Postinfluenza
bacterial pneumonia is associated with significant mortality and morbidity.
MicroRNAs (
miRNAs) are small, noncoding RNAs that regulate gene expression posttranscriptionally. miR-155 has recently emerged as a crucial regulator of innate immunity and inflammatory responses and is induced in macrophages during
infection. We hypothesized upregulation of miR-155 inhibits
IL-17 and increases susceptibility to secondary
bacterial pneumonia. Mice were challenged with 100 plaque-forming units H1N1 intranasally and were infected with 10(7) colony-forming units of MRSA intratracheally at day 5 postviral challenge. Lungs were harvested 24 h later, and expression of miR-155,
IL-17, and
IL-23 was measured by real-time RT-PCR. Induction of miR-155 was 3.6-fold higher in dual-infected lungs compared with single
infection. miR-155(-/-) mice were protected with significantly lower (4-fold) bacterial burden and no differences in viral load, associated with robust induction of
IL-23 and
IL-17 (2.2- and 4.8-fold, respectively) postsequential challenge with virus and bacteria, compared with WT mice. Treatment with miR-155
antagomir improved lung bacterial clearance by 4.2-fold compared with control
antagomir postsequential
infection with virus and bacteria. Moreover, lung macrophages collected from patients with postviral
bacterial pneumonia also had upregulation of miR-155 expression compared with healthy controls, consistent with observations in our murine model. This is the first demonstration that cellular
miRNAs regulate postinfluenza immune response to subsequent bacterial challenge by suppressing the
IL-17 pathway in the lung. Our findings suggest that antagonizing certain
microRNA might serve as a potential therapeutic strategy against secondary
bacterial infection.