Mucosal innate immune defense to Rift Valley fever virus

针对裂谷热病毒的粘膜先天免疫防御

• 批准号: 8070132
• 负责人: Amy G Hise
• 金额: $ 1.4万
• 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/8070132
• 关键词: Acute; Aerosols; Affect; African; Agriculture; Attenuated; Bite; Blood; Body Fluids; Breathing; Bunyaviridae; Categories; Cell secretion; Cells; Cessation of life; Clinical; Culicidae; Disease; Dose; Encephalitis; Epithelial Cells; Epithelium; Event; Exposure to; Family; Fever; Food Contamination; Genus Phlebovirus; Germ Lines; Histopathology; Host Defense; Human; Immune; Immune response; Immunity; Immunologic Receptors; In Vitro; Individual; Infection; Inflammatory Response; Inflammatory Response Pathway; Interferons; Lead; Livestock; Lung; Madagascar; Mediating; Modeling; Molecular; Mucosal Immunity; Mucous Membrane; Mus; Natural Immunity; North America; Oral; Oral mucous membrane structure; Organ; Parents; Pathogenesis; Pathology; Pathway interactions; Pattern; Pattern recognition receptor; Prevention; Production; Public Health; RNA Helicase; Research; Respiratory Tract Infections; Retinitis; Rift Valley fever virus; Role; Route; Saudi Arabia; Severities; Signal Transduction; Spleen; Time; Toll-like receptors; Viral; Viral Hemorrhagic Fevers; Viral Proteins; Viremia; Virulence; Virulence Factors; Virus; Virus Diseases; Yemen; aerosolized; base; biodefense; cell motility; cell type; chemokine; cytokine; defined contribution; early onset; epizootic; human disease; immunogenicity; in vivo; lymph nodes; member; mutant; novel; pathogen; permissiveness; reconstitution; respiratory; response; tool; transmission process; virus tropism

DESCRIPTION (provided by applicant): This study will define mucosal virulence and mechanism of innate immune host defense against aerosolized Rift Valley fever virus, a Category A biodefense pathogen. Rift Valley Fever virus (RVFV) is designated a priority pathogen based upon its projected severe impact on public health and agriculture in North America in the event of a deliberate release. Transmission to humans can occur either by mosquito bite, food contamination or aerosol inhalation during exposure to body fluids of RVFV-infected livestock. Whether the transmission route determines the severity of human RVF is not well defined, nor is it known which route is of primary importance during epizootics. Human RVF disease manifests most commonly as an acute self-limiting febrile illness, but can also lead to encephalitis, retinitis, and hemorrhagic fever. When hemorrhagic disease occurs, it usually begins on day 3 of illness; this acute onset of severe disease suggests an important role for innate immunity in defining human RVF disease manifestations. The mechanisms of aerosolized RVFV infection and mucosal immunity that are critical for protective immunity are poorly understood. In human infection, a delayed onset of type I IFN production is associated with the more severe forms of RVFV-induced clinical disease. Members of the Toll-like receptor (TLRs) and RNA helicase families are germ-line encoded pattern-recognition receptors (PRRs) capable of detecting viral pathogen associated molecular patterns (PAMPs). When activated, PRRs stimulate type I IFN and other inflammatory cytokine responses to control viral replication and disease. We propose to define RVFV virulence and innate immune responses in different mucosal cell types hypothesized to be critical for host defense against aerosolized RVFV. Therefore, we will develop in vitro human and murine models of aerosolized RVFV infection to define the role of innate PRRs in mucosal responses and clinical disease pathogenesis. We hypothesize that type I IFN responses to RVFV infection in the oral and pulmonary mucosa is directed by innate PRRs of infected epithelial cells and localized immune cells, and that the intensity and duration of this response is dependent on viral dose, mucosal cell permissiveness and immune cell migration. Specifically, we aim to define innate immunity to RVFV infection in human mucosa and to define the role of nonstructural RVFV proteins NSs and NSm in infection and the innate immune response utilizing a murine model of aerosolized attenuated RVFV infection. 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. Transmission to humans can occur either by mosquito bite, food contamination or aerosol inhalation. Human RVF disease manifests most commonly as an acute self-limiting febrile illness, but can also lead to encephalitis, retinitis, and hemorrhagic fever. Our studies to define mucosal innate immune responses to RVFV are novel, relevant and have potential to expand prevention and treatment options. Additionally, the research tools that we develop, including a murine inhalation model will have wider applicability to the study of viruses transmitted via a respiratory route.

描述（由申请人提供）：本研究将定义粘膜毒力和先天免疫宿主防御抗雾化的裂谷谷热病毒的机理，这是一种生物固定病原体的类别。 Rift Valley Fever病毒（RVFV）被指定为重点病原体，其预计在故意释放的情况下对北美的公共卫生和农业的严重影响。在暴露于RVFV感染的牲畜体液时，可以通过蚊子咬伤，食物污染或气溶胶吸入来传播。传输途径是否确定人RVF的严重程度不是很好的定义，也不知道哪种途径在Epizootics期间起主要重要性。人RVF疾病最常表现为急性自限制的热疾病，但也可能导致脑炎，视网膜炎和出血热。当出血性疾病发生时，通常从疾病的第3天开始。这种严重疾病的急性发作表明，先天免疫在定义人RVF疾病表现方面的重要作用。对保护性免疫至关重要的雾化RVFV感染和粘膜免疫的机制知之甚少。在人类感染中，I型IFN产生的延迟发作与RVFV诱导的临床疾病的更严重形式有关。 Toll样受体（TLR）和RNA解旋酶家族的成员是能够检测病毒病原体相关分子模式（PAMP）的种系编码模式识别受体（PRR）。激活后，PRR刺激I型IFN和其他炎症细胞因子对控制病毒复制和疾病的反应。我们建议在不同的粘膜细胞类型中定义RVFV的毒力和先天免疫反应，认为这对于宿主防御了抗气溶性RVFV至关重要。因此，我们将开发雾化RVFV感染的体外人和鼠模型，以定义先天PRR在粘膜反应和临床疾病发病机理中的作用。我们假设IFN对口服和肺粘膜中RVFV感染的反应是由感染上皮细胞和局部免疫细胞的先天PRR指导的，并且这种反应的强度和持续时间取决于病毒剂量，粘膜细胞允许和免疫细胞的迁移。具体而言，我们旨在确定对人粘膜中RVFV感染的先天免疫力，并通过使用雾化的减弱的RVFV感染的鼠模型来定义非结构性RVFV蛋白NS和NSM在感染中的作用以及先天免疫反应。我们提出了高度相关的研究，以定义针对Rift Valley Fever病毒的早期宿主防御涉及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。可以通过蚊子咬伤，食物污染或气溶胶吸入来传播人类。人RVF疾病最常表现为急性自限制的热疾病，但也可能导致脑炎，视网膜炎和出血热。我们定义对RVFV的粘膜先天免疫反应的研究是新颖的，相关的，并且具有扩展预防和治疗选择的潜力。此外，我们开发的研究工具（包括鼠吸入模型）将对通过呼吸道传播的病毒的研究更广泛地适用。