Innate immune recognition and response to Rift Valley fever virus

对裂谷热病毒的先天免疫识别和反应

• 批准号: 10512807
• 负责人: Anita K McElroy
• 金额: $ 46.95万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-25 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10512807
• 关键词: Acute; Adult; African; Antiviral Response; Area; Biological Response Modifiers; Cell Compartmentation; Cells; Clinical; Data; Disease; Encephalitis; Exhibits; Fever; Genes; Goals; Hematopoietic; Hepatitis; Hepatocyte; Human; IFNAR1 gene; Immune; In Vitro; Infection; Innate Immune Response; Innate Immune System; Interferons; Knowledge; Mediating; Mononuclear; Mus; Natural Immunity; Neurons; Pathogenesis; Phagocytes; Play; Population; Prevention; Primary Infection; Production; Proteins; Recombinants; Research; Rift Valley fever virus; Role; Secondary to; Severity of illness; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; TLR3 gene; TNF gene; Testing; Tissue-Specific Gene Expression; Viral; Viral Pathogenesis; Virus; Virus Diseases; Virus Replication; antagonist; base; cell type; defined contribution; human data; in vivo; innate immune function; innate immune mechanisms; interferon antagonist; macrophage; monocyte; pathogen; prevent; programs; receptor; response; sensor; virus host interaction

Rift Valley fever virus (RVFV) is widespread throughout the entire African continent and in some endemic areas over 50% of the population is exposed by adulthood. Antiviral responses induced by interferon (IFN) signaling can limit RVFV replication and inhibit RVFV pathogenesis in vivo. RVFV is known to infect mononuclear phagocytic cells (MPCs), hepatocytes, and neurons, consistent with its main clinical manifestations of acute febrile illness, hepatitis, or encephalitis. However, it is largely unknown how each of these cell types recognizes and responds to RVFV infection or how cell type specific innate immune responses modulate viral pathogenesis. The overall objective for this proposal is to determine how the mammalian host innate immune system recognizes and responds to RVFV infection and how this modulates viral pathogenesis. Our central hypothesis is that differential innate immune recognition and response by infected cells modulates viral pathogenesis. To test this hypothesis, we will 1) identify the innate immune sensors and effectors active in biologically relevant human primary cells, 2) define the contribution of key innate immune sensors and effectors in recognition and response to RVFV infection in vivo and 3) define the role of hematopoietic cell infection in RVFV pathogenesis in vivo. The results of this research will define the mechanisms of innate immune recognition and response following RVFV infection. Moreover, it will inform on cell type-specific responses to infection and how virally mediated antagonism of those responses contributes to viral pathogenesis.

裂谷热病毒(RVFV)在整个非洲大陆和一些地方性疾病中广泛传播 超过50%的人口在成年前暴露在空气中的地区。干扰素诱导的抗病毒反应 信号转导可以限制RVFV在体内的复制，抑制RVFV的发病。RVFV已知会感染 单核巨噬细胞、肝细胞和神经元，与其主要临床表现一致 急性发热病、肝炎或脑炎的表现。然而，很大程度上还不清楚每一个人是如何 这些细胞类型识别和响应RVFV感染或细胞类型特定的先天免疫反应 调节病毒的致病机制。这项提案的总体目标是确定哺乳动物宿主如何 先天性免疫系统识别RVFV感染并对其做出反应，以及这种感染如何调节病毒的致病机制。 我们的中心假设是受感染细胞的不同先天免疫识别和反应调节 病毒致病机制。为了验证这一假设，我们将1)确定活跃在 生物学上相关的人类原代细胞，2)定义关键的先天免疫感受器和 体内RVFV感染的识别和应答的效应物以及3)造血细胞的作用 RVFV体内感染致病机制的研究这项研究的结果将确定先天的机制 RVFV感染后的免疫识别和反应。此外，它还将通知特定的细胞类型 对感染的反应以及病毒介导的这些反应的拮抗作用如何有助于病毒 发病机制。