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

流感病毒在正常宿主和慢性疾病宿主中的发病机制

• 批准号: 10198309
• 负责人: Jie Sun
• 金额: $ 49.41万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10198309
• 关键词: Animals; Antiviral Agents; Apoptosis; BCL6 gene; Blood Circulation; Bone Marrow; Bronchopulmonary Dysplasia; Cellular Structures; Child; Chronic; Chronic Disease; Chronic lung disease; Data; Development; Disease; Genetic; Immune; Infection; Inflammation; Inflammation Mediators; Influenza; Influenza A virus; Lower Respiratory Tract Infection; Lung; Lung diseases; Mediating; Mediator of activation protein; Modeling; Molecular; Neonatal Hyperoxic Injury; Pathogenesis; Pathology; Pathway interactions; Patients; Phagocytosis; Pharmacology; Play; Predisposition; Premature Birth; Production; Public Health; Pulmonary Inflammation; Recovery; Regulation; Role; Seasons; Severity of illness; Site; T-Lymphocyte; TP53 gene; Tissues; United States; Viral; Viral Pathogenesis; Virus; Virus Diseases; antimicrobial; base; disease phenotype; global health; high risk; immunopathology; influenzavirus; insight; mouse model; neutrophil; novel; premature lungs; recruit; response; seasonal influenza; transcription factor

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.

流感病毒（IAV）是上呼吸道感染的主要原因，构成了对全球健康的持续威胁。每年在美国，季节性流感在全球占50万人，多达50,000人丧生。 IAV感染在患有慢性肺部疾病（CLD）的儿童（例如支气管肺发育不全（BPD））中尤其有问题，这是一种与肺早产相关的慢性肺部疾病，并因早产而停止发育。目前，BPD儿童IAV感染增强疾病发展的基础的分子和细胞机制并不十分清晰，这在很大程度上是由于动物研究相对缺乏对BPD儿童的严重IAV感染进行建模。在此应用中，我们希望揭示中性粒细胞在正常宿主或具有BPD宿主的IAV发病机理中的作用。基于我们最近的激动人心的初步数据，我们将重点阐明调节感染肺部中性粒细胞凋亡和功能的机制，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途径的轴在调节感染肺中嗜中性粒细胞凋亡中起着至关重要的作用，从而通过IAV感染后直接或间接机制调节肺部炎症发育。此外，使用实验室最近建立的BPD的新生儿高氧小鼠模型，我们将研究夸张的中性粒细胞反应在患有BPD宿主的严重IAV相关疾病的发展中的作用。提出了三个具体目标。目的1：确定BCl6调节IAV感染期间Bcl6调节中性粒细胞存活和肺部炎症的机制。目标2：阐明过度嗜中性粒细胞积累促进IAV感染期间夸张的肺部炎症和疾病发育的机制。目标3：确定夸张的中性粒细胞反应在BPD宿主中严重IAV相关疾病的发展中的作用。