Role of Hypoxia-Inducible Factors (HIFs) in Respiratory Syncytial Virus Infection

缺氧诱导因子 (HIF) 在呼吸道合胞病毒感染中的作用

基本信息

批准号：
10742170
负责人：
Antonella Casola
金额：
$ 24万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-16 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10742170
关键词：
2019-nCoV Acute Acute Lung Injury Anemia Animal Cancer Model Animal Model Antibody Formation Antiviral Response Autoimmunity B-Lymphocytes Cancer Model Cell Survival Cells Cellular Metabolic Process Child Chronic Chronic Kidney Failure Clinical Clinical Trials Collagen Complex Cytokine Gene Data Dendritic Cells Deposition Development Disease Drug Modulation Drug usage Elderly Epithelial Cells Exhibits Flow Cytometry Functional disorder Gene Expression Genetic Genetic Transcription Goals Histopathology Human Hypoxia Hypoxia Inducible Factor Immune Immune response In Vitro Inbred BALB C Mice Infant Infection Inflammation Interleukin-10 Investigation Kinetics Knowledge Laboratories Licensing Lower Respiratory Tract Infection Lung Lung diseases Lung infections Macrophage Malignant Neoplasms Mediating Metabolic Metabolic Pathway Molecular Mucous body substance Mus Outcome Pathogenesis Pathogenicity Patients Phase III Clinical Trials Phenotype Play Population Process Production Productivity Proteins Publications Pulmonary Inflammation Respiratory Syncytial Virus Infections Respiratory Tract Infections Respiratory syncytial virus Role Shapes Signal Transduction Structure T-Lymphocyte Testing Therapeutic Transcription Process Transcriptional Regulation Transforming Growth Factor beta Vaccines Viral Viral Pathogenesis Viral Respiratory Tract Infection Virion Virus Virus Diseases Virus Replication Work airway epithelium airway remodeling antiviral immunity cancer type cytokine drug development experience extracellular factor A high risk hypoxia inducible factor 1 immune activation immunoregulation improved in vivo Model inhibitor lung injury migration mouse model neutrophil novel pharmacologic protective effect pulmonary function respiratory respiratory virus response side effect therapeutically effective tissue regeneration vaccine access

项目摘要

PROJECT SUMMARY/ABSTRACT Several viruses have been shown to induce metabolic reprogramming of host cells to establish productive infections. One common mechanism utilized by viruses is the stabilization of hypoxia-inducible-factors (HIF). The HIF complex, comprised of an inducible α subunit (HIF-1α or HIF-2α) and a constitutively expressed β subunit (HIF-1β), is known to control diverse transcriptional processes in response to hypoxia and other disease states. The use of both HIF inhibitors and stabilizers has been investigated in models of cancer, autoimmunity, and non-infectious acute lung injury, with several compounds for both classes currently being tested in phase 3 clinical trials for a variety of clinical disorders. However, there are no publications describing the use of a HIF specific inhibitors or stabilizers in in vivo models of viral infections. In vitro studies have suggested that inhibiting HIF-1α could represent an effective anti-viral strategy, including against respiratory viruses such as respiratory syncytial virus (RSV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, our preliminary data in a mouse model of RSV infection, the leading cause of severe acute lung illness in infants for which there are no effective therapeutics or licensed vaccines, did not support this strategy, as we found that inhibition of HIF-1α worsen clinical disease and favors viral replication, while stabilization of HIF proteins improves clinical disease and lung function. The central hypothesis of this application is that during RSV infection (and possibly other respiratory viruses) HIFs mediate activation and survival of key immune cells that control antiviral responses while maintaining lung integrity and function. We will test this hypothesis in a well-established mouse model of RSV infection. In Specific Aim 1, we will determine the contributions of HIF-1α and/or HIF-2α to RSV-mediated clinical disease, lung function, immune modulation, and viral replication using inhibitors specific for each of the HIF-αsubunits. In Specific Aim 2, we will test the hypothesis that HIF stabilization protects the airways from experimental RSV infection and modulate antiviral immune responses, using similar disease and viral outcomes. This is a novel project with a long-term goal to uncover the unique and complex contribution of HIFs to both antiviral immunity and lung pathophysiology, and with wider relevance for human respiratory infections. This contribution is significant as these studies will provide important new information for ongoing clinical trials of HIF inhibitors, used in patients with cancers and other diseases who could be at higher risk for more severe respiratory viral infections, as well the potential use of HIF stabilizers as therapeutic approach for respiratory virus associated lung diseases.

项目概要/摘要几种病毒已被证明可以诱导宿主细胞的代谢重编程以建立生产力病毒利用的一种常见机制是稳定缺氧诱导因子（HIF）。 HIF 复合物由诱导型 α 亚基（HIF-1α 或 HIF-2α）和组成型表达的 β 组成亚基（HIF-1β），已知可控制多种转录过程以应对缺氧和其他疾病 HIF 抑制剂和稳定剂的使用已在癌症、自身免疫、和非感染性急性肺损伤，目前正在第三阶段测试这两类的几种化合物针对各种临床疾病的临床试验然而，还没有描述 HIF 使用的出版物。体外研究表明，特定抑制剂或稳定剂可以抑制病毒感染的体内模型。 HIF-1α 可能代表一种有效的抗病毒策略，包括针对呼吸道病毒，例如呼吸道病毒然而，合胞病毒 (RSV) 和严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2)。 RSV 感染小鼠模型的初步数据，RSV 感染是婴儿严重急性肺病的主要原因没有有效的治疗方法或许可的疫苗，不支持这一策略，因为我们发现抑制 HIF-1α 会恶化临床疾病并有利于病毒复制，同时稳定 HIF 蛋白该应用的中心假设是在RSV感染期间改善临床疾病和肺功能。（以及可能的其他呼吸道病毒）HIF 介导控制关键免疫细胞的激活和存活我们将在一个成熟的模型中检验这一假设。在特定目标 1 中，我们将确定 HIF-1α 和/或 HIF-2α 对 RSV 感染的小鼠模型。 RSV 介导的临床疾病、肺功能、免疫调节和使用特异性抑制剂的病毒复制对于每个 HIF-α 亚基，在特定目标 2 中，我们将检验 HIF 稳定保护的假设。使用类似的疾病和方法，抑制实验性 RSV 感染的气道并调节抗病毒免疫反应这是一个新颖的项目，其长期目标是揭示独特而复杂的贡献。 HIF 与抗病毒免疫和肺病理生理学有关，并且与人类呼吸系统具有更广泛的相关性这一贡献意义重大，因为这些研究将为正在进行的感染提供重要的新信息。 HIF 抑制剂的临床试验，用于癌症和其他疾病风险较高的患者更严重的呼吸道病毒感染，以及 HIF 稳定剂作为治疗方法的潜在用途呼吸道病毒相关的肺部疾病。