Respiratory syncytial virus infection in the absence of STAT1 results in airway dysfunction, airway mucus, and augmented IL-17 levels

Background: Respiratory syncytial virus (RSV) is the leading infectious cause of respiratory failure and wheezing in infants and young children. Prematurity is the greatest risk factor for severe RSV-induced disease, and recent studies suggest that premature children have lower levels of the type I IFNs (alpha/beta), for which signal transducer and activator of transcription (STAT) 1 is a critical intracellular signaling molecule. Objective: We hypothesized that RSV infection in STAT-1 knockout (STAT1 KO) mice would result in both increased airway resistance and airway hyperresponsiveness. Methods: Wild-type (WT) and STAT1 KO mice on a BALB/c background were either RSV or mock infected. Phenotypic response to infection was assessed by means of plethysmography, immunohistochemistry, and lung cytokine measurement. Results: We found that STAT1 KO mice infected with RSV (STAT1 KO-RSV) had greater baseline lung resistance (P = .05) and airway responsiveness (P < .001) than mock-infected STAT1 KO (STAT1 KO-MOCK), RSV-infected wild type (WT-RSV), and mock-infected wild type (WT-MOCK) mice. In addition, the STAT1 KO-RSV mice showed induction of mucus production and expression of gob-5 and Muc5ac, conditions not present in any of the other 3 groups. IL-17, a cytokine that regulates Muc5ac expression, was expressed in the lungs of the STAT1 KO-RSV mice, whereas lung levels of IL-17 were undetectable in the remaining groups. Expression of the IL-23-specific p19 subunit was also increased in the STAT1 KO-RSV mice but not in the WT-RSV mice. Conclusion: These results show that STAT1 has an important regulatory role in RSV-induced alteration of airway function.