Influenza A virus (IAV) is a highly contagious single-stranded RNA virus that is responsible for 3–5 million cases of severe infection and up to 500,000 deaths annually worldwide. The burden of IAV infection is greatest among children, the elderly, and persons with chronic medical conditions. Each year, up to 40% of the pediatric population younger than 5 years in the United States will contract influenza. Young children who develop lower respiratory tract IAV infection are at risk of severe, life-threatening disease. Underlying medical conditions such as asthma or premature birth place certain children at increased risk of severe IAV infection, but these conditions account for only a about half of the morbidity and mortality of influenza. The other half occurs in previously healthy children with no predisposing medical conditions. In contrast, predisposing risk factors such as chronic medical conditions or advanced age account for almost all of the morbidity and mortality of influenza among adults. Why healthy children are much more likely to contract severe, life-threatening IAV infection than are healthy adults is unclear. Anatomical factors and immature immune systems contribute to the increased vulnerability of young children to IAV infection, but they do not adequately explain the susceptibility to severe disease observed in this population.
To investigate the differences between adults and children in the host response to IAV infection, we have developed a mouse model of pediatric influenza using 4-week-old juvenile mice infected with the mouse-adapted IAV strain A/WSN/1933(H1N1). As with humans, juvenile mice infected with IAV have increased morbidity and mortality compared to adult mice. However, the viral clearance is similar between juvenile and adult mice, so the increased disease severity in juvenile mice is not associated with higher viral titers. Instead, it is associated with increased production of the inflammatory cytokine IL-18 and an increase in the recruitment of inflammatory monocytes to the lungs in juvenile mice. We have found that inhibition of monocyte recruitment by treatment with an anti-CCR2 antibody improved survival and decreased inflammatory lung injury in juvenile mice infected with IAV. We also found that treatment of IAV-infected juvenile mice with the compound MCC950, which inhibits IL-18 production, resulted in decreased mortality, reduced lung injury, and attenuated secretion of IL-18. These findings will improve our understanding of the innate immune response in children and help us develop targeted therapeutic strategies and improved vaccines for the pediatric population.