Mechanisms of influenza viral pathogenesis in normal hosts and hosts with chronic diseases

甲型流感病毒(IAV)是上呼吸道和下呼吸道感染的主要原因，对全球健康构成持续威胁。季节性流感每年导致全球约50万人死亡，美国多达5万人死亡。IAV感染在患有慢性肺部疾病(CLD)的儿童中尤其严重，例如支气管肺发育不良(BPD)，这是一种与肺部早产和因早产而停止发育有关的慢性肺部疾病。目前，BPD儿童IAV感染促进疾病发展的分子和细胞机制尚不十分清楚，这主要是因为相对缺乏动物研究来模拟BPD儿童严重的IAV感染。在这一应用中，我们希望揭示中性粒细胞在正常宿主或BPD宿主IAV发病中的作用。基于我们最近令人兴奋的初步数据，我们将重点阐明感染肺中中性粒细胞凋亡和功能的调节机制，以及IAV感染后对肺部炎症和恢复的下游影响。我们的主要假设是，涉及bcl6和p53通路的一个轴在调节感染肺中中性粒细胞凋亡方面发挥关键作用，从而通过直接或间接机制调节IAV感染后肺部炎症的发展。此外，利用实验室最近建立的新生儿BPD高氧小鼠模型，我们将研究中性粒细胞反应过度在BPD宿主严重IAV相关疾病发展中的作用。提出了三个具体目标。目的1：探讨BCL6在IAV感染过程中调节组织中性粒细胞存活和肺部炎症的机制。目的：阐明IAV感染过程中中性粒细胞过度聚集促进肺部过度炎症和疾病发展的机制。目的3：探讨BPD患者中性粒细胞过度反应在严重IAV相关疾病发生中的作用。

Influenza A virus (IAV) is the leading cause of upper and lower respiratory infection and constitutes an ongoing threat to global health. Seasonal influenza kills ~500,000 people globally and up to 50,000 people in the United States each year. IAV infection is especially problematic in children with chronic lung diseases (CLD) such as bronchopulmonary dysplasia (BPD), a chronic lung condition associated with lung prematurity and halted development due to preterm birth. Currently, the molecular and cellular mechanisms underlying the enhanced disease development of IAV infection in BPD children are not very clear, largely due to the relative lack of animal studies to model severe IAV infection in children with BPD. In this application, we wish to unravel the roles of neutrophils in IAV pathogenesis in normal hosts or hosts with BPD. Based on our recent exciting preliminary data, we will focus on elucidating the mechanisms regulating neutrophil apoptosis and function at the infected lungs, and the downstream effects on pulmonary inflammation and recovery following IAV infection. Our main hypothesis is that an axis involving with BCL6 and P53 pathway plays a critical role in regulating neutrophil apoptosis in the infected lungs, thereby modulating pulmonary inflammation development through direct or indirect mechanisms following IAV infection. Furthermore, using a neonatal hyperoxia mouse model of BPD recently-established in the lab, we will investigate the roles of exaggerated neutrophil responses in the development of severe IAV-associated diseases in hosts with BPD. Three specific aims are proposed. Aim 1: To determine the mechanisms by which BCL6 regulates tissue neutrophil survival and pulmonary inflammation during IAV infection. Aim 2: To elucidate the mechanisms by which excessive neutrophil accumulation promotes exaggerated pulmonary inflammation and disease development during IAV infection. Aim 3: To determine the roles of exaggerated neutrophil responses in the development of severe IAV-associated diseases in BPD hosts.