Collectin-Mediated Defense Against Influenza

集合素介导的流感防御

• 批准号: 7571650
• 负责人: Kevan L Hartshorn
• 金额: $ 38.17万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-12-12 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7571650
• 关键词: Alveolus; Anatomy; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antiviral Agents; Antiviral Response; Apoptotic; Binding; Birds; Carbohydrates; Cell Culture Techniques; Cells; Collectins; Data; Defensins; Epithelial Cells; Epithelium; Functional disorder; Genes; Genetic; Genetic Variation; Goals; Health; Human; Immune; Immune response; Immunity; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Influenza; Influenza A virus; Life Cycle Stages; Lung; Mediating; Modeling; Molecular; Monitor; Mus; Neuraminidase; Oxidants; Pathology; Phase; Play; Prevention strategy; Property; Proteins; Pulmonary Surfactant-Associated Protein D; Recombinants; Relative (related person); Resistance; Respiratory Burst; Role; Severities; Signal Transduction; Site; Structure of respiratory epithelium; Testing; Time; Variant; Viral; Virus Diseases; Virus Replication; Weight Gain; Wild Type Mouse; glycoprotein 340; in vivo; in vivo Model; indexing; lung injury; mutant; neutrophil; pandemic disease; prevent; receptor; resistant strain; respiratory; response; scavenger receptor; superinfection; uptake

Influenza A virus (IAV) is a major threat due to evasion of adaptive immunity through genetic variation. Innate defenses, including surfactant protein D (SP-D) are critical in the early phase IAV infection. Our core hypothesis is that SP-D inhibits IAV infectivity directly and also reduces inflammatory responses during IAV infection through effects on respiratory epithelium and polymorphonuclear neutrophils (PMNs). We aim to determine how these effects relate and which is most important. Aim 1 will examine how SP-D modulates infection of respiratory epithelium in vitro and in vivo. We will make use of SP-D-resistant and -senstive IAV strains and conditionally SP-D gene-deleted (SP-D -/-) mice to clarify how SP-D inhibits IAV replication and how this relates to reduction of inflammatory responses by SP-D. In vitro studies of IAV infection in respiratory epithelial cells will determine in detail how SP-D modulates the viral life cycle and cell signaling. Aim 2 will make use of a panel of recombinantly modified forms of SP-D to determine which molecular features of SP-D are critical for antiviral and anti-inflammatory activities. These recombinant SP-D variants will be tested both in vitro (in human respiratory cell culture) and in vivo using instillation and genetic rescue to correct abnormalities in the antiviral response of conditional SP-D -/- mice. Our hypothesis is that multimerzation and saccharide binding properties of SP-D are both important in determing its antiviral and anti-inflammatory effects, and that the constructs will help separate out these efects. Aim 3 will determine how SP-D downregulates PMN influx during IAV infection and the contribution of PMNs to lung injury or control of viral replication in vivo. In vitro studies with human PMNs will determine how SP-D modulates the uptake of IAV by PMNs and how SP-D modulates respiratory burst responses of lAV-infected PMNs. SP-D can eitehr increase or reduce respiratory burst responses of lAV-treated PMNs in vitro depending on sequence of addition of SP-D and IAV to the cells. The role of specific PMN receptors for IAV and SP-D in these effects will be evaluated. Aim 4 will evaluate two other innate immune proteins that have antiviral activity in their own right but also bind to, and modify function of SP-D. These are scavenger receptor rich glycoprotein 340 (gp340) and human neutronphil defensins (HNPs). These studies should elucidate important aspectsof defense against IAV and be relevant to treatment and prevention strategies.

甲型流感病毒（IAV）是通过遗传变异逃避适应性免疫的主要威胁。