Comparative Analysis of Bunyavirus Neuropathogenesis

布尼亚病毒神经发病机制的比较分析

• 批准号: 10675190
• 负责人: Amy L Hartman
• 金额: $ 114.92万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-24 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10675190
• 关键词: Address; Adult; Affect; Africa; Age; Animals; Antiviral Response; Arboviruses; Biological Models; Brain; Category A pathogen; Cell Death; Cells; Central Nervous System Diseases; Central Nervous System Infections; Childhood; Culicidae; Dengue; Dependence; Disease; Disease Outbreaks; Epidemic; Fever; Flavivirus; Future; Genome; Goals; Health; Human; Immunologist; In Vitro; Individual; Infection; Innate Immune Response; Insect Vectors; Knowledge; La Crosse virus; Mediating; Medical; Molecular; Morbidity - disease rate; Mus; National Institute of Allergy and Infectious Disease; Neuraxis; Neurobiology; Neurologic; Neurons; Neuropathogenesis; Nonstructural Protein; North America; Oropouche virus; Orthobunyavirus; Pathogenesis; Pathogenicity; Pathway interactions; Proteins; Publishing; Research; Rift Valley Fever; Rift Valley fever virus; Rodent; Role; Route; Slice; South America; Survivors; System; Tropism; United States; Variant; Viral; Viral Encephalitis; Virulence; Virulent; Virus; Virus Diseases; age related; antagonist; cell type; cellular targeting; chikungunya; climate change; comparative; global health; human pathogen; induced pluripotent stem cell; inhibitor; innate immune pathways; interdisciplinary approach; long-term sequelae; mortality; mouse model; nervous system disorder; neurovirulence; novel; organizational structure; pathogen; protein function; prototype; response; stem; transcriptomics; vector-borne; virology

PROJECT SUMMARY/ABSTRACT Bunyaviruses are a large, diverse group of vector-borne viruses with the capacity to cause neurological disease with morbidity and mortality. A major limitation in our basic scientific understanding of bunyavirus neuropathogenesis stems from the fact that key target cells in the brain are not fully defined, therefore the effect of infection on target cells is unknown, and viral determinants that contribute to neurological disease have not been delineated. A broader, understanding of how bunyaviruses interact with the central nervous system (CNS), including molecular mechanisms of host-viral interactions, is fundamental for future goal of mitigating effects of disease and long-term sequelae in survivors. Here, we propose a comparative analysis of the basic neuropathogenesis of 3 important emerging bunyaviruses: Rift Valley fever (RVFV), Oropouche (OROV), and La Crosse (LACV). Infection by each of these viruses have the potential to cause significant neurological disease in humans. However, substantial gaps remain in our understanding of bunyavirus neuropathogenesis, including molecular mechanisms that contribute to disease. A limitation is the lack of rigor of prior research is that published studies on these viruses as they are difficult to directly compare due to use of different in vitro cell systems and disparate mouse models, including variations in age and infection route. We will address this gap by directly comparing CNS cell tropism, innate responses, and cell death pathways induced by RVFV, OROV, and LACV using novel in vitro and ex vivo model systems. Given the potential for diverse bunyaviruses to cause neurological sequelae in a subset of human cases, and the fact that all 3 are lethal in neurological mouse models, we hypothesize that diverse bunyaviruses have common target cells in the CNS and that neuronal infection is mediated by Lrp1, a newly identified host entry factor for RVFV. A key feature of bunyaviral virology is the expression of the viral non-structural protein produced from the small genome segment (NSs). NSs is the main antagonist of host cell antiviral responses. Each virus expresses a different NSs protein, and thus we further hypothesize that the degree of neurovirulence of each virus is directly related to NSs protein function, with RVFV NSs being the most potent inhibitor of innate responses. Our highly collaborative and synergistic team is led by Dr. Amy Hartman (PI), an expert in the pathogenesis of RVFV, Dr. Anita McElroy (Co-I), a molecular virologist and immunologist with expertise in emerging viral diseases, Dr. Gaya Amarasinghe (Co-I), a biochemist with expertise in host-pathogen interactions. Two additional Co-I’s are Dr. Leonard D’Aiuto and Dr. Zachary Wills, who are experts in viral infection of human neurons and rodent neurobiology, respectively. This R01 proposal represents a multidisciplinary approach to advance our understanding of bunyavirus interactions with the brain.

项目概要/摘要 布尼亚病毒是一大类多样化的媒介传播病毒，能够引起神经系统疾病 与发病率和死亡率。我们对布尼亚病毒的基本科学理解的一个主要限制 神经发病机制源于大脑中关键靶细胞尚未完全确定的事实，因此影响 of infection on target cells is unknown, and viral determinants that contribute to neurological disease have not 被划定。对布尼亚病毒如何与中枢神经系统 (CNS) 相互作用有更广泛的了解， 包括宿主与病毒相互作用的分子机制，对于未来减轻病毒影响的目标至关重要 幸存者的疾病和长期后遗症。在此，我们对基本情况进行比较分析 3 种重要的新兴布尼亚病毒的神经发病机制：裂谷热 (RVFV)、奥罗普切病毒 (OROV) 和 拉克罗斯 (LACV)。这些病毒的感染都有可能导致严重的神经系统疾病 在人类中。然而，我们对布尼亚病毒神经发病机制的理解仍然存在很大差距，包括 导致疾病的分子机制。一个局限性是先前研究缺乏严谨性，即已发表的研究 对这些病毒的研究，因为由于使用不同的体外细胞系统而很难直接比较它们 不同的小鼠模型，包括年龄和感染途径的差异。我们将通过直接解决这一差距 比较 RVFV、OROV 和 LACV 诱导的 CNS 细胞趋向性、先天反应和细胞死亡途径 使用新颖的体外和离体模型系统。鉴于多种布尼亚病毒可能导致 在部分人类病例中会出现神经系统后遗症，而且这三种情况在神经系统小鼠模型中都是致命的， 我们假设不同的布尼亚病毒在中枢神经系统中有共同的靶细胞，并且神经元感染是 由 Lrp1 介导，Lrp1 是一种新发现的 RVFV 宿主进入因子。布尼亚病毒学的一个关键特征是 由小基因组片段（NS）产生的病毒非结构蛋白的表达。 NS是主要的 宿主细胞抗病毒反应的拮抗剂。每种病毒表达不同的 NSs 蛋白，因此我们进一步 假设每种病毒的神经毒力程度与 NSs 蛋白功能直接相关，其中 RVFV NS 是先天反应最有效的抑制剂。我们高度协作和协同的团队由以下人员领导 Amy Hartman 博士（PI），RVFV 发病机制专家，Anita McElroy 博士（Co-I），分子病毒学家 Gaya Amarasinghe 博士 (Co-I) 是一位生物化学家，在新兴病毒性疾病方面拥有丰富的专业知识。 宿主与病原体相互作用方面的专业知识。另外两位 Co-I 是 Leonard D’Aiuto 博士和 Zachary Wills 博士， 他们分别是人类神经元病毒感染和啮齿动物神经生物学方面的专家。这个R01提案 代表了一种多学科方法，以增进我们对布尼亚病毒与大脑相互作用的理解。