Regulation of NOD-like receptors in juvenile influenza A virus infection

The paucity of information regarding why children are highly susceptible to viral respiratory infections, coupled with the limited clinical tools to treat this vulnerable population, has inspired me to pursue the project outlined in this proposal. Specifically, I will explore the role of NOD-like receptor (NLR) proteins in the development of viral pneumonia following infection with influenza A virus (IAV). The current proposal extends my long-standing interest in host-pathogen relationships, acute lung injury, and the need to alleviate the suffering of children afflicted with viral respiratory diseases. I am particularly interested in defining the role of NLR proteins in the development of viral pneumonia using a clinically relevant model of IAV infection in juvenile mice. Completion of this project will help advance my long-term career goal of developing an independent research laboratory focusing on understanding the mechanisms of pediatric susceptibility to lung injury during viral infections, and optimizing immune function in these critically ill children.

IAV is a highly contagious virus that causes respiratory tract infections in up to 40% of the pediatric population each year. Underlying medical conditions place certain children at increased risk of severe IAV pneumonia, but 50% of IAV-related deaths in children in the United States occur in previously healthy children without identifiable risk factors. In our preliminary data, we show that morbidity during IAV infection is much higher in healthy juvenile mice than in healthy adult mice, which is independent of viral clearance rates. This increased incidence of lung injury in juvenile mice is associated with a robust activation of the NLRP3 inflammasome, resulting in increased IL-1/IL-18 levels in response to IAV that persists beyond viral elimination. Interestingly, we show that juvenile NLRP3−/− mice and mice treated with NLRP3 inflammasome inhibitors are protected from acute lung injury following infection with IAV. We hypothesize that the innate immune response to IAV is distinct in juvenile mice, and that robust and sustained activation of the NLRP3 inflammasome exacerbates IAV-induced lung injury in juvenile mice. We reason that a failure to resolve IAV-triggered inflammation may contribute to the development of lung injury following infection with IAV in children. We have formulated three interrelated specific aims to study the regulation of NLR signaling in both in vivo and in vitro models of juvenile influenza A virus-induced lung injury: Specific Aim 1: To determine the mechanism by which activation of NLR proteins contributes to IAV-induced acute lung injury in juvenile mice. Specific Aim 2: To determine whether alveolar epithelial cells and/or macrophage cells are required for the activation of NLR proteins in response to IAV. Aim 3: To determine whether inhibiting NLR proteins is protective in a preclinical juvenile mouse model of IAV-induced acute lung injury.

This award will be instrumental to my continued success as a pediatric physician-scientist. It will enable me to garner additional training to develop hypothesis driven, clinically relevant questions and advance the scientific understanding of pediatric acute lung injury secondary to viral infections. With the guidance of my mentor and scientific advisory committee, I will have access to the necessary training, didactic classes, and resources to foster my growth into an independent investigator and position myself as a leader in the field. One of my long-term goals is to train junior inv