Project Summary:
Viral respiratory infections are a leading cause of hospitalization in children. In the absence of co-morbidities,
children are much more likely than adults to require hospitalization for most respiratory viruses, including
influenza A virus (IAV). Age-related changes in innate immune signaling over the first few years of life likely
impact the course of viral respiratory infections, but the mechanisms driving viral-induced respiratory failure in
children are unknown. Viral load has not been associated with severity of illness in children with IAV pneumonia,
so failure to control viral replication is not likely the primary driver of severe illness in children. We have found
that juvenile mice recruit more monocyte-derived alveolar macrophages and have increased activation of the
NLRP3 inflammasome compared to adult mice late in IAV infection. This was associated with increased
production of type I interferon (IFN) in juvenile mice, despite equal viral burden. Importantly, inhibition of
macrophage recruitment decreased type I IFN levels and improved survival in juvenile IAV infection. These data
suggest that age-related differences in type I IFN production in response to IAV infection promote the recruitment
of inflammatory macrophages and contribute to mortality in juvenile mice. In preliminary data, we now show that
genetic deletion or pharmacologic inhibition of the type I IFN receptor, IFNAR1, on recruited macrophages
improves survival in IAV-infected juvenile mice. Therefore, we hypothesize that children fail to recover from
IAV infection due to increased type I IFN signaling and macrophage recruitment to the lungs. We further
hypothesize that recruited macrophages maintain an injurious inflammatory phenotype in the juvenile
lung due to age-related differences in the lung microenvironment. We will test these hypotheses in the
following specific aims: Aim 1: Determine whether age-related differences in the microenvironment of the
juvenile lung promote an inflammatory phenotype in recruited macrophages. Aim 2: Determine whether inhibition
of type I IFN signaling in recruited macrophages decreases lung injury and improves outcomes in juvenile viral
pneumonia. Aim 3: Determine whether increased type I IFN signaling in epithelial cells contributes to severity of
illness in juvenile viral pneumonia. Completion of these aims will identify mechanisms driving viral-induced
respiratory failure in the juvenile host and explore the potential benefit of targeting IFNAR1 signaling in
macrophages to minimize lung injury caused by viral respiratory infections in children. Using age-appropriate
mouse models of IAV pneumonia and multidimensional phenotyping of children with viral-induced respiratory
failure, we are positioned to define key determinants of disease severity in children with IAV pneumonia that will
support the rationale design of new treatment strategies to minimize lung injury and optimize recovery.
