Innate Immune Sensing of Rift Valley Fever Virus

裂谷热病毒的先天免疫感应

• 批准号: 8070135
• 负责人: Amy G Hise
• 金额: $ 1.57万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2011-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8070135
• 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; immune activation; 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）：本试验项目将使用已建立的人源转化细胞系和特定基因敲除小鼠的鼠细胞，通过阐述体外对裂谷热病毒（RVFV）的早期细胞应答的分子组分，确定宿主对A类生物防御病原体（RVFV）应答的关键先天免疫途径。在非洲和阿拉伯半岛的半干旱地区，RVFV在野生动物和家畜中每8年发生一次自然流行。这些暴发与受影响牲畜的高死亡率有关，并且通常与RVFV相关人类疾病的同时流行有关。在这种情况下，通过昆虫叮咬或气雾剂吸入传播给人类，这发生在暴露于RVFV感染动物的体液期间。根据最近在肯尼亚的工作，我们已经确定RVFV传播给人类的程度比以前怀疑的要大得多，无论是在流行期间还是在流行期间，在受威胁的人类社区中RVFV感染的终生风险高达25%。对RVFV的天然免疫尚未得到广泛表征。在RVFV感染的动物模型中，已经确定了早期I型干扰素（IFN）应答的强保护作用。此外，在人类感染中，IFN应答的延迟发作与RVFV诱导的临床疾病的更严重形式相关。Toll样受体（TLR）构成一类膜结合的、种系编码的模式识别受体（PRR），其能够检测病毒颗粒或病毒复制产物，并刺激早期IFN应答。另一类细胞质分子最近被牵连在病毒诱导的IFN基因调控。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），两种DExD/H盒RNA解旋酶含有蛋白相互作用半胱天冬酶募集和激活结构域（CARD）并识别特异性病毒产物。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是至关重要的，作为在人类感染过程中发生的早期保护性和/或疾病介导的免疫应答的一部分。具体地，我们的目标是1）确定TLR或RNA解旋酶各自的共同接头信号传导在RVFV复制和先天免疫激活中的相对作用，2）确定参与RVFV诱导的I型IFN和炎性细胞因子应答的特异性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、基于人群的项目，该项目将提交给NIAID以获得校外资助。我们提出了高度相关的研究，以确定先天免疫受体和参与早期宿主防御裂谷热病毒的途径。裂谷热病毒（RVFV）是布尼亚病毒科的一种白蛉病毒，根据其在故意释放的情况下对北美公共卫生和农业的严重影响，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，RVFV在野生动物和家畜中每8年发生一次自然流行。这些暴发与受影响牲畜的高死亡率有关，并且通常与RVFV相关人类疾病的同时流行有关。根据最近在肯尼亚的工作，我们已经确定RVFV传播给人类的程度比以前怀疑的要大得多，无论是在流行期间还是在流行期间，在受威胁的人类社区中RVFV感染的终生风险高达25%。