Influenza virus infections result in substantial illness, mortality and societal impact worldwide. Influenza A virus (IAV) infections originate in epithelial cells of the respiratory tract and can become systemic, potentially resulting in multi-organ failure and death. Neutrophils play a critical role in the vertebrate immune response to bacterial and fungal infections, but until recently it had been assumed that neutrophils are not essential for immune defense against viral infections. Recent evidence, however, suggests that neutrophils are involved in the immune response to IAV and may give rise to both positive and negative outcomes resulting from inflammation. This research will determine whether neutrophils, in the process of controlling IAV infections, trigger excessive inflammation through mechanisms involving reactive oxygen species (ROS) production and signaling via the cytokine, type I interferon. In the proposed project, the zebrafish serves as a novel animal model in which the innate immune response to influenza viral infection can be studied in the context of the whole animal. This work will involve a combination of molecular techniques and imaging microscopy to identify molecular mechanisms that are responsible for neutrophil recruitment to localized sites of infection in an effort to identify potential targets for intervention. Individual components of the respiratory burst, such as NADPH oxidase and myeloperoxidase, regulate ROS levels in order to contain IAV infections. By dissecting the pathways that control respiratory burst function, we expect to characterize how ROS control neutrophil behavior during an IAV infection to coordinate the antiviral response. We will determine how hyperinflammation occurs as part of an IAV infection so that therapeutic measures that preserve the antiviral response, yet contain the associated inflammation, can be developed. Through these studies we hope to gain valuable insight into the neutrophil response to IAV infection and the specific factors controlling the balance between optimum antiviral activity and excessive inflammation. Our new understanding will lead to positive human health benefits by serving as the basis for development of treatment strategies for maintaining effective antiviral activity against IAV infections while controlling the potentially damaging effects of the neutrophil inflammatory response.
Neutrophils play a critical role in the vertebrate immune response to bacterial and fungal infections, but until recently it had been assumed that neutrophils are not essential for immune defense against viral infections. Recent evidence, however, suggests that neutrophils are involved in viral infections and may give rise to both positive and negative outcomes resulting from inflammatory responses. In the proposed work, the zebrafish serves as a novel animal model in which the innate immune response to influenza viral infection will be studied. The roles of cytokines and reactive oxygen species in generating neutrophil responses, as well as the activity of these molecules in controlling viral infection and inflammation, will be elucidated. Since excessive inflammation brought about by neutrophil involvement in response to pathogens can be highly problematic, mechanisms for reducing hyperinflammatory responses initiated by viral infections will also be explored.
