Essential Role of MHC II in the Antitubercular Efficacy of Pyrazinamide

Abstract Antibacterial drug mechanisms have traditionally been examined through a drug-pathogen lens, often overlooking the host’s role in shaping drug activity. However, growing evidence suggests that the host environment is crucial for antibacterial efficacy. Pyrazinamide (PZA), a key component of modern tuberculosis therapy, exemplifies this complexity—exhibiting potent in vivo activity despite its inability to reduce Mycobacterium tuberculosis viability in standard in vitro culture. Here, using macrophage and murine infection models, we identify a critical role for host cell-mediated immunity in PZA’s antitubercular action. Through the use of MHC II knockout mice, we demonstrate that CD4 T cell help is essential for PZA efficacy. Notably, while IFN-γ is required for PZA-mediated clearance of M. tuberculosis at extrapulmonary sites, bacterial reduction in the lungs occurs independently of IFN-γ signaling. Additionally, we show that PZA leverages cell-mediated immunity in part through activation of the oxidative burst. Our findings underscore the need to incorporate host factors into antibacterial drug evaluation and highlight potential avenues for host-directed therapies and adjunctive antibiotics in first- and second-line tuberculosis treatment.