Mycobacterium tuberculosis (Mtb) is a human pathogen of global and domestic significance. Whereas progress has been made in development of new Mtb antibiotic regimens, adjunct therapies including those based on autophagy are currently being sought to improve control of Mtb, inflammation, and reduce chronic pulmonary impairment after completion of antibacterial TB chemotherapy. Understanding the role and mechanisms of autophagy in control of TB has been and remains the focus of our program. Before we can harness the power of autophagy for TB treatments, which is the long-term objective of our project, we must delineate the roles of canonical and noncanonical autophagy and identify specific human factors that control them. This renewal project’s scope remains to define the molecular entities that marshal autophagic control of intracellular Mtb and counter tissue damage in TB, with the focus on links between innate immunity signaling and the general membrane homeostatic processes associated with autophagy. We hypothesize that pattern recognition receptors (PRRs), the uniquely human autophagy factor IRGM, and other entities, sense and integrate signals coming from membrane damage caused by virulent Mtb to deploy components of the autophagic apparatus and protect the host. Completion of the specific objectives of this project will deliver a comprehensive understanding of how Mtb damages host cells and tissues to cause pathology and how autophagy and the autophagy-related processes of membrane homeostasis protect against TB. The scope and specific aims remain the same with updates based on progress made. The specific aims are: Specific Aim 1. Determine how the mammalian autophagic apparatus recognizes phagosomal and other host cell membrane damage caused by virulent Mtb and how this contributes to autophagic control of Mtb. Specific Aim 2. Define the mechanism of action of human IRGM in autophagic processes in response to intracellular Mtb. The scope of the project remains unchanged with logical extensions reflecting the progress made to date. The key objectives are to understand how host cells detect presence of intracellular Mtb via membrane damage, how PRRs and IRGM function in this context, how signals are transmitted to the key regulators of autophagy, and how the membrane homeostasis via the autophagic component of Atg8ylation counters Mtb pathogenesis. This will deliver a new conceptual framework and specific targets for therapeutic interventions in TB.