Role of the novel entry factor Lrp1 in in vivo tropism and pathogenesis of Rift Valley fever virus

新型进入因子Lrp1在裂谷热病毒体内趋向性和发病机制中的作用

基本信息

批准号：
10447151
负责人：
Amy L Hartman
金额：
$ 19.51万
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：
2021
资助国家：
美国
起止时间：
2021-07-07 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10447151
关键词：
Address Adenoviruses Affect Africa Albumins Animal Model Animals Binding Biological Bunyaviridae CD209 gene CRISPR/Cas technology Category A pathogen Cattle Cell Surface Receptors Cells Cessation of life Clinical Collaborations Country Cre lox recombination system Culicidae Data Disease Emerging Communicable Diseases Encephalitis Enterobacteria phage P1 Cre recombinase Epidemic Gene Deletion Genetic Glycoproteins Goals Hamsters Heparitin Sulfate Hepatocyte Heterozygote Human In Vitro Infection Injections Insecta Integration Host Factors Knock-out Knockout Mice Knowledge LDL-Receptor Related Protein 1 Lectin Lethal Dose 50 Lipids Liver Liver diseases Livestock LoxP-flanked allele Mediating Molecular Molecular Chaperones Monkeys Mouse Strains Mus Myelogenous Myeloid Cells National Institute of Allergy and Infectious Disease Neurons Outcome Pathogenesis Pathogenicity Pathway interactions Persons Proteins Readiness Reagent Receptor Cell Retinitis Rift Valley fever virus Role Saudi Arabia Sheep Surface Survivors Techniques Testing Tissues Tropism Vaccines Viral Hemorrhagic Fevers Viral Load result Viral Pathogenesis Virulent Virus Virus Diseases World Health Organization Zoonoses base cell type conditional knockout genome-wide global health hepatic necrosis high reward high risk in vivo innovation knockout gene lipid metabolism mosquito-borne mouse model nervous system disorder novel pathogen programs promoter public health emergency receptor receptor expression socioeconomics transmission process virus tropism

项目摘要

PROJECT SUMMARY/ABSTRACT The World Health Organization warns of a pending public health emergency caused by mosquito-borne Rift Valley fever virus (RVFV). RVF is an important disease of domesticated livestock that is zoonotically transmitted to people, where it causes a spectrum of illness from mild to lethal. The significance of RVFV is highlighted by its designation as a NIAID Category A pathogen and its inclusion on the WHO's Blueprint of Priority Diseases, emphasizing the potential impact of RVFV on the global health and economy. Little is known about the entry factors that RVFV uses to infect cells from multiple species. Our rigorous and convincing preliminary data identify a cell surface receptor in the host lipid metabolism pathway that mediates infection of cells by RVFV. This proposal will determine the biological significance of this lipid receptor protein in RVFV disease in mice through conditional knockouts in cell types that are relevant to RVFV infection, including hepatocytes, neurons, and myeloid cells. We will use transient and genetic tissue-specific conditional gene knockouts of the lipid receptor generated using the Cre/Lox system. We hypothesize that eliminating lipid receptor expression in the liver will rescue mice from an otherwise highly lethal infection. We further hypothesize that conditional and tissue-specific gene deletions of the lipid receptor in mice will limit RVFV-associated pathogenic outcomes, including hepatic disease and encephalitis. Our highly collaborative and synergistic team is led by Dr. Amy Hartman (PI), an expert in the pathogenesis of RVFV, and by Dr. Gaya Amarasinghe (Co-I), a biochemist and biophysicist with expertise in host-pathogen interactions. This R21 proposal presents an opportunity to expand upon our collaborative efforts to determine the biological relevance of the RVFV-lipid receptor interaction in the mouse model. Completion of this proposal will have high impact on the field because it is the first in vivo assessment of receptor usage by RVFV. All reagents are available including mouse strains, viruses, and techniques; thus, the feasibility is high.

项目摘要/摘要世界卫生组织警告蚊子出生造成的未决公共卫生紧急情况裂谷发烧病毒（RVFV）。 RVF是驯化牲畜的重要疾病传输给人们，在那里引起各种各样的疾病，从轻度到致命。 RVFV的意义是以其称为NIAID类别的病原体及其属于WHO的蓝图的指定强调优先疾病，强调RVFV对全球健康和经济的潜在影响。鲜为人知关于RVFV用来感染多种物种细胞的进入因子。我们严格而令人信服的初步数据确定宿主脂质代谢途径中的细胞表面受体，该途径介导 RVFV的细胞。该建议将确定RVFV中该脂质受体蛋白的生物学意义通过有条件敲除与RVFV感染相关的细胞类型的小鼠疾病，包括肝细胞，神经元和髓样细胞。我们将使用瞬态和遗传组织特异性条件基因使用CRE/LOX系统产生的脂质受体的敲除。我们假设消除脂质肝脏中的受体表达将使小鼠从原本高致命的感染中拯救小鼠。我们进一步假设小鼠脂质受体的条件和组织特异性基因缺失将限制与RVFV相关的致病结果，包括肝病和脑炎。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（PI）和Gaya Amarasinghe博士（CO-I）领导具有宿主病原体相互作用专业知识的生物化学家和生物物理学家。该R21提案提出了扩大我们协作努力来确定RVFV-lipid的生物学相关性的机会小鼠模型中的受体相互作用。该提案的完成将对该领域产生重大影响，因为这是RVFV对受体使用情况的首次体内评估。所有试剂都可以使用，包括鼠标应变，病毒和技术；因此，可行性很高。