止先天免疫信号的细胞病变效应的途径。在此之前，我们描述了Niv的角色 基质蛋白(NIV-M)在人TRIM6降解中的作用，抑制TRIM6介导的IKKε活化 依赖干扰素-I的产生和信号转导。我们发现BAT TRIM6与Niv-M相互作用，但BAT TRIM6抵抗 Niv-M介导的降解。由于这种特定物种的差异，我们有兴趣确定 BAT对TRIM6降解抗性的机制及TRIM6在NIV中的作用 感染。 在这个建议中，我们假设新城疫病毒感染诱导免疫抑制修剪蛋白在 促进耐受性的蝙蝠细胞，而不是人类细胞，以及NIV-M介导的物种特异性差异 TRIM6的降解影响感染过程。我们将通过两个具体的例子来验证我们的假设 目的：(1)鉴定新城疫病毒感染后差异表达的翼状旁腺素和人TRIM同源基因。 确定它们在先天免疫调节中的作用；(2)阐明人类和蝙蝠的机制作用 TRIM6在调节新城疫病毒感染中的作用。总括而言，拟议研究的结果将会促进我们对 翼鸟碱对蝙蝠干扰素-I途径的分子调控及其潜在的促进蝙蝠生长的因素 对HNV的耐受性。阐明促进对HNV耐受性的机制可能成为 人类治疗学的发展。

Project Summary Bat species are the natural hosts of several emerging and re-emerging viruses including henipaviruses (HNVs). Although infection with these viruses causes high case fatality rates in humans, bats appear tolerant. Old World fruit bats in the family Pteropodidae are the natural reservoirs of HNVs, including Henda (HeV) and Nipah (NiV). HNV-pteropine bat ecological interactions are well-studied, but the mechanisms underlying the limited immunopathology in pteropine bats following HNV infection are unknown. During HNV infection in humans, the antiviral type I interferon (IFN-I) pathways are suppressed in part through the antagonism of tripartite motif proteins (TRIMs). TRIMs are involved in modulating antiviral immune responses including IFN-I production and signaling pathways. Some members of the TRIM E3 ubiquitin ligase family stimulate the IFN-I and pro-inflammatory antiviral pathways to promote viral clearance while others antagonize these pathways to limit immune-associated pathology. We have generated preliminary data that demonstrates NiV activates the IFN-I signaling pathway human cells late in infection, but IFN-I signaling remains antagonized efficiently in bat cells throughout the duration of infection. Based on this observation, we predict that bats have evolved to express a TRIM in response to NiV infection that negatively regulates the cytoplasmic RNA recognition pathway to prevent the cytopathic effects of innate immune signaling. Previously, we described the role of NiV matrix protein (NiV-M) in the degradation of human TRIM6, which inhibits TRIM6-mediated activation of IKKε- dependent IFN-I production and signaling. We found that bat TRIM6 interacts with NiV-M, but bat TRIM6 resists NiV-M mediated degradation. Due to this species-specific difference, we are interested in identifying the mechanisms that confer degradation resistance to bat TRIM6 and understanding the roles of TRIM6 during NiV infection. In this proposal, we hypothesize that NiV infection induces the expression of an immunosuppressive TRIM in bat, but not human, cells that promotes tolerance, and that species-specific differences in NiV-M-mediated TRIM6 degradation influences the course of infection. We will interrogate our hypothesis through two specific aims: (1) to identify pteropine and human TRIM orthologs differentially expressed after NiV infection and determine their roles in innate immune regulation and (2) To elucidate the mechanistic roles of human and bat TRIM6 in regulating NiV infection. Overall, the results of the proposed study will promote our understanding of the molecular regulation of pteropine bat IFN-I pathways and potentially identify factors that facilitate bats’ tolerance to HNVs. Elucidating the mechanisms that promote tolerance to HNV may serve as a basis for the development of human therapeutics.