MMP-8 Deficiency Improves Host Responses to Influenza Viral Infections

MMP-8 缺乏可改善宿主对流感病毒感染的反应

• 批准号: 10260933
• 负责人: Xiaoyun Wang
• 金额: $ 5.03万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-15 至 2022-05-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10260933
• 关键词: Active Sites; Animals; Antiviral Agents; B-Lymphocytes; Body Weight decreased; CD4 Positive T Lymphocytes; Cell Count; Cessation of life; Cleaved cell; Data; Diagnosis; Epithelial; Epithelial Cells; Epithelium; Fellowship; Future; Goals; Healthcare; Histocompatibility Antigens Class II; Immune response; Individual; Inflammation Mediators; Inflammatory Response; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A virus; Interferon Type I; Interferons; Leukocytes; Link; Lung; Lung diseases; Matrix Metalloproteinases; Morbidity - disease rate; Mus; Neutrophil Collagenase; Oseltamivir; Pathogenesis; Patients; Plasma; Population; Pre-Clinical Model; Proteins; Regimen; Severities; Stimulus; System; Testing; Therapeutic Effect; Time; Toxic effect; Treatment Efficacy; Vaccinated; Vaccines; Viral; Viral Load result; Viral Proteins; Virus; Virus Diseases; Virus Replication; adaptive immune response; adverse outcome; airway epithelium; care burden; effective therapy; human subject; improved; improved outcome; influenza virus vaccine; inhibitor/antagonist; insight; macrophage; macrophage product; mortality; nanobodies; new therapeutic target; novel; pandemic disease; prevent; response; safety testing; seasonal influenza; small molecule; therapeutic evaluation; therapeutic target

Project Summary/ Abstract Seasonal influenza causes 0.25-0.5 million deaths/year world-wide and mortality increases substantially in pandemic years. Although influenza vaccines are developed annually, only 49% of the US population was vaccinated in 2010-2011, and not all subjects develop robust protective immune responses to these vaccines. Current anti-viral drugs (e.g. oseltamivir) target only the virus and do not prevent influenza-associated mortality in all individuals. Thus, there is an urgent need to develop more effective therapies that limit the mortality and high health care burden that are associated with influenza A viral (IAV) infections. MMP-8 cleaves pro- inflammatory mediators to regulate inflammatory responses to various stimuli, but its contributions to the pathogenesis of IAV disease have not been evaluated. My novel preliminary data strongly link Matrix metalloproteinase-8 (Mmp-8) to adverse outcomes in animals infected with IAV. Plasma MMP-8 levels are significantly upregulated in patients diagnosed with pandemic H1N1 and seasonal IAV infections, and levels correlate inversely with the PaO2/FiO2 ratio. Mmp-8 lung levels are also increased in the lungs of H1N1- infected WT mice and localized to airway epithelial cells and airway macrophages. Compared with WT mice, Mmp-8-/- mice have reduced H1N1 IAV-induced mortality; lower lung viral burdens; increased lung levels of type I interferons (IFNs) and products of activated M1 macrophages, and increased necroptosis of virally- infected epithelial cells. Thus, our data identifying MMP-8 for the first time as a novel therapeutic target during serious IAV infections. The goal of this postdoctoral fellowship is to test the central hypotheses: Mmp-8 deficiency in leukocytes (macrophages) reduces lung viral burdens and improves outcomes in IAV-infected mice by increasing: 1) M1 macrophage polarization to induce a more effective (Th1) adaptive immune response to IAV; 2) the lung macrophage type I IFN response; and 3) type I IFN induced-necroptosis of IAV- infected epithelial cells to limit IAV viral replication and spreading. Small molecule MMP-8 inhibitors are not selective and have off-target toxic effects. Our studies will also determine the extent to which a novel nanobody inhibitor (Nb14_NbAlb) that selectively inhibits this host protein has therapeutic efficacy in a pre-clinical model of IAV infection. Successful completion of these studies will pave the way for future IND-enabling studies to test the safety and efficacy of a “first in class” therapeutic targeting the host response to reduce the morbidity and mortality associated with serious IAV infections.

项目摘要/摘要 季节性影响0.25-050万次/年，全球死亡人数大幅增加，死亡率大大增加 大流行年。尽管每年都会发展影响，但美国人口中只有49％是 在2010 - 2011年接种疫苗，并非所有受试者都会对这些疫苗产生强大的保护免疫回报。 当前的抗病毒药物（例如Oseltamivir）仅针对该病毒，并且不能阻止与影响ZA相关的死亡率 在所有个人中。这是迫切需要开发更有效的疗法，以限制死亡率和 与影响力（IAV）感染有关的高医疗保健负担。 MMP-8裂片Pro- 炎症介质调节对各种刺激的炎症反应，但其对 IAV疾病的发病机理尚未评估。我的小说初步数据强烈链接矩阵 金属蛋白酶8（MMP-8）下降了感染IAV的动物的结局。血浆MMP-8级别为 被诊断为大流行H1N1和季节性IAV感染的患者以及水平显着更新 与PAO2/FIO2比率成反比。 H1N1-肺的MMP-8肺水平也升高 感染了WT小鼠，并局部在气道上皮细胞和气道巨噬细胞中。与WT小鼠相比 MMP-8 - / - 小鼠降低了H1N1 IAV诱导的死亡率；下肺病毒伯恩斯；肺部水平增加 I型干扰素（IFN）和活化的M1巨噬细胞的产物，实际上增加了坏死性 感染的上皮细胞。这，我们的数据首次将MMP-8识别为新的热目标 严重的IAV感染。该博士后奖学金的目的是检验中心假设：MMP-8 白细胞（巨噬细胞）的缺乏可减少肺病毒伯恩氏菌，并改善IAV感染的结果 通过增加小鼠：1）M1巨噬细胞极化以诱导更有效的自适应免疫 对IAV的反应； 2）I型肺巨噬细胞反应； 3）I型IFN诱导IAV-诱导的胞菌病 感染上皮细胞以限制IAV病毒复制和扩散。小分子MMP-8抑制剂不是 选择性并具有脱靶的有毒作用。我们的研究还将确定新颖的纳米病的程度 抑制剂（NB14_NBALB）有选择地抑制该宿主蛋白具有治疗效率 IAV感染。这些研究的成功完成将为未来的辅助研究铺平道路测试 针对宿主反应的“首先”治疗的安全性和效率，以降低发病率和 与严重IAV感染相关的死亡率。