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.
We will determine the cellular and molecular mechanisms by which neutrophils regulate the development of immune-mediated pathology following influenza virus infection in normal hosts or hosts with bronchopulmonary dysplasia (BPD). If successful, the results will not only provide novel insights on influenza pathogenesis, but may open the door for the development of novel treatment for severe influenza-associated diseases, particularly in those high-risk patients with underlying chronic lung conditions such as BPD.
