Host-immune responses to RSV infection and associated lung injury is modulated by Osteopontin (OPN) in age-dependent fashion

Abstract

RSV bronchiolitis and pneumonia causes significant mortality in young infants every year. The survivors become susceptible to asthma. In our present study, using a mouse model of BALB/C and NKT−/− mice, we examined the pulmonary responses to RSV infection in the very young hosts as opposed to relatively older hosts. We also examined the effects of exogenous osteopontin (OPN) administration on the alveolar cellular constitution by direct microscopy and flowcytometry and the role of NKT cells in this process. Pulmonary damage was assessed by measuring the Lactic Dehydrogenase (LDH) levels in the BALF by ELISA and histopathological examination by microscopy. Microscopy revealed a decreased lymphocyte response in the bronchoalevolar lavage fluid (BALF) of RSV-infected-4-day- old pups as compared to that of -14- and -20-day-old mice; but an enhanced neutrophil response, which was associated with increased LDH levels. Flowcytometry revealed that administration of OPN had downregulatory effects on lung lymphocyte (CD4+ and CD8+) responses in all age groups with proportional upregulation of lung macrophage (CD11bmed/hi, CD11Clo/−) responses. This effect was less pronounced in the older age groups. Additionally, activation of macrophages, as indicated by MHCII expression, was NKT dependent. Moreover, RSV- infection significantly inhibited lung CD8+ T cell activation as indicated by decreased CD44 expression, which was recovered by OPN administration. Understanding the underlying mechanisms of RSV-infection induced differential immune responses and OPN-mediated differential immunomodulation in different age groups may help develop newer therapeutic strategies.