Influenza-induced Susceptibility to Secondary Bacterial Pneumonia Is Rescued in STAT2-/- Mice Via an IL-23 Independent Mechanism
Methods: Adult male wild-type (WT) and STAT2-/- mice were infected with influenza A/PR/8/34 H1N1 or vehicle. On day 6, mice were challenged with vehicle or MRSA (USA300). Mice were sacrificed on day 7; bronchoalveolar lavage (BAL) was performed for cell count and lungs were harvested for flow cytometry, bacterial burden, cytokine level, and gene expression.
Results: STAT2-/- mice had more weight loss compared to WT on day 6 of influenza infection (89.5% vs 84.2% of starting weight); on day 7, STAT2-/- mice had significantly increased influenza viral burden and a higher percentage of neutrophils in BAL fluid (72% vs 40%), although total cell counts did not differ. Compared to mice infected with MRSA alone, WT mice with co-infection had increased bacterial burden that was not seen in STAT2-/- mice. Furthermore, influenza-infected STAT2-/- mice had significantly prolonged survival following challenge with MRSA at a dose lethal to WT mice (median survival, 30 vs 18 hours). In WT mice, IL-17 and IL-22 producing CD4+T cells were reduced in co-infected mice compared to MRSA alone, but these cells were preserved in STAT2-/- mice. However, no differences in IFN-β or IL-23 gene expression or IL-23 concentration were detected in whole lung, although IL-22 gene expression was increased.
Conclusion: STAT2-/- mice are protected from impaired clearance of MRSA from the lung and from mortality during influenza co-infection despite increased influenza severity. This effect may be mediated by IL-22 rescue that is IL-23 independent, but the mechanism requires further elucidation.
S. Mandalapu, None
J. Alcorn, None