Efficacy of Adjunctive Tofacitinib Therapy in Mouse Models of Tuberculosis

The global tuberculosis (TB) epidemic and the spread of multi- and extensively-drug resistant strains of Mycobacterium tuberculosis (M.tb) have been fueled by low adherence to following lengthy treatment protocols, and the rapid spread of HIV (Human Immunodeficiency Virus). Persistence of the infection in immunocompetent individuals follows from the ability of M.tb to subvert host immune responses in favor of survival within macrophages. Alternative host-directed strategies are therefore being currently sought to improve treatment efficacy and duration. In this study, we evaluated tofacitinib, a new oral Janus kinase (JAK) blocker with anti-inflammatory properties, in shortening tuberculosis treatment. BALB/c mice, which are immunocompetent, showed acceleration of M.tb clearance achieving apparent sterilization after 16weeks of adjunctive tofacitinib therapy at average exposures higher than recommended in humans, while mice receiving standard treatment alone did not achieve clearance until 24weeks. True sterilization with tofacitinib was not achieved until five months. C3HeB/FeJ mice, which show reduced pro-inflammatory cytokines during M.tb infection, did not show improved clearance with adjunctive tofacitinib therapy, indicating that the nature of granulomatous lesions and host immunity may influence responsiveness to tofacitinib. Our findings suggest that the JAK pathway could be explored further for host-directed therapy in immunocompetent individuals. •We evaluated tofacitinib, an anti-inflammatory oral Janus kinase blocker, in shortening tuberculosis treatment.•M.tb clearance was achieved after 16 weeks of tofacitinib therapy in BALB/c mice compared to 24 weeks of standard therapy.•C3HeB/FeJ mice did not show improved clearance, suggesting that host immunity may influence responsiveness to tofacitinib.Tuberculosis (TB) remains a leading cause of morbidity and mortality worldwide. The persistence of Mycobacterium tuberculosis infection follows from its ability to subvert host immune responses in favor of survival within macrophages. There is now growing recognition that therapies targeting the host immune system could serve as a unique approach to TB treatment. Here we examined the potential of tofacitinib, an anti-inflammatory agent, as an adjunctive, host-directed therapy for TB. We found apparent sterilization after 16weeks of adjunctive tofacitinib therapy, compared to 24weeks with standard treatment in immunocompetent BALB/c mice.