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.

项目概要/摘要 布尼亚病毒是与全球健康相关的多种动物和人类病原体。 尽管序列不同，但病毒家族仍具有相似的基因组和蛋白质组织。 这些媒介传播病毒的共同点是能够引起中枢神经系统 (CNS) 疾病 缺乏大脑中关键靶细胞的定义及其影响。 病毒感染对大脑微环境的影响是我们对布尼亚病毒了解的主要限制 神经发病机制也限制了我们制定对策的能力。 细胞感染尚不清楚，神经系统疾病的病毒决定因素尚未确定。 鉴于此限制，我们提出对 3 个医学上重要的原型的神经发病机制进行比较分析 新兴的布尼亚病毒并确定相关神经元细胞感染和发病机制的贡献者。 克罗斯病毒 (LACV) 发现于北美，是该地区小儿病毒性脑炎的主要原因。 美国。裂谷热病毒（RVFV）是世界卫生组织的重点疾病，导致出血热暴发。 和整个非洲的脑炎（OROV），在南美洲发现并导致更多。 由于缺乏直接比较，超过 30 次大型流行病导致超过 50 万例人类发热病例。 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，包括分子机制 该提案将对所有 3 种病毒的中枢神经系统细胞趋向性进行比较分析， 使用我们最近的新型体外和离体模型系统研究先天免疫反应和细胞死亡途径。 已发表的数据表明，宿主细胞蛋白 LDL 受体相关蛋白 1 (Lrp1) 对于高效 Lrp1 在 LACV 感染中的作用的初步数据进一步支持了 RVFV 和 OROV 的细胞感染。 我们勇敢地承认，这些神经毒力病毒具有重叠的目标。 中枢神经系统细胞介导的由宿主细胞蛋白Lrp1产生的病毒非结构蛋白。 基因组片段（NSs）作为宿主细胞抗病毒反应的主要拮抗剂和关键调节剂 我们进一步探究，每种病毒的神经毒力程度与NSs蛋白有关。 我们高度协作和协同的团队由 Amy Hartman 博士 (PI) 领导，她是该领域的专家。 RVFV 的发病机制和 Gaya Amarasinghe 博士（Co-I），一位在宿主病原体方面具有专业知识的生物化学家 另外两位 Co-I 是 Leonard D’Aiuto 博士和 Zachary Wills 博士，他们是病毒感染方面的专家。 R01 提案分别代表了人类神经元和啮齿动物神经生物学的多学科研究。 提高我们对布尼亚病毒与神经元相互作用的理解的方法。