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: 7712717
• 负责人: Amy G Hise
• 金额: $ 24.32万
• 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: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7712717
• 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(申请人提供)：这项研究将确定粘膜毒力和天然免疫宿主防御气雾化裂谷热病毒的机制，气雾化裂谷热病毒是一种A类生物防御病原体。裂谷热病毒(RVFV)被指定为优先病原体，因为如果故意释放病毒，预计会对北美的公共卫生和农业造成严重影响。在接触受RVFV感染的牲畜的体液期间，可通过蚊子叮咬、食物污染或吸入气雾剂向人类传播。传播途径是否决定人类裂谷热的严重程度还没有很好的定义，也不知道哪条途径在流行性出血热期间是首要的。人类裂谷热最常见的表现是一种急性自限性发热性疾病，但也可导致脑炎、视网膜炎和出血热。当出血性疾病发生时，通常在发病第3天开始；这种严重疾病的急性发作表明，先天免疫在确定人类裂谷热疾病的表现方面发挥了重要作用。RVFV雾化感染和粘膜免疫对保护性免疫至关重要的机制还知之甚少。在人类感染中，I型干扰素产生延迟与RVFV引起的更严重的临床疾病有关。Toll样受体(TLRs)和RNA解旋酶家族的成员是胚系编码的模式识别受体(PRRs)，能够检测病毒病原体相关分子模式(PAMPs)。当被激活时，PRRs刺激I型干扰素和其他炎性细胞因子反应，以控制病毒复制和疾病。我们建议定义RVFV毒力和不同粘膜细胞类型的先天免疫反应，这些细胞类型被认为是宿主抵御雾化RVFV的关键。因此，我们将建立体外人和小鼠RVFV雾化感染模型，以确定先天PRRs在粘膜反应和临床疾病发病机制中的作用。我们假设，口腔和肺粘膜对RVFV感染的I型干扰素反应是由感染的上皮细胞和局部免疫细胞的固有PRR决定的，这种反应的强度和持续时间取决于病毒剂量、粘膜细胞的通透性和免疫细胞的迁移。具体地说，我们的目标是确定人粘膜对RVFV感染的先天免疫，并利用雾化减毒RVFV感染的小鼠模型来确定非结构RVFV蛋白NSS和NSM在感染和先天免疫反应中的作用。我们提出了高度相关的研究，以确定参与裂谷热病毒早期宿主防御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喉病毒，被指定为A类生物防御病原体，因为如果故意释放，它将对北美的公共卫生和农业造成严重影响。传播给人类可能通过蚊子叮咬、食物污染或吸入气雾剂发生。人类裂谷热最常见的表现是一种急性自限性发热性疾病，但也可导致脑炎、视网膜炎和出血热。我们的研究确定了针对RVFV的粘膜先天免疫反应是新颖的、相关的，并有可能扩大预防和治疗选择。此外，我们开发的研究工具，包括小鼠吸入模型，将对通过呼吸道传播的病毒的研究具有更广泛的适用性。