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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.

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RSV bronchiolitis and pneumonia in infancy is known to be associated with increased susceptibility to asthma. This phenomenon is characterized by a hyper reactive airway with a predominant Th2 response and a skewed dendritic cell (DC) polarization, which can be modulated by exogenous OPN administration. OPN is an immunomodulatory agent inducing a strong Th1 polarization in RSV infected lungs. In our present study, we used a neonatal mouse model to examine the transcriptional regulation of this immunomodulation in RSV-infected pups. RSV-infected pups were intranasally administered with or without different doses of OPN, and messenger RNA (mRNA) expression of GATA-3 and STAT-6 were examined by PCR and RTPCR methods. At day 3 post-infection, GATA-3 expression was significantly higher in the OPN treated lungs compared to that in the PBS treated lungs, contradicting the enhanced Th1 cytokine responses observed after OPN treatment. Interestingly, an enhanced expression of STAT-6 was also observed at the same time point in the OPN treated and RSV infected pups compared to that in the PBS treated pups. Of note, STAT-6 influences IL4 transcription which has a prominent role in Th2 differentiation. On the other hand, IL-4 instructs DC to promote Th1 differentiation which is STAT-6 dependent. Thus, the transcriptional regulation of OPN-induced immunomodulation is not one-dimensional and will need further investigations into the dynamics of other transcriptional factors (e.g. T-bet and Foxp3) to establish OPN as a novel therapeutic in the prevention of RSV-induced susceptibility to asthma.

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