Comparative Analysis of Bunyavirus Neuropathogenesis

布尼亚病毒神经发病机制的比较分析

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要 Bunya病毒是一个大型，潜水的媒介传播病毒，具有引起神经系统疾病的能力有发病率和死亡率。我们对BUNYAVIRUS的基本科学理解的主要局限性神经病生成的步骤是从大脑中的关键靶细胞没有完全定义的事实，因此效应靶细胞上的感染尚不清楚，导致神经系统疾病的病毒决定剂尚未被描绘了。广播公司了解Bunyavires如何与中枢神经系统（CNS）相互作用，包括宿主 - 病毒相互作用的分子机制生存中的疾病和长期后遗症。在这里，我们提出了基本的比较分析 3个重要的新兴Bunyaviruses的神经病发生：Rift Valley Fever（RVFV），Oropouche（Orov）和 La Crosse（LACV）。这些病毒中的每一种都有可能引起严重神经疾病在人类中。然而，我们对Bunyavirus神经病发生的理解仍然存在很大的差距，包括有助于疾病的分子机制。限制是缺乏先前研究的严格性是发表的这些病毒的研究由于使用不同的体外细胞系统和不同的小鼠模型，包括年龄和感染途径的变化。我们将直接解决这个差距比较RVFV，OROV和LACV诱导的CNS细胞向量，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。鉴于潜在的潜力bunyavirus会引起在人类病例的一部分中，神经后遗症，以及所有3个在神经小鼠模型中均致命的事实，我们假设潜水的Bunyavirus在中枢神经系统中具有共同的靶细胞，并且神经元感染是由LRP1介导，RRP1是RVFV的新识别的主机进入因子。 Bunyaviral病毒学的一个关键特征是由小基因组段（NSS）产生的病毒非结构蛋白的表达。 NSS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病毒程度与NSS蛋白功能直接相关，而RVFV NSS是先天反应的最潜在抑制剂。我们高度协作和协同的团队由 RVFV发病机理的专家Amy Hartman博士，Anita McElroy博士（CO-I），一名分子病毒学家和具有新兴病毒疾病专业知识的免疫学家，Gaya Amarasinghe博士（CO-I），一位生物化学家，宿主 - 病原体相互作用方面的专业知识。伦纳德·D'Aiuto博士和Zachary Wills博士是另外两个共同体，分别是人类神经元和啮齿动物神经生物学病毒感染的专家。此R01提案代表了一种多学科的方法，可以促进我们对Bunyavirus与大脑相互作用的理解。