Research Projects

Tuberculosis (TB) persists as a significant global health challenge, demanding innovative approaches to counter the rise of drug resistance and latent infection. Host-directed therapies, focused on potentiating innate immune mechanisms, offer a promising avenue for novel TB treatments. Autophagy, a critical intracellular degradation pathway, plays a central role in controlling Mycobacterium tuberculosis (Mtb) infection. This project will undertake a rigorous investigation of the molecular mechanisms underlying interferon-gamma (IFNG)-induced autophagy in macrophages, the primary host cells for Mtb. Recent seminal work has revealed a novel signaling axis wherein IFNG stimulation triggers the expression of heme oxygenase-1 (HMOX1), leading to the production of carbon monoxide (CO). Unexpectedly, CO functions as a critical signaling intermediary, eliciting an elevation in cytosolic calcium levels that activate Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy. This orchestrated cascade culminates in the enhanced clearance of intracellular Mtb. This project aims to comprehensively define the molecular underpinnings of this pathway, focusing on the precise mechanisms by which CO modulates calcium signaling and autophagy in the context of Mtb infection. Focus: ● Calcium Signaling Dynamics: We will perform an in-depth analysis of CO-mediated calcium signaling in macrophages, including the characterization of calcium influx, release from intracellular stores (e.g., endoplasmic reticulum, lysosomes), and the spatiotemporal regulation of calcium signals. ● Molecular Intermediaries: We will identify and characterize the specific calcium channels and signaling proteins involved in CO-mediated calcium signaling and autophagy induction. This will include a detailed investigation of lysosomal calcium channels (e.g., MCOLN1, TPCs), plasma membrane channels (e.g., TRP channels), and their integration with broader signaling networks. ● Mtb-Host Interactions: We will systematically examine how Mtb infection perturbs calcium homeostasis, HMOX1 expression, and the activity of key regulators of autophagy, such as PPP3 (calcineurin). We will further investigate how different Mtb strains (virulent vs. attenuated) differentially modulate these host pathways. ● ROS-Mediated Regulation: We will explore the involvement of reactive oxygen species (ROS) in CO-mediated calcium signaling and autophagy, examining their sources, regulatory mechanisms, and interplay with calcium channels and signaling pathways. By elucidating these intricate and interconnected processes, this research will significantly advance our understanding of the host's innate immune response to Mtb infection. Furthermore, it will identify potential therapeutic targets for host-directed therapies aimed at enhancing autophagy and bolstering the host's ability to eliminate Mtb.