Divergent macrophage induced lung pathology occurs between infants and adults during respiratory viral infection

Abstract

Young children, especially those aged 4 months to 2 years of age, frequently exhibit severe morbidity during respiratory viral infections. For influenza infections, macrophages/monocytes serve as front line defenses against early viral replication in the lungs until the adaptive immune system arrives to clear virus. However, infiltrating inflammatory monocytes are a significant cause of influenza induced lung pathology/morbidity. We utilized a young murine model of respiratory viral infections using 21-day-old mice to investigate the mechanisms driving the heightened influenza induced morbidity observed in human young children. We hypothesized that macrophages/monocytes responses to influenza would diverge between young and older mice despite our evidence that macrophages from both groups appear to control viral replication at similar rates. While inflammatory monocyte infiltration contributed to influenza induced morbidity/lung inflammation in adults, they did not appear to contribute to morbidity in young mice. Instead, young mice appeared to develop lung inflammation through a lack of interferon gamma (IFN{psi}) and infection of macrophage populations. In contrast, adult mice controlled early viral replication through macrophage populations (alveolar, interstitial, and inflammatory) and inflammatory monocytes. While intrinsic limitations in anti-viral cytokine responses, especially IFN{psi}, characterized the macrophage response to viral infection in young mice, the innate immune response to infection appears diminished compared to adults. This study highlights the intrinsic limitations in macrophage effector functions that may arise in young children but that also contribute to disease pathology.