Epithelial STAT3-induced antimicrobial protein, Reg3γ is required for host defense against MRSA pneumonia in mice (55.15)

Abstract

Abstract Incidence of community-associated Methicillin-resistant Staphylococcus aureus (CA-MRSA) pneumonia has increased and is associated with high mortality rates. Patients with Hyper IgE Syndrome (HIES), resulting from mutations in signal transducer and activator of transcription 3 (STAT3), are susceptible to recurrent SA pneumonia. USA300 (2x107 CFU), the most prevalent pneumonia-causing strain, was oropharyngeally administered to C57BL/6 (WT) and various knockout mice. Bacterial burden, gene expression, and protein levels were determined in the lung 20 hours post-infection. Although, Rag2γc-/- mice clear SA as well as WT mice, GP130 or STAT3 inhibited mice had increased bacterial burden. USA300 infection leads to IL-6 induction. IL-6 binds to GP130 and activates STAT3 in lung epithelium during infection as seen by IHC. IL-6 induction also occurred in Rag2γc-/- mice indicating that B, T, NK, and NK T cells are dispensable for this response. IL-6 induces STAT3 signaling and Reg3γ production by mouse lung epithelial (MLE12) cells. Furthermore, STAT3-dependent Reg3γ limits USA300 growth in vitro. Therefore, STAT3 signaling is necessary for host defense against MRSA pneumonia. Although, HIES patients have decreased Th17 cells, recurrent SA pneumonias are likely due to impairment of STAT3 signaling in innate immune and epithelial cells. Reg3γ, with antimicrobial activity against USA300, may be the basis for new therapies for CA-MRSA pneumonia.