Failure to generate protective T-cells coupled with enhanced inflammation exacerbates lung damage in a pediatric model of influenza infection (92.21)

Abstract

Abstract Influenza virus causes severe morbidity/mortality in young children; however the exact mechanisms driving increased pathogenesis in children, as compared to adults, is not fully defined. We determined that pediatric mice (21 days old), were actively generating memory T-cells as would be expected in young children, while memory populations were firmly established in older “adult” mice. We infected pediatric and adult mice with influenza PR8 and found pediatric mice had elevated morbidity as measured by enhanced weight loss and lower oxygen saturation levels throughout infection thus modeling higher morbidity observed in children. Early viral loads were comparable but pediatric mice failed to clear virus by 10 days post-infection that coupled with apoptosis and poor lung recruitment of the responding T-cells while adult mice generated a strong antiviral response and cleared virus. In contrast to adult mice, IL-10 was not detected in the lungs of pediatric mice thus favoring a pro-inflammatory environment predominated by innate anti-viral responses. In addition, pediatric mice had extensive lung damage and pathology throughout infection that coupled with higher levels of pro-inflammatory innate cytokines. Reciprocal T-cell transfers revealed that both the T-cells and the inflammatory lung environment contribute to lung damage in pediatric mice. Therefore, this study highlights the key inflammatory mechanisms that drive enhanced morbidity in children infected with influenza.