Abstract
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.
