Mechanistic Insights of TIMP-1 in Influenza Virus Infection

TIMP-1 在流感病毒感染中的机制见解

• 批准号: 10431082
• 负责人: Xiaoyun Wang
• 金额: $ 7.55万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10431082
• 关键词: 18 year old; Activated Lymphocyte; Acute Lung Injury; Antiviral Agents; Apoptotic; Attenuated; B-Cell Activation; B-Lymphocytes; Bacterial Pneumonia; Biological Response Modifiers; Blood Vessels; Blood capillaries; Body Weight decreased; Capillary Permeability; Cell Proliferation; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Data; Development; Diagnosis; Epidemic; Extracellular Matrix; Extracellular Matrix Degradation; Future; Goals; Healthcare; Immune response; Immunofluorescence Immunologic; Impairment; In Vitro; Individual; Inflammatory Response; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A virus; Investigational Drugs; Knowledge; Link; Lung; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Measures; Mediating; Morbidity - disease rate; Multiple Organ Failure; Mus; Myofibroblast; Oseltamivir; Outcome; Oxygen; Pathogenesis; Patients; Peptide Hydrolases; Plasma; Proteins; Pulmonary Inflammation; Regulation; Role; Seasons; Severities; Stains; Structure of parenchyma of lung; T-Lymphocyte; Testing; Tissue Inhibitor of Metalloproteinase-1; Vaccinated; Vaccinee; Vaccines; Viral Proteins; Virus; Virus Diseases; Virus Replication; Wild Type Mouse; adaptive immune response; base; care burden; cell type; cytokine release syndrome; effective therapy; experimental study; human subject; influenza infection; influenza virus vaccine; insight; lung injury; mortality; new therapeutic target; novel; pandemic disease; prevent; protective effect; recruit; safety testing; seasonal influenza; therapeutic target; transdifferentiation; vaccine development

PROJECT SUMMARY/ ABSTRACT Influenza A virus (IAV) epidemics are associated with high morbidity and mortality. Complications such as the development of secondary bacterial pneumonia and cytokine storm leading to multi-organ failure increase morbidity and mortality. Although vaccines are developed annually for emerging IAV strains, not all subjects are vaccinated or able to mount robust protective immune responses to the vaccines. Anti-viral drugs such as oseltamivir are not fully effective at preventing mortality associated with severe IAV infections. Thus, there is an urgent need to identify new therapeutic targets to facilitate the development of more effective antiviral agents to limit the high global healthcare burden associated with IAV infections. TIMP-1 (tissue inhibitor of metalloproteinases 1) controls the enzymatic activity of matrix metalloproteinases (MMPs) and is well-known for regulating extracellular matrix (ECM) turnover, but its contributions to the pathogenesis of IAV disease have not been deeply explored. Our novel preliminary data showed that plasma TIMP-1 levels are significantly upregulated in patients diagnosed with pandemic H1N1 and seasonal IAV infections, and levels correlate inversely with the PaO2/FiO2 ratio. Furthermore, our data using immunofluorescence staining suggested TIMP- 1 is dramatically induced in lipofibroblasts. Compared with WT mice, Timp-1-/- mice have reduced H1N1 IAV- induced body weight loss; mortality; lung injury; increased adaptive immune responses and T cell and B cell activation, and attenuated capillary leak. Based on our data, TIMP-1 might serve as a novel therapeutic target during serious IAV infection. The experiments proposed in this application aim to 1) identify the regulation and function of TIMP-1 during the IAV infection; 2) provide novel insights into the mechanism by which Timp-1 deficiency provides better outcomes during IAV infection. Successful completion of these studies will pave the way for future investigational new drug (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 infection.

项目概要/摘要 甲型流感病毒 (IAV) 流行与高发病率和死亡率有关。并发症如 继发性细菌性肺炎和细胞因子风暴的发展导致多器官衰竭增加 发病率和死亡率。尽管每年都会针对新出现的 IAV 毒株开发疫苗，但并非所有受试者 已接种疫苗或能够对疫苗产生强大的保护性免疫反应。抗病毒药物如 奥司他韦在预防与严重 IAV 感染相关的死亡方面并不完全有效。因此，有 迫切需要确定新的治疗靶点，以促进更有效的抗病毒药物的开发 限制与 IAV 感染相关的全球高医疗负担的药物。 TIMP-1（组织抑制剂 金属蛋白酶 1) 控制基质金属蛋白酶 (MMP) 的酶活性，这是众所周知的 调节细胞外基质 (ECM) 周转，但其对 IAV 疾病发病机制的贡献 没有被深入探讨。我们新的初步数据表明血浆 TIMP-1 水平显着 在诊断为大流行性 H1N1 和季节性 IAV 感染的患者中表达上调，且水平相关 与 PaO2/FiO2 比率成反比。此外，我们使用免疫荧光染色的数据表明 TIMP- 1 在脂肪成纤维细胞中显着诱导。与 WT 小鼠相比，Timp-1-/- 小鼠的 H1N1 IAV- 减少 引起体重减轻；死亡;肺损伤；增强适应性免疫反应以及 T 细胞和 B 细胞 激活，并减弱毛细血管渗漏。根据我们的数据，TIMP-1可能作为一个新的治疗靶点 严重 IAV 感染期间。本申请中提出的实验旨在 1) 确定调节和 TIMP-1在IAV感染过程中的功能； 2) 提供对 Timp-1 作用机制的新颖见解 缺乏可在 IAV 感染期间提供更好的结果。成功完成这些研究将为 未来研究性新药（IND）研究的方式，以测试“一流”的安全性和有效性 针对宿主反应的治疗，以降低与严重 IAV 相关的发病率和死亡率 感染。