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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

基本信息

批准号：
10264958
负责人：
Xiaoyun Wang
金额：
$ 7.18万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
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/10264958
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 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 infection 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

项目摘要

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.

项目总结/摘要季节性流感每年在全世界造成25 - 50万人死亡，流行病年份尽管每年都在开发流感疫苗，但只有49%的美国人口接种了流感疫苗。在2010-2011年接种了疫苗的受试者中，并不是所有受试者都对这些疫苗产生了强有力的保护性免疫应答。目前的抗病毒药物（如奥司他韦）仅针对病毒，不能预防流感相关死亡在所有个人中。因此，迫切需要开发更有效的治疗方法，以限制死亡率，与甲型流感病毒（IAV）感染相关的高卫生保健负担。MMP-8切割前体，炎症介质调节炎症反应的各种刺激，但其贡献的 IAV疾病的发病机制尚未评估。我的小说初步数据将矩阵金属蛋白酶-8（Mmp-8）对感染IAV动物的不良结局的影响。血浆MMP-8水平是在诊断为大流行性H1N1和季节性IAV感染的患者中显著上调，与PaO 2/FiO 2比值呈负相关。Mmp-8肺水平也在H1N1患者的肺中增加，感染WT小鼠，并定位于气道上皮细胞和气道巨噬细胞。与WT小鼠相比， Mmp-8-/-小鼠具有降低的H1N1 IAV诱导的死亡率;降低的肺病毒负荷;增加的肺病毒水平。 I型干扰素（IFN）和活化的M1巨噬细胞的产物，以及增加的病毒性感染的上皮细胞因此，我们的数据首次确定MMP-8作为一种新的治疗靶点，严重的IAV感染。这个博士后奖学金的目标是测试中心假设：Mmp-8 白细胞（巨噬细胞）缺乏可降低IAV感染者的肺病毒负荷并改善其预后通过增加小鼠：1）M1巨噬细胞极化以诱导更有效的（Th 1）适应性免疫对IAV的反应; 2）肺巨噬细胞I型IFN反应;和3）I型IFN诱导的IAV的坏死性凋亡。感染的上皮细胞，以限制IAV病毒的复制和传播。小分子MMP-8抑制剂不是具有选择性和脱靶毒性作用。我们的研究还将确定一种新型纳米抗体选择性抑制该宿主蛋白的抑制剂（Nb14_NbAlb）在以下临床前模型中具有治疗功效： IAV感染。这些研究的成功完成将为未来的IND使能研究铺平道路，靶向宿主反应以降低发病率的“一流”治疗剂的安全性和有效性，与严重IAV感染相关的死亡率。