Innate Immune Response to Influenza A Virus Infection in the Zebrafish

The World Health Organization has estimated that up to 650,000 deaths occur per year from respiratory diseases associated with seasonal influenza infections. Influenza A virus (IAV) causes severe disease in older adults and individuals with chronic health conditions. IAV vaccines against specific viral antigens are difficult to design because of constant changes in the viral genome. The long-term goal of our studies is to understand the molecular mechanisms of the innate immune response to IAV infection and find new antiviral therapeutic targets. Neutrophils have essential roles in innate immunity to bacterial and fungal infections, but their roles in antiviral responses are understudied. Recently, it was demonstrated that IAV infection can be established in zebrafish (Danio rerio) larvae. The zebrafish is a powerful vertebrate model system that has been used to study infection and innate immunity. We are using this model to study the roles neutrophils have in controlling IAV infection and how over-activation of neutrophils during IAV infection trigger a damaging hyperinflammatory response. First, we are examining pathways that control the respiratory burst function and how reactive oxidative species control neutrophil function during IAV infection. Ongoing studies of IAV-infected neutrophil cytosolic factor 1 (ncf1) morphants show increased survival compared to control morphants over controls. Survival studies of IAV-infected WHIM (Tg1(-8mpx:cxcr4b-EGFP)) mutants that overexpress a truncated cxcr4b transgene also show decreased survival compared to sibling controls that underscores the roles of neutrophils. Second, we are investigating how hyperinflammation occurs during IAV infection so that therapeutic measures that preserve the antiviral response, yet contain the associated inflammation, can be developed. This work is supported by the National Institute of Allergy and Infectious Disease of the National Institutes of Health under grant number R15AI131202, and National National Institute of General Medical Sciences of the National Institutes of Health under grant number P20GM103423.