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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.

项目总结/文摘