Essential Role of CD4 T Cells in the Antitubercular Efficacy of Pyrazinamide

Abstract

Defining the mechanisms that govern antibacterial drugs has largely centered on the drug-parasite paradigm, which has untethered the host as a significant contributor in drug activity. Yet, a growing body of evidence has shown that the host environment is critical for antibacterial drug efficacy. Pyrazinamide, a cornerstone of modern therapy for tuberculosis, has long perplexed researchers by its potent activity in vivo and inability to reduce Mycobacterium tuberculosis viability in standard culture medium in vitro. Here, we use a combination of macrophage and murine infection models to uncover a critical role for cell-mediated responses in the antitubercular action of pyrazinamide in vivo.  Through the use of a MHC II knockout mouse model we show that CD4 T cell help is essential for pyrazinamide action. Interestingly, while IFN-γ plays a significant role in pyrazinamide-mediated clearance of M. tuberculosis at extrapulmonary sites, IFN-γ independent signals are sufficient for pyrazinamide to reduce bacterial burden in the lungs. Further, we demonstrate that cell-mediated responses contribute to pyrazinamide action in part through activation of the oxidative burst. Collectively, our data highlight the importance of host consideration when evaluating newly developed antitubercular drugs and provide multiple avenues for host-directed treatments and other antibiotics as adjunctive drugs in first- and second-line tuberculosis therapies.

Keywords: Pyrazinamide, tuberculosis, interferon-gamma, oxidative burst, CD4 T cells, cell-mediated immunity