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Influenza-induced Susceptibility to Secondary Bacterial Pneumonia Is Rescued in STAT2-/- Mice Via an IL-23 Independent Mechanism

Session: Oral Abstract Session: Immune Response to Microbial Infection
Thursday, October 9, 2014: 10:30 AM
Room: The Pennsylvania Convention Center: 111-AB
Background:  Secondary bacterial pneumonia is a well-recognized complication of influenza infection. In mice, Th17 activation is critical for host bacterial lung defense but is attenuated by preceding influenza, resulting in exacerbation of pneumonia. Mice lacking the type I interferon (IFN) receptor are protected from impaired bacterial clearance, suggesting a role for type I IFN in co-infection pathogenesis. Type I IFN is upregulated by influenza, inhibits dendritic cell production of Th17-activating IL-23 and IL-1β, and utilizes STAT1 and STAT2 for signaling. We explored the requirement for STAT2 in influenza-associated impairment of lung bacterial clearance in a mouse model of influenza A and methicillin-resistant Staphylococcus aureus(MRSA) co-infection using STAT2-/- mice.

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.

Benjamin Lee, MD, Kevin Mchugh, BA, Sivanarayana Mandalapu, MS and John Alcorn, PhD, Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA

Disclosures:

B. Lee, None

K. Mchugh, None

S. Mandalapu, None

J. Alcorn, None

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