Innate Immune Sensing of Rift Valley Fever Virus

裂谷热病毒的先天免疫感应

• 批准号: 7513357
• 负责人: Amy G Hise
• 金额: $ 24.84万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-18 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7513357
• 关键词: Aerosols; Affect; Africa; Agriculture; Animal Model; Animals; Area; Attenuated; Binding; Body Fluids; Boxing; Breathing; Bunyaviridae; Caspase; Categories; Cells; Clinical; Collaborations; Communities; Critical Pathways; Data; Dendritic Cells; Development; Disease; Disease Outbreaks; Domestic Animals; Enzyme-Linked Immunosorbent Assay; Epidemic; Event; Exposure to; Extramural Activities; Family; Funding; Funding Mechanisms; Future; Gene Expression Regulation; Genes; Genetic Polymorphism; Genus Phlebovirus; Germ Lines; Host Defense; Human; Immune; Immune response; Immunologic Receptors; In Vitro; Individual; Infection; Inflammatory; Inflammatory Response Pathway; Insect Bites; Interferon Type I; Interferons; Kenya; Knockout Mice; Livestock; Mediating; Membrane; Molecular; Mus; Myelogenous; National Institute of Allergy and Infectious Disease; Natural Immunity; North America; Outcome; Pathway interactions; Pattern recognition receptor; Pilot Projects; Population; Production; Proteins; Public Health; RNA Helicase; Receptor Signaling; Relative (related person); Rift Valley fever virus; Role; Signal Pathway; Signal Transduction; Toll-like receptors; Transformed Cell Line; Tretinoin; Vaccines; Variant; Viral; Viral Nonstructural Proteins; Viral Proteins; Virus; Virus Diseases; Virus Replication; Work; base; biodefense; cell type; cytokine; epizootic; helicase; human disease; inhibitor/antagonist; lifetime risk; melanoma; member; monocyte; mortality; mutant; novel; particle; pathogen; population based; public health relevance; response; transmission process; vaccine candidate

DESCRIPTION (provided by applicant): This pilot project will define the innate immune pathways critical for host response to a Category A biodefense pathogen, Rift Valley Fever Virus (RVFV), by elaborating molecular components of early cellular responses to RVFV in vitro, using established human-derived transformed cell lines and murine cells from specific gene knockout mice. In semi-arid regions of Africa and the Arabian Peninsula, natural epizootics of RVFV occur every ~8 years among wildlife and domestic animals. These outbreaks are associated with high mortality among affected livestock, and are usually associated with simultaneous epidemics of RVFV-associated human disease. In such settings, transmission to humans occurs either by insect bite or aerosol inhalation, which occurs during exposure to body fluids of RVFV-infected animals. Based on recent work in Kenya, we have determined that the extent of RVFV transmission to humans is much greater than previously suspected, both during epidemics and inter-epidemic periods, with up to 25% lifetime risk of RVFV infection in threatened human communities. Innate immunity to RVFV has not been extensively characterized. In animal models of RVFV infection, a strong protective role has been identified for early type I interferon (IFN) responses. In addition, in human infection, a delayed onset of IFN response is associated with the more severe forms of RVFV-induced clinical disease. Toll-like receptors (TLRs) constitute a class of membrane bound, germ-line encoded pattern-recognition receptors (PRRs) capable of detecting viral particles or products of viral replication, and stimulating early IFN responses. Another class of cytoplasmic molecules has recently been implicated in virus-induced IFN gene regulation. Retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (Mda-5)/Helicard), two DExD/H box RNA helicases contain protein interaction caspase recruitment and activation domains (CARD) and recognize specific viral products. We propose to identify critical PRRs and signaling pathways involved in the innate response to Rift Valley Fever virus. We hypothesize that interactions of RVFV with TLRs and/or RIG-I and Mda-5 are critical for the induction of type I IFNs as part of the early protective and/or disease-mediating immune responses that occur during the course of human infection. Specifically our aims are to 1) to define the relative role TLRs or RNA helicase respective common adaptor signaling in RVFV replication and innate immune activation, 2) to define specific TLRs and/or helicases involved in RVFV induced type I IFN and inflammatory cytokine responses. Novel results from the proposed studies will be used to support development of a larger, population-based project to be submitted to NIAID for extramural funding. PUBLIC HEALTH RELEVANCE We proposed highly relevant studies to define the innate immune receptors and pathways involved in early host defense against Rift Valley fever Virus. Rift Valley Fever virus (RVFV), a Phlebovirus in the Bunyaviridae family, is designated a Category A biodefense pathogen based upon its projected severe impact on public health and agriculture in North America in the event of a deliberate release. In semi-arid regions of Africa and the Arabian Peninsula, natural epizootics of RVFV occur every ~8 years among wildlife and domestic animals. These outbreaks are associated with high mortality among affected livestock, and are usually associated with simultaneous epidemics of RVFV-associated human disease. Based on recent work in Kenya, we have determined that the extent of RVFV transmission to humans is much greater than previously suspected, both during epidemics and inter-epidemic periods, with up to 25% lifetime risk of RVFV infection in threatened human communities.

描述（由申请人提供）：该试点项目将通过在体外详细阐述对 RVFV 的早期细胞反应的分子成分，利用已建立的人源转化细胞系和来自特定基因敲除小鼠的鼠细胞。在非洲和阿拉伯半岛的半干旱地区，野生动物和家畜中裂谷热病毒的自然流行每约8年发生一次。这些疫情与受影响牲畜的高死亡率有关，并且通常与裂谷热病毒相关人类疾病的同时流行有关。在这种情况下，病毒可通过昆虫叮咬或气溶胶吸入传播给人类，而气溶胶吸入是在接触感染RVFV的动物的体液时发生的。根据最近在肯尼亚开展的工作，我们确定，无论是在流行期间还是流行期间，RVFV 向人类传播的程度都比之前怀疑的要大得多，在受威胁的人类社区中，RVFV 终生感染风险高达 25%。对 RVFV 的先天免疫尚未得到广泛表征。在 RVFV 感染的动物模型中，已发现早期 I 型干扰素 (IFN) 反应具有强大的保护作用。此外，在人类感染中，IFN 反应的延迟发生与 RVFV 诱发的更严重的临床疾病有关。 Toll 样受体 (TLR) 构成一类膜结合、种系编码的模式识别受体 (PRR)，能够检测病毒颗粒或病毒复制产物，并刺激早期 IFN 反应。最近，另一类细胞质分子与病毒诱导的 IFN 基因调控有关。视黄酸诱导基因-I (RIG-I) 和黑色素瘤分化相关基因 5 (Mda-5)/Helicard)，两个 DExD/H 盒 RNA 解旋酶含有蛋白质相互作用半胱天冬酶募集和激活结构域 (CARD)，并识别特定病毒产品。我们建议确定参与裂谷热病毒先天反应的关键 PRR 和信号通路。我们假设 RVFV 与 TLR 和/或 RIG-I 和 Mda-5 的相互作用对于诱导 I 型 IFN 至关重要，作为人类感染过程中发生的早期保护性和/或疾病介导免疫反应的一部分。具体而言，我们的目标是 1) 定义 TLR 或 RNA 解旋酶各自常见接头信号传导在 RVFV 复制和先天免疫激活中的相对作用，2) 定义参与 RVFV 诱导的 I 型 IFN 和炎症细胞因子反应的特定 TLR 和/或解旋酶。拟议研究的新结果将用于支持开发一个更大的、以人口为基础的项目，该项目将提交给 NIAID 以获得外部资助。公共卫生相关性我们提出了高度相关的研究来定义参与早期宿主防御裂谷热病毒的先天免疫受体和途径。裂谷热病毒 (RVFV) 是布尼亚病毒科的一种白蛉病毒，由于其蓄意释放后预计会对北美公共卫生和农业造成严重影响，因此被指定为 A 类生物防御病原体。在非洲和阿拉伯半岛的半干旱地区，野生动物和家畜中裂谷热病毒的自然流行每约8年发生一次。这些疫情与受影响牲畜的高死亡率有关，并且通常与裂谷热病毒相关人类疾病的同时流行有关。根据最近在肯尼亚开展的工作，我们确定，无论是在流行期间还是流行期间，RVFV 向人类传播的程度都比之前怀疑的要大得多，在受威胁的人类社区中，RVFV 终生感染风险高达 25%。