Mechanisms of Neuronal Infection by Prototype Emerging Bunyaviruses

原型新兴布尼亚病毒感染神经元的机制

• 批准号: 10728597
• 负责人: Amy L Hartman
• 金额: $ 77.24万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-07 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10728597
• 关键词: Affect; Africa; Animals; Antiviral Response; Binding; Biological Models; Brain; Bunyavirales; Bunyavirus Infections; Cell Death; Cells; Central Nervous System; Central Nervous System Diseases; Central Nervous System Infections; Childhood; Complement; Data; Dependence; Disease; Disease Outbreaks; Encephalitis; Epidemic; Family; Fever; Genome; Genomic Segment; Geographic Locations; Goals; Health; Human; Immune; Immune response; In Vitro; Individual; Infection; Innate Immune Response; Insect Vectors; Integration Host Factors; Knowledge; LDL-Receptor Related Protein 1; LDL-Receptor Related Proteins; La Crosse virus; Ligands; Mediating; Medical; Molecular; Morbidity - disease rate; Mus; National Institute of Allergy and Infectious Disease; Neurobiology; Neurons; Neuropathogenesis; North America; Oropouche virus; Orthobunyavirus; Pathogenesis; Pathway interactions; Periodicals; Productivity; Proteins; Publishing; Research; Rift Valley fever virus; Rodent; Role; Slice; South America; Tropism; United States; Universities; Viral; Viral Encephalitis; Viral Hemorrhagic Fevers; Viral Nonstructural Proteins; Virulent; Virus; Virus Diseases; Washington; Work; antagonist; climate change; comparative; global health; human pathogen; induced pluripotent stem cell; innate immune pathways; interdisciplinary approach; loss of function; mortality; multidisciplinary; mutant; nerve stem cell; nervous system disorder; neuroinflammation; neuropathology; neurovirulence; novel; pandemic preparedness; pathogen; protein function; prototype; response; stem; transcriptomics; vector-borne

PROJECT SUMMARY/ABSTRACT Bunyaviruses are a diverse group of animal and human pathogens of global health relevance. Bunyavirales order encompasses viral families with similar genome and protein organization despite divergent sequences. Common to these vector-borne viruses is the ability to cause central nervous system (CNS) disease with concomitant morbidity and occasional mortality. Lack of definition of key target cells in the brain and the effect of virus infection on the brain microenvironment are major limitations in our knowledge of bunyavirus neuropathogenesis that has also limited our ability to develop countermeasures. The consequences of target cell infection are unknown, and viral determinants of neurologic disease have not been delineated. To overcome this limitation, we propose a comparative analysis of the neuropathogenesis of 3 medically important prototype emerging bunyaviruses and define contributors to infection and pathogenesis in relevant neuronal cells. La Crosse virus (LACV) is found in North America and is the primary cause of pediatric viral encephalitis in the United States. Rift Valley Fever virus (RVFV), a WHO Priority Disease, causes outbreaks of hemorrhagic fever and encephalitis throughout Africa. Oropouche virus (OROV), is found in South America and has caused more than 30 large epidemics resulting in over 500,000 human cases of febrile illness. Due lack of direct comparisons, substantial gaps remain in our understanding of bunyavirus neuropathogenesis, including molecular mechanisms. This proposal will provide comparative analysis of all 3 viruses with regards to CNS cell tropism, innate immune responses, and cell death pathways using novel in vitro and ex vivo model systems. Our recently published data shows that the host cell protein LDL-receptor related protein 1 (Lrp1) is important for efficient cellular infection by RVFV and OROV. Preliminary data on the role of Lrp1 in LACV infection further supports similar tropisms by divergent viruses. We hypothesize that these neurovirulent viruses share overlapping target cells in the CNS mediated by the host cell protein Lrp1. Viral non-structural protein produced from the small genome segment (NSs) functions as the main antagonist of host cell antiviral responses and a key modulator during infection. We further hypothesize that the degree of neurovirulence of each virus is related to NSs protein function. Our highly collaborative and synergistic team is led by Dr. Amy Hartman (PI), an expert in the pathogenesis of RVFV and 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, 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 neurons.

项目摘要/摘要 Bunyasavirus是一群属于全球健康相关性的动物和人类病原体的潜水者。 Bunyaviruses 秩序包括具有相似基因组和蛋白质组织目的地序列的病毒家族。 这些载体传播病毒常见的是引起中枢神经系统（CNS）疾病的能力 随之而来的发病率和偶尔死亡率。缺乏对大脑中关键靶细胞的定义及其效果 在大脑微环境上的病毒感染是我们对Bunyavirus的主要局限性 神经病发生也限制了我们发展对策的能力。目标的后果 细胞感染未知，尚未描述神经系统疾病的病毒决定剂。克服 这一局限性，我们提出了3个医学上重要原型的神经病发生的比较分析 新兴的Bunyaviruses并定义了相关神经元细胞感染和发病机理的贡献者。洛杉矶 Crosse病毒（LACV）在北美发现，是小儿病毒脑炎的主要原因 美国。裂谷发烧病毒（RVFV）是一种优先疾病，导致出血热爆发 和整个非洲的脑炎。 Oropouche病毒（OROV）在南美发现，并引起了更多 超过30个大型流行病，导致500,000多人发热的病例。由于缺乏直接比较， 在我们对Bunyavirus神经病发生的理解中，存在很大的差距，包括分子 机制。该提案将对CNS细胞卓越的所有3种病毒提供比较分析， 使用新型体外和体内模型系统的先天免疫反应以及细胞死亡途径。我们最近 发布的数据表明，宿主细胞蛋白LDL受体相关蛋白1（LRP1）对于有效 RVFV和OROV的细胞感染。关于LRP1在LACV感染中作用的初步数据进一步支持 不同的病毒类似的向流。我们假设这些神经病毒病毒共享重叠的靶标 由宿主细胞蛋白LRP1介导的中枢神经系统中的细胞。由小的病毒非结构蛋白 基因组段（NS）充当宿主细胞抗病毒反应的主要拮抗剂和关键调节剂 在感染期间。我们进一步假设每种病毒的神经病毒程度与NSS蛋白有关 功能。我们高度合作和协同的团队由Amy Hartman博士（PI）领导，专家 RVFV和Gaya Amarasinghe博士（CO-I）的发病机理，这是一位具有宿主病原体专业知识的生物化学家 互动。伦纳德·D'Aiuto博士和Zachary Wills博士是另外两个共同体，是病毒感染的专家 人类神经元和啮齿动物神经生物学。该R01提案代表一个多学科 促进我们对Bunyavirus与神经元相互作用的理解的方法。