IL-10 Modulation Increases Pyrazinamide’s Antimycobacterial Efficacy against Mycobacterium tuberculosis Infection in Mice

Abstract

Abstract Mechanisms to shorten the duration of tuberculosis (TB) treatment include new drug formulations or schedules and the development of host-directed therapies (HDTs) that better enable the host immune system to eliminate Mycobacterium tuberculosis. Previous studies have shown that pyrazinamide, a first-line antibiotic, can also modulate immune function, making it an attractive target for combinatorial HDT/antibiotic therapy, with the goal to accelerate clearance of M. tuberculosis. In this study, we assessed the value of anti–IL-10R1 as an HDT along with pyrazinamide and show that short-term anti–IL-10R1 blockade during pyrazinamide treatment enhanced the antimycobacterial efficacy of pyrazinamide, resulting in faster clearance of M. tuberculosis in mice. Furthermore, 45 d of pyrazinamide treatment in a functionally IL-10–deficient environment resulted in sterilizing clearance of M. tuberculosis. Our data suggest that short-term IL-10 blockade with standard TB drugs has the potential to improve clinical outcome by reducing the treatment duration.