Influenza-induced type I interferon enhances susceptibility to gram-negative and gram-positive bacterial pneumonia in mice

Abstract

Suppression of type 17 immunity by type I interferon (IFN) during influenza A infection has been shown to enhance susceptibility to secondary bacterial pneumonia. Although this mechanism has been described in coinfection with gram-positive bacteria, it is unclear whether similar mechanisms may impair lung defense against gram-negative infections. Furthermore, precise delineation of the duration of type I IFN-associated susceptibility to bacterial infection remains underexplored. Therefore, we investigated the effects of preceding influenza A virus infection on subsequent challenge with the gram-negative bacteria Escherichia coli or Pseudomonas aeruginosa and the temporal association between IFN expression with susceptibility to Staphylococcus aureus challenge in a mouse model of influenza and bacterial coinfection. Here we demonstrate that preceding influenza A virus led to increased lung E. coli and P. aeruginosa bacterial burden, which was associated with suppression of type 17 immunity and attenuation of antimicrobial peptide expression. Enhanced susceptibility to S. aureus coinfection ceased at day 14 of influenza infection, when influenza-associated type I IFN levels had returned to baseline levels, further suggesting a key role for type I IFN in coinfection pathogenesis. These findings further implicate type I IFN-associated suppression of type 17 immunity and antimicrobial peptide production as a conserved mechanism for enhanced susceptibility to both gram-positive and gram-negative bacterial coinfection during influenza infection.

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). IL-17 and IL-22 were both shown to promote clearance of bacteria through the recruitment of phagocytes and induction of antimicrobial peptides (AMPs).…”

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.…”

Digging through the Obstruction: Insight into the Epithelial Cell Response to Respiratory Virus Infection in Patients with Cystic Fibrosis

“…These studies provide further evidence that respiratory viral infections negatively affect disease severity in CF. It is unlikely that IFN-mediated bacterial growth is specific to CF lung disease, as previous studies have demonstrated that in models of acute influenza virus-bacterial coinfections, the type I IFN response to influenza virus is responsible for increased bacterial burdens in the lung (20)(21)(22). Type III IFN signaling also has adverse effects on bacterial clearance from the airways.…”