Regulation of IFN‐γ by IL‐13 dictates susceptibility to secondary postinfluenza MRSA pneumonia

Abstract

Super infection in mice at day 7 post-influenza infection exacerbates bacterial pneumonia at least in part via downstream effects of increased IFN-γ signaling. Here we show that up to 3 days post-influenza infection mice have reduced susceptibility to super infection with methicillin-resistant Staphylococcus aureus (MRSA), but that super infection during that time exacerbated influenza disease. This was due to IL-13 signaling that was advantageous for resolving MRSA infection via inhibition of IFN-γ, but was detrimental to clearance of influenza virus. However, if super infection did not occur until the near resolution of influenza infection (day 7), IL-13 signaling was inhibited, at least in part by up regulation of IL-13 decoy receptor (IL-13Rα2), which in turn caused increases in IFN-γ signaling and exacerbation of bacterial infection. Understanding these cytokine sequelae is critical to development of immunotherapies for influenza-MRSA coinfection since perturbations of these sequelae at the wrong time could increase susceptibility to MRSA and/or influenza.

Influenza and Bacterial Superinfection: Illuminating the Immunologic Mechanisms of Disease

“…These data suggest that enhanced neutrophil-mediated responses, perhaps mediated by an IL-13-dependent mechanism, may contribute to improved resolution of superinfection early after influenza virus infection (day 3) (20)(21)(22). As in prior experiments with pneumococcal pneumonia, depletion of neutrophils (with anti-Ly6G antibodies) in mice infected with influenza virus for 3 days significantly increased their susceptibility to S. aureus superinfection compared to mice infected only with bacteria (A. Rynda-Apple, unpublished observation).…”

“…Reduced susceptibility to S. aureus superinfection in mice infected with influenza virus for 2 to 3 days compared to mice infected only with bacteria is dependent on both increased levels of interleukin-13 (IL-13) (20) and the presence of neutrophils in the lung (unpublished observation). These data suggest that enhanced neutrophil-mediated responses, perhaps mediated by an IL-13-dependent mechanism, may contribute to improved resolution of superinfection early after influenza virus infection (day 3) (20)(21)(22).…”

“…Type 2 immune responses and related regulatory T cell cytokine production have been implicated in susceptibility to secondary infection. The canonical type 2 cytokine IL-13 was shown to be beneficial in host defense against S. aureus superinfection early after influenza virus infection (20). Although IL-13 may be derived from a non-T-cell source early during the course of influenza virus infection, it was shown to attenuate IFN-␥ production when mice were challenged with S. aureus 3 days after influenza virus infection.…”

Novel protective mechanism for interleukin-33 at the mucosal barrier during influenza-associated bacterial superinfection

“…IL-13 has shown to be protective early in the course of influenza and MRSA super-infection, although the cellular source of IL-13 has not been shown. By day seven post-influenza infection, IL-13 levels are decreased in part due to the soluble IL-13 decoy receptor and mice are more susceptible to secondary MRSA pneumonia 26,27 . In a post-influenza pneumococcal pneumonia model, ST2−/− mice have been compared to wild-type mice and showed increased bacterial burden in the lung at 48 hours post-bacterial challenge when receiving S. pneumoniae at day 14 of influenza infection 28 .…”

Viruses and bacteria in Th2‐biased allergic airway disease

“…In humans with acute respiratory illnesses, however, children with HRSV and Mycoplasma pneumonia co-infection had more severe airway inflammation than those with HRSV infection alone (91); bacteria (influenzae, catarrhalis, and pneumoniae) are more likely to be detected among virusnegative specimens compared to virus-positive burden (92). Similarly, mice with presymptomatic influenza infection are less susceptible to secondary MRSA infection (93), due to the persistence of IL-13 signaling that was advantageous for resolving MRSA infection. These observations suggest a profound deference of host defense upon different pathogen species infection.…”