Influenza A Exacerbates Staphylococcus aureus Pneumonia by Attenuating IL-1β Production in Mice

Abstract

Pneumonia is a leading cause of death worldwide. Staphylococcal aureus can be a cause of severe pneumonia alone or as a common pathogen in secondary pneumonia following influenza. Recently, we have reported that preceding influenza attenuated the Type 17 pathway, increasing the lung’s susceptibility to secondary infection. IL-1β is known to regulate host defense including playing a role in TH17 polarization. We examined if IL-1β signaling is required for S. aureus host defense and whether influenza infection impacted S. aureus induced IL-1β production and subsequent Type 17 pathway activation. Mice were challenged with S. aureus (USA300) with or without preceding influenza A/PR/8/34 H1N1 infection. IL-1receptor1 −/− mice had significantly higher S. aureus burden, increased mortality, and decreased Type 17 pathway activation following S. aureus challenge. Co-infected mice had significantly decreased IL-1β production versus S. aureus alone at early time points following bacterial challenge. Preceding influenza did not attenuate S. aureus induced inflammasome activation, but there was early suppression of NF-κB activation, suggesting an inhibition of NF-κB dependent transcription of pro- IL-1β. Furthermore, overexpression of IL-1β in influenza, S. aureus co-infected mice rescued the induction of IL-17 and IL-22 by S. aureus and improved bacterial clearance. Finally, exogenous IL-1β did not significantly rescue S. aureus host defense during co-infection in IL-17RA −/− mice or in mice in which IL-17 and IL-22 activity were blocked. These data reveal a novel mechanism by which influenza A inhibits S. aureus induced IL-1β production resulting in attenuation of Type 17 immunity and increased susceptibility to bacterial infection.

Comparison of innate immune agonists for induction of tracheal antimicrobial peptide gene expression in tracheal epithelial cells of cattle

“…IL-17 is important for defence of the respiratory tract against bacterial pathogens including Staphylococcus aureus, Pseudomonas aeruginosa and Legionella pneumophila infections in mice [30][31][32]. In the present study, IL-17A receptor subunit A gene expression was identified in bTEC, consistent with prior findings in human airway epithelial cells [33].…”

IFN-γ Priming of Macrophages Represses a Part of the Inflammatory Program and Attenuates Neutrophil Recruitment

“…We found that IFN-g priming decreased LPS-induced neutrophil recruitment both in vitro and in vivo. It has been reported previously that IFN-g (and also type I IFNs) produced during viral infections in mice suppresses innate protection against subsequent bacterial pathogens (26,(46)(47)(48)(49). Also, in humans, postinfluenza patients are more susceptible to secondary bacterial infections, particularly pneumococcal pneumonia.…”

Influenza and Bacterial Superinfection: Illuminating the Immunologic Mechanisms of Disease

“…A critical role for immunity mediated by type 17 cytokines against secondary infections with either S. aureus or S. pneumoniae has been previously demonstrated (16,18,44,49). In addition, preceding influenza virus infection was shown to suppress type 17 immune activation against secondary infection with the Gram-negative pathogens Escherichia coli and Pseudomonas aeruginosa (50).…”

“…As such, type I IFN signaling inhibited production of IL-23 and IL-1␤, critical type 17 immunoregulatory cytokines (16,44). Further, type I IFN receptor-deficient mice had elevated type 17 immune responses (whose importance in the context of superinfection is discussed below) and were protected against postinfluenza staphylococcal pneumonia.…”