ABSTRACT Mycobacterium tuberculosis (Mtb) was the world’s single leading cause of death from infection before COVID- 19. Direct-acting antimycobacterial regimens are long, often toxic and plagued by emergence of drug resistance. Adjunctive therapies could potentially speed the cure of tuberculosis by targeting a process in the host that alters the host-pathogen interaction to the advantage of the host. One potential form of host-directed therapy would be to help macrophages better survive Mtb infection. In vitro, the death of Mtb-infected mouse macrophages is co- dependent on a type I interferon (IFN), IFN-beta, that macrophages produce in response to Mtb, along with an additional contribution by Mtb. This application seeks to identify specific molecular participants in Mtb-induced macrophage death that are downstream of the type I IFN receptor. We have identified potential molecular participants by two approaches—a CRISPR activation screen that restored Mtb-induced cell death to macrophages lacking the type I IFN receptor, and an innovative biochemical pulldown approach using a probe based on a small chemical compound that rescues Mtb-infected macrophages from Mtb-induced cell death without impairing the growth of Mtb. This application aims to validate the candidates genetically, test the ability of already existing inhibitors to recapitulate the effect of knocking them out, and then place the validated candidates on a mechanistic path. That would set the stage for future studies, beyond the scope of this application, to find, improve or develop drug-like inhibitors for tests in preclinical models of TB to see if they mitigate pathology and hasten cure when used in combination with direct-acting antimycobacterial agents.