Essential Role of MHC II in the Antitubercular Efficacy of Pyrazinamide

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.