Influenza A Inhibits Th17-Mediated Host Defense against Bacterial Pneumonia in Mice

Abstract

Staphylococcus aureus is a significant cause of hospital and community acquired pneumonia and causes secondary infection after influenza A. Recently, patients with hyper-IgE syndrome, who often present with S. aureus infections of the lung and skin, were found to have mutations in STAT3, required for Th17 immunity, suggesting a potential critical role for Th17 cells in S. aureus pneumonia. Indeed, IL-17R−/− and IL-22−/− mice displayed impaired bacterial clearance of S. aureus compared with that of wild-type mice. Mice challenged with influenza A PR/8/34 H1N1 and subsequently with S. aureus had increased inflammation and decreased clearance of both virus and bacteria. Coinfection resulted in greater type I and II IFN production in the lung compared with that with virus infection alone. Importantly, influenza A coinfection resulted in substantially decreased IL-17, IL-22, and IL-23 production after S. aureus infection. The decrease in S. aureus-induced IL-17, IL-22, and IL-23 was independent of type II IFN but required type I IFN production in influenza A-infected mice. Furthermore, overexpression of IL-23 in influenza A, S. aureus-coinfected mice rescued the induction of IL-17 and IL-22 and markedly improved bacterial clearance. These data indicate a novel mechanism by which influenza A-induced type I IFNs inhibit Th17 immunity and increase susceptibility to secondary bacterial pneumonia.

IL-17 response mediates acute lung injury induced by the 2009 Pandemic Influenza A (H1N1) Virus

“…The role of IL-17 is more complicated when bacterial pneumonia is studied in the context of influenza A co-infection. Kudva et al [30] found that influenza A inhibits the Th-17-mediated host defense against bacterial pneumonia in mice. Although further studies are necessary to elucidate the complex role of IL-17 in PR8 influenza infection, our S-OIV infection studies support the hypothesis that IL-17 mediates acute lung injury in mice.…”

“…IL-17 has been associated with tissue damage in the brain, joints, heart, lungs and intestines, in experimental models [25][26][27]. However, the role of IL-17 in lung injury induced by influenza is controversial [28][29][30]. Here, the establishment of a suitable mouse model enabled us to directly test whether IL-17 mediates or protects from the acute lung injury induced by 2009 pandemic influenza infection.…”

Epigenetic and Transcriptomic Regulation of Lung Repair during Recovery from Influenza Infection

“…10,14e17 A primary mechanism by which influenza impairs host defense against extracellular bacteria was through type I IFN-mediated suppression of Type 17 immunity. 10,14 Type I IFN levels peak during the first week of influenza infection and diminish as viral clearance occurs.…”

“…8,10 Dispersed single-cell preparations were restimulated with 50 ng/mL PMA and 750 ng/mL ionomycin for 5 hours at 37 C. Cells were then stained with fluorescentconjugated antibodies to CD4 and CD8, followed by permeabilization and staining for interferon (IFN)-g, and IL-17A (BD Biosciences, Franklin Lakes, NJ). Stained cells were analyzed using a FACSAria apparatus (BD Biosciences).…”

Interfering with Immunity: Detrimental Role of Type I IFNs during Infection

“…The enhanced bacterial clearance in Ifnar1 2/2 mice is due to increased neutrophil influx resulting from the upregulation of chemokines KC and Mip2, as well as elevated production of IL-17 (202,203). S. pneumoniaesuperinfected Ifnar1 2/2 mice show increased IL-17A production by pulmonary gd T cells (203).…”