Mycobacterium tuberculosis Induces CREB Activation in Human Macrophages Through the MAPK Pathway

Chrissy M. Leopold Wager, Eusondia Arnett, Larry S. Schlesinger
Texas Biomedical Research Institute, San Antonio, Texas

Tuberculosis (TB) is the leading cause of death from a single infectious agent. Mycobacterium tuberculosis (M.tb), the etiological agent, is a host-adapted intracellular pathogen that exploits host macrophages to create an intracellular niche where it can survive. Macrophages are often the first line of defense against M.tb in the lungs, thus it is critical that we fully understand the mechanism(s) by which M.tb modifies macrophage responses resulting in an environment advantageous to bacterial growth. Macrophage recognition of M.tb through pattern recognition receptors (PRRs) and the resulting initiation of metabolic and inflammatory signaling networks directly affects the overall host immune response. In recent work, we have determined that infection of human monocyte derived macrophages (MDMs) with virulent M.tb rapidly induces activation of cAMP Response Element Binding Protein (CREB), a transcription factor that regulates diverse cellular responses including transcriptional induction of inflammatory mediators such as IL-2, IL-6, IL-10 and TNF-a. However, the mechanism(s) behind CREB activation and its downstream role in human macrophage responses to M.tb are largely unknown. We have determined through the use of small molecule inhibitors that during M.tb infection of human macrophages, CREB activation occurs independent of cAMP but dependent on activation of p38 mitogen activation protein kinase. siRNA knockdown of the mannose receptor and complement receptor 3, two receptors largely responsible for phagocytosis of M.tb by human macrophages, revealed that neither receptor plays  a role in CREB activation. These data suggest that recognition of M.tb by PRRs such as certain Toll-like receptors, may be responsible for initiating this signaling cascade. In addition, siRNA knockdown of CREB during M.tb infection revealed that CREB impacts gene expression of various nuclear receptors and co-regulators, suggesting that CREB may be a master regulator of the macrophage response to M.tb infection. Future work will focus on determining how CREB modulates the macrophage response, its effect on intracellular M.tb growth, and the receptor(s) responsible for initiating the signaling cascade. These data will enhance our understanding of how M.tb evades the immune system and has the potential to lead to novel therapeutics to combat TB.