Investigating The Role of The Human Mannose Receptor (CD206) During M. tuberculosis Infection in a Novel Transgenic Mouse - PROJECT SUMMARY/ABSTRACT Mycobacterium tuberculosis (M.tb), the etiological agent responsible for tuberculosis (TB), remains the leading cause of death from a single infectious agent, with ~23% of cases resulting in mortality. The rise in cases and the increase in global mortality emphasize the immediate need for novel therapeutic approaches, including host- directed therapies (HDT). Alveolar macrophages (AMs) are critical immune cells that maintain homeostasis by clearing pathogens and debris without damaging lung tissue. Upon infection, M.tb establishes a niche in AMs creating an environment conducive to intracellular replication while subverting host macrophage defenses. Thus, understanding mechanisms by which M.tb modifies macrophage responses beneficial to M.tb is critical. The mannose receptor (MR, CD206) is abundantly expressed on AMs, and we have shown that MR on human macrophages is important for phagocytosing M.tb. However, the signaling pathways downstream of MR engagement with M.tb are poorly understood. We have shown that MR activation in human macrophages activates peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathways and limits phagosome- lysosome fusion, favoring M.tb survival. Thus, MR signaling in humans results in susceptibility to infection, however, studies in mice indicate that MR does not play a role in TB pathogenesis. We previously determined that the mouse MR (mMR) and human MR (hMR) differ in amino acid sequence and downstream signaling. Thus, studies in mice targeting MR do not necessarily recapitulate its role in human disease. To overcome this limitation, this project uses a novel transgenic mouse, generated by our lab, that exclusively expresses the hMR. We will use this mouse model to investigate hMR-driven signaling pathways, focusing on AM responses and TB pathogenesis. We hypothesize that hMR expression on murine macrophages enhances susceptibility to M.tb, leading to increased bacterial burden and impaired immune control in vitro and in vivo. The Specific Aims are to: 1) Determine the impact of hMR in macrophage recognition, intracellular trafficking, and signaling; and 2) Determine the role of hMR in M.tb pathogenesis in vivo. Studying hMR in this model is expected to reveal potential, novel TB HDT targets by uncovering how MR signaling contributes to immune modulation, bacterial survival, and the lung environment during M.tb infection. Under Dr. Schlesinger’s mentorship, the proposed research and training plan will provide essential experience in advanced techniques, infectious disease models, and data analysis. The structured training will enhance the PI trainee skills in communication, critical thinking, and grantsmanship. All work will be conducted at Texas Biomedical Research Institute, which offers robust support for trainee development, including a trainee association, unique workshops and seminars, including an NIH P30 TB center, and a strong research community. Upon completion, the PI trainee will be prepared for the next step as a postdoctoral scientist, advancing the PI’s career goal to become an independent investigator.
