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）：该试点项目将定义对宿主对生物幻想病原体的反应至关重要的宿主免疫途径，该类别通过使用既定的人类在体面的RVFV对早期细胞反应的早期细胞响应的分子成分，使用既定的人类细胞系和鼠类鼠类的基因敲除特定的基因敲除，这是通过详细阐述对RVFV的早期细胞响应的分子成分。在非洲和阿拉伯半岛的半干旱地区，野生动物和家畜每8年就会发生RVFV的天然Epizootics。这些暴发与受影响的牲畜的死亡率高有关，通常与RVFV相关的人类疾病的同时流行病有关。在这种情况下，向人类传播是通过昆虫咬合或气溶胶吸入发生的，这是在暴露于RVFV感染动物体液时发生的。根据肯尼亚最近的工作，我们确定向人类向人类传播的程度比在流行病和流行期期间的先前怀疑要大得多，在受威胁的人类社区中，RVFV感染的终身风险高达25％。对RVFV的先天免疫尚未得到广泛的特征。在RVFV感染的动物模型中，已经确定了早期I型干扰素（IFN）反应的强大保护作用。此外，在人类感染中，IFN反应的延迟发作与RVFV诱导的临床疾病的更严重形式有关。 Toll样受体（TLR）构成了一类膜结合的，种系编码的模式识别受体（PRR），能够检测病毒复制的病毒颗粒或产物，并刺激早期IFN反应。最近，另一类的细胞质分子与病毒诱导的IFN基因调节有关。视黄酸诱导的基因1（RIG-I）和黑色素瘤分化相关基因5（MDA-5）/螺旋六角），两个DEXD/H盒RNA盒RNA解旋酶包含蛋白质相互作用的caspase caspase募集和激活结构域（CARD）并识别特定病毒产物。我们建议确定对裂谷发烧病毒的先天反应涉及的关键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作为早期保护性和/或中疾病中的免疫反应的一部分至关重要。具体而言，我们的目的是1）定义RVFV复制和先天免疫激活中的相对作用TLR或RNA解旋酶各自的共同衔接子信号传导，2）定义参与RVFV诱导的I型I IFN和炎症细胞因子反应的特定TLR和/或Helicase。拟议研究的新结果将用于支持一个基于人群的大型项目的开发，该项目将提交给NIAID进行壁外资金。我们提出的公共卫生相关性提出了高度相关的研究，以定义与早期宿主防御Rift Valley Fever病毒有关的先天免疫受体和途径。 Rift Valley Fever病毒（RVFV）是Bunyaviridae家族中的一种静脉病毒，在故意释放的情况下，基于其对北美公共卫生和农业的严重影响，被指定为一种生物防腐病原体。在非洲和阿拉伯半岛的半干旱地区，野生动物和家畜每8年就会发生RVFV的天然Epizootics。这些暴发与受影响的牲畜的死亡率高有关，通常与RVFV相关的人类疾病的同时流行病有关。根据肯尼亚最近的工作，我们确定向人类向人类传播的程度比在流行病和流行期期间的先前怀疑要大得多，在受威胁的人类社区中，RVFV感染的终身风险高达25％。