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: 7924122
• 负责人: Amy G Hise
• 金额: $ 18.92万
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7924122
• 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雾化裂谷热病毒（一种 A 类生物防御病原体）的机制。裂谷热病毒 (RVFV) 被指定为优先病原体，因为如果故意释放该病毒，预计会对北美的公共卫生和农业造成严重影响。通过蚊虫叮咬、食物污染或接触受 RVFV 感染的牲畜的体液时吸入气溶胶，可传播给人类。传播途径是否决定人类裂谷热的严重程度尚不清楚，也不知道在动物流行期间哪种途径最重要。人类裂谷热疾病最常见地表现为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。当发生出血性疾病时，通常从患病第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类裂谷热疾病表现中发挥着重要作用。对于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 型干扰素产生的延迟与 RVFV 诱发的更严重的临床疾病有关。 Toll 样受体 (TLR) 和 RNA 解旋酶家族的成员是种系编码的模式识别受体 (PRR)，能够检测病毒病原体相关分子模式 (PAMP)。当激活时，PRR 会刺激 I 型 IFN 和其他炎症细胞因子反应，以控制病毒复制和疾病。我们建议定义不同粘膜细胞类型中的 RVFV 毒力和先天免疫反应，假设它们对于宿主防御雾化 RVFV 至关重要。因此，我们将开发雾化RVFV感染的体外人类和小鼠模型，以确定先天PRR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中对 RVFV 感染的 I 型 IFN 反应是由受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、粘膜细胞的容许度和免疫。细胞迁移。具体来说，我们的目标是定义人类粘膜对 RVFV 感染的先天免疫，并利用雾化减毒 RVFV 感染的小鼠模型来定义非结构 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。通过蚊虫叮咬、食物污染或气溶胶吸入可以传播给人类。人类裂谷热疾病最常见地表现为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。我们对 RVFV 粘膜先天免疫反应的研究是新颖的、相关的，并且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，将更广泛地适用于通过呼吸道传播的病毒的研究。