Deciphering the role of CREB activation in early human macrophage responses to Mycobacterium tuberculosis 3301

Abstract Description Mycobacterium tuberculosis (Mtb) exploits host macrophages as an intracellular niche to ensure its survival and replication. Our goal is to identify signaling pathways leveraged by Mtb to manipulate macrophage responses. We recently found that Mtb infection of human monocyte-derived macrophages (MDM) triggers activation of the transcription factor CREB, which was critical for bacterial growth. CREB inhibition significantly decreased gene and protein expression of certain Mtb-induced immediate early genes. However, CREB’s full role in human macrophage responses to Mtb remains largely unknown. Therefore, we infected MDMs with Mtb ± CREB inhibition and performed NanoString to identify differentially expressed genes (DEG). Pathway analysis of the DEGs revealed that CREB inhibition suppressed pathways involved in cytokine signaling, classical macrophage activation and inflammasome signaling. NanoString analysis also identified genes associated with Type I/II interferon signaling, costimulatory molecules and T cell trafficking. Further investigation suggests that CREB is important for Mtb-induced surface expression of CD40 and CD80. Our observation that CREB enhances macrophage susceptibility to Mtb, yet may also facilitate protective, adaptive immune responses underscores the complexity of CREB’s signaling networks. Understanding CREB’s contributions to both susceptibility and resistance to Mtb could lead to identification of novel targets for host-directed therapeutics for TB. Funding Sources Supported by Parker B. Francis Foundation, NIH R01AI136831 and P30AI168439. Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)