Roles of Pteropine Bat and Human TRIMs in Regulating Henipavirus Infection

Pteropine 蝙蝠和人类 TRIM 在调节亨尼帕病毒感染中的作用

• 批准号: 10373965
• 负责人: Sarah van Tol
• 金额: $ 1.25万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10373965
• 关键词: 2019-nCoV; Amino Acid Motifs; Antiviral Response; Binding; Biological Assay; Case Fatality Rates; Cells; Chiroptera; Conflict (Psychology); Data; Data Set; Development; Disease; Ecology; Family; Family Pteropodidae; Fruit; Gene Expression Profiling; Goals; Hendra Virus; Henipavirus; Henipavirus Infections; Human; Immune; Immune response; Immune signaling; Immunomodulators; Infection; Inflammatory; Inflammatory Response; Integration Host Factors; Interferon Type I; Interferons; Knowledge; Mammals; Mediating; Molecular; Natural Immunity; Nipah Virus; Orthologous Gene; Paramyxovirus; Pathology; Pathway interactions; Patients; Production; Proteins; Public Health; Publishing; RNA; Regulation; Resistance; Role; Satellite Viruses; Signal Pathway; Signal Transduction; TRIM Motif; Therapeutic; Translating; Viral; Viral Proteins; Virulent; Virus; Virus Diseases; Zoonoses; antagonist; base; cell immortalization; differential expression; immunopathology; immunoregulation; interest; member; overexpression; prevent; protein expression; response; side effect; targeted treatment; transcriptomics; ubiquitin-protein ligase

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.

项目摘要 蝙蝠物种是包括亨尼帕病毒（HNV）在内的几种新出现和重新出现的病毒的天然宿主。 虽然感染这些病毒会导致人类的高病死率，但蝙蝠似乎对这些病毒具有耐受性。旧世界 狐蝠科的果蝠是HNV的天然宿主，包括Henda（HeV）和Nipah（NiV）。 HNV-狐蝠生态相互作用已经得到了很好的研究，但是HNV-狐蝠生态相互作用的机制有限。 HNV感染后狐蝠免疫病理学是未知的。 在人类HNV感染期间，抗病毒I型干扰素（IFN-I）途径通过以下途径被部分抑制： 三重基序蛋白（TRIMs）的拮抗作用。TRIMs参与调节抗病毒免疫应答 包括IFN-I的产生和信号通路。TRIM E3泛素连接酶家族的一些成员 刺激IFN-I和促炎性抗病毒途径，以促进病毒清除，而其他拮抗 这些途径来限制免疫相关的病理学。我们得到的初步数据表明 NiV在感染后期激活IFN-I信号传导途径人类细胞，但IFN-I信号传导仍然被拮抗 在蝙蝠细胞中有效地表达。基于这一观察，我们预测蝙蝠 进化为表达TRIM以响应NiV感染，其负调节细胞质RNA识别 这是一种预防先天免疫信号传导的细胞病变效应的途径。之前，我们描述了NiV的作用 基质蛋白（NiV-M）在人TRIM 6降解中的作用，其抑制TRIM 6介导的IKKε- 依赖IFN-I产生和信号传导。我们发现蝙蝠TRIM 6与NiV-M相互作用，但蝙蝠TRIM 6抵抗NiV-M。 NiV-M介导的降解。由于这种物种特异性差异，我们有兴趣确定 赋予蝙蝠TRIM 6降解抗性的机制，并了解TRIM 6在NiV过程中的作用 感染 在这个建议中，我们假设NiV感染诱导了免疫抑制性TRIM的表达。 蝙蝠，而不是人类，细胞，促进耐受性，并在NiV-M介导的物种特异性差异， TRIM 6降解影响感染过程。我们将通过两个具体的假设来验证我们的假设。 目的：（1）鉴定在NiV感染后差异表达的Pteropine和人TRIM同源物， 确定它们在先天免疫调节中的作用;（2）阐明人和蝙蝠在先天免疫调节中的机制作用 TRIM 6在调节NiV感染中的作用总的来说，拟议研究的结果将促进我们对 蝙蝠IFN-I途径的分子调控，并可能识别促进蝙蝠 对HNV的耐受性。阐明促进对HNV耐受性的机制可作为治疗HNV的基础。 人类治疗学的发展。