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

项目摘要/摘要 几种病毒已被证明可以诱导宿主细胞的新陈代谢重新编程，以建立 感染。病毒利用的一个常见机制是稳定低氧诱导因子(HIF)。 HIF复合体，由可诱导的α亚基(HIF-1α或HIF-2α)和结构性表达的β组成 亚基(HIF-1β)，已知控制不同的转录过程，以响应缺氧和其他疾病 各州。HIF抑制剂和稳定剂的使用已经在癌症、自身免疫、 和非传染性急性肺损伤，这两个类别的几种化合物目前正在第三阶段进行测试 针对各种临床疾病的临床试验。然而，没有出版物描述HIF的使用 病毒感染体内模型中的特定抑制剂或稳定剂。体外研究表明，抑制作用 低氧诱导因子-1α可能是一种有效的抗病毒策略，包括对抗呼吸道病毒 合胞病毒(RSV)和严重急性呼吸综合征冠状病毒2(SARS-CoV-2)。然而，我们的 呼吸道合胞病毒感染小鼠模型的初步数据，呼吸道合胞病毒感染是婴儿严重急性肺部疾病的主要原因 没有有效的治疗方法或许可的疫苗，并不支持这一战略，因为我们发现 抑制HIF-1α使临床疾病恶化，有利于病毒复制，同时稳定HIF蛋白 改善临床疾病和肺功能。这一应用的中心假设是在RSV感染期间 (可能还有其他呼吸道病毒)HIF介导了关键免疫细胞的激活和存活 抗病毒反应，同时保持肺的完整性和功能。我们将在一个公认的 呼吸道合胞病毒感染小鼠模型。在具体目标1中，我们将确定HIF-1α和/或HIF-2α对 使用特定抑制物的RSV介导的临床疾病、肺功能、免疫调节和病毒复制 对于每个Hif-α亚基。在特定的目标2中，我们将检验HIF稳定化保护 呼吸道感染和调节抗病毒免疫反应，使用类似的疾病和 病毒式的结果。这是一个具有长期目标的新项目，旨在揭示 HIF对抗病毒免疫和肺病理生理的作用，与人类呼吸道的更广泛的相关性 感染。这一贡献意义重大，因为这些研究将为正在进行的 HIF抑制剂的临床试验，用于癌症和其他疾病患者，这些患者可能有较高的 更严重的呼吸道病毒感染，以及使用HIF稳定剂作为治疗方法的可能性 呼吸道病毒相关的肺部疾病。

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.