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

Abstract

Influenza A is a highly contagious respiratory virus that causes seasonal epidemics and occasional worldwide pandemics. The primary cause of influenza-related mortality is bacterial super-infection. There are numerous mechanisms by which preceding influenza infection attenuates host defense, allowing for increased susceptibility to bacterial pneumonia. Herein, we demonstrate that influenza inhibits Staphylococcus aureus-induced production of IL-33. Restoration of IL-33 during influenza A and MRSA super-infection enhanced bacterial clearance and improved mortality. ILC2s and alternatively activated macrophages are not required for IL-33 mediated protection during super-infection. We show that IL-33 treatment resulted in neutrophil recruitment to the lung, associated with improved bacterial clearance. These findings identify a novel role for IL-33 in anti-bacterial host defense at the mucosal barrier.

Interferon Lambda Inhibits Bacterial Uptake during Influenza Superinfection

“…We expect that the high levels of type I IFN in the influenza-infected mouse may synergize with our administered IFN-to produce this increase in bacterial burden that we see during superinfection but not bacterial infection alone. Many other cytokines are induced by influenza and play significant roles in its pathogenesis, including type 17 cytokines (23) and IL-1 family members (42). There is likely an interactive role for these players as well in the complex cytokine environment of the influenza-infected lung.…”

Survival during influenza-associated bacterial superinfection improves following viral- and bacterial-specific monoclonal antibody treatment

“…Although there were changes in chemoattractants, we did not see any differences in components of the type 17 immune pathway. This finding is noteworthy because we have previously shown that IL-17 and IL-1 play a role in promoting bacterial clearance during influenza infection (16,22,31). We also investigated components of the type 2 immune pathway and did not measure any differences except for increased gene expression of IL-33 in mice that received FY1 earlier in the course of infection.…”

“…We also investigated components of the type 2 immune pathway and did not measure any differences except for increased gene expression of IL-33 in mice that received FY1 earlier in the course of infection. We have previously shown that IL-33 recruits functional phagocytic neutrophils to the lung during postinfluenza MRSA pneumonia and that neutrophil depletion with IL-33 treatment led to increased susceptibility to MRSA pneumonia (22). We suspect that although IL-33 is increased in the mice that received FY1 earlier in the course of influenza infection, it is likely not playing a role in the context of measuring any differences in other type 2 immune pathway cytokines.…”

“…Flow cytometry. Whole mouse lungs were digested with collagenase as previously described (22). Cells were stained with fluorescent conjugated antibodies for F4/80, CD11b, CD11c, Ly6G, and Siglec-F (BD Biosciences).…”

Monocytes Represent One Source of Bacterial Shielding from Antibiotics following Influenza Virus Infection

“…Considering the relative antimicrobial capacity of each phagocyte subset, neutrophils are likely most important for phagocytic killing of S. aureus in the lung (39,40). Indeed, on a per cell basis, AMs and monocytes in influenza-infected WT lungs contain 10-fold more viable bacteria than neutrophils ( Fig.…”