title: Efficacy of Adjunctive Tofacitinib Therapy in Mouse Models of Tuberculosis.
abstract: 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 16 weeks of adjunctive tofacitinib therapy at average exposures higher than recommended in humans, while mice receiving standard treatment alone did not achieve clearance until 24 weeks. 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.
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA ; Université des Sciences, des Techniques et des Technologies de Bamako (USTTB), Bamako, Mali.
authors.forename: Mamoudou
authors.initials: M
authors.lastname: Maiga
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA ; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
authors.forename: Bintou Ahmadou
authors.initials: BA
authors.lastname: Ahidjo
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA ; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
authors.forename: Mariama C
authors.initials: MC
authors.lastname: Maiga
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA ; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
authors.forename: Laurene
authors.initials: L
authors.lastname: Cheung
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA ; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
authors.forename: Shaaretha
authors.initials: S
authors.lastname: Pelly
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Shichun
authors.initials: S
authors.lastname: Lun
authors.affiliation: Université des Sciences, des Techniques et des Technologies de Bamako (USTTB), Bamako, Mali.
authors.forename: Flabou
authors.initials: F
authors.lastname: Bougoudogo
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA ; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Bishai
mesh_terms: D000818:Animals; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D010880:Piperidines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D014376:Tuberculosis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology
chemical_list: D016207:Cytokines; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib
keywords: Host-directed therapy; Tofacitinib; Tuberculosis