Innate Immunity Immunomodulators in Post-Influenza Bacterial Pneumonia

Post-influenza bacterial pneumonia is a major cause of morbidity and mortality worldwide. One mechanism for enhanced susceptibility to bacterial infection after influenza is down-regulation of a major phagocytic receptor on alveolar macrophages, macrophage receptor with collagenous structure (MARCO), by interferon- (IFN-), which leads to diminished bacterial clearance. Nrf2, a transcription factor that regulates expression of antioxidant genes, is one of the regulators of MARCO expression. We show that the Nrf2 activator sulforaphane improves MARCO expression and bacterial phagocytosis in alveolar macrophage (AM)-like human monocyte-derived macrophages (HMDMs). It also improves host survival by up-regulating MARCO in a murine model of post-influenza pneumococcal pneumonia. MARCO is spontaneously restored and upregulated in the later phase of influenza virus infection. Initially, elevated IFN levels following influenza infection coincide with attenuated MARCO expression in the lungs. However, as IFN levels returned to normal levels on post-influenza day 11, there was a striking 4.86-fold increase of MARCO expression compared to the low level observed on day 9. To identify regulatory mechanisms underlying this rebound or enhanced post-influenza MARCO expression, we performed RNA sequencing analysis of purified lung macrophages from post-influenza day 9 and 11. Among the differentially expressed genes between post-influenza day 9 and day 11 macrophages were MARCO and Akt. The Akt activator SC79 significantly increased MARCO expression on IFN-treated AM-like HMDMs, whereas the Akt inhibitor perifosine reduced MARCO expression on HMDMs. SC79 treatment significantly improved mouse survival in post-influenza pneumococcal pneumonia. Transcription factor E-box (TFEB) is one of the overrepresented transcription factors binding to candidate genes in our RNA sequencing analysis. SC79-induced MARCO expression in IFN-treated HMDMs was abrogated in TFEB knockdown cells compared to controls. The results suggest that Akt regulates MARCO expression through effects on the transcription factor TFEB. In summary, immunomodulators like Nrf2 activators and Akt activators may promote MARCO expression and host survival in post-influenza bacterial pneumonia, and provide effective preventive and therapeutic strategies against a common and important complication of influenza. Further elucidation of the Akt-TFEB-MARCO pathway may inform therapies to reduce susceptibility to post-influenza bacterial pneumonia.Environmental Healt