title: Inhibition of apoptosis by Rv2456c through Nuclear factor-κB extends the survival of Mycobacterium tuberculosis.
abstract: Mycobacterium tuberculosis, the causative agent of tuberculosis, is an intracellular pathogen with several survival mechanisms aimed at subverting the host immune system. Apoptosis has been shown to be mycobactericidal, to activate CD8+T cells, and to be modulated by mycobacterial proteins. Since few mycobacterial proteins have so far been directly implicated in the interactions between M. tuberculosis and host cell apoptosis, we screened M. tuberculosis H37Rv transposon mutants to identify mutants that fail to inhibit cell death (FID). One of these FID mutants, FID19, had a transposon insertion in Rv2456c and is important for survival in host cells. The lack of the protein resulted in enhanced caspase-3 mediated apoptosis, which is probably due to an inability to activate nuclear factor-κB. Additionally, FID19 infection enhanced polyfunctional CD8+T cells and induced a higher frequency of interferon-γ secreting immune cells in a murine model. Taken together, our data suggest that Rv2456c is important for the survival of H37Rv by subduing the innate and ultimately adaptive immune responses of its host by preventing apoptosis of the infected cell. Better understanding of the host-mycobacterial interactions may be beneficial to develop novel drug targets and engineer more efficacious vaccine strains against tuberculosis.
authors.affiliation: Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Jurcic Smith
authors.affiliation: Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA; Department of Pathology, Duke University School of Medicine, Durham, NC, USA. Electronic address: Sunhee.lee@duke.edu.
authors.forename: Sunhee
authors.initials: S
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism*; D002460:Cell Line; D004251:DNA Transposable Elements; D004195:Disease Models, Animal; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D008810:Mice, Inbred C57BL; D050296:Microbial Viability; D016254:Mutagenesis, Insertional; D009169:Mycobacterium tuberculosis / Q000276:immunology / Q000502:physiology*; D014376:Tuberculosis / Q000382:microbiology / Q000473:pathology
chemical_list: D051017:Apoptosis Regulatory Proteins; D001426:Bacterial Proteins; D004251:DNA Transposable Elements
keywords: Apoptosis; Mycobacterium tuberculosis; Tuberculosis; Vaccine