title: A recombinant Mycobacterium smegmatis induces potent bactericidal immunity against Mycobacterium tuberculosis.
abstract: We report the involvement of an evolutionarily conserved set of mycobacterial genes, the esx-3 region, in evasion of bacterial killing by innate immunity. Whereas high-dose intravenous infections of mice with the rapidly growing mycobacterial species Mycobacterium smegmatis bearing an intact esx-3 locus were rapidly lethal, infection with an M. smegmatis Δesx-3 mutant (here designated as the IKE strain) was controlled and cleared by a MyD88-dependent bactericidal immune response. Introduction of the orthologous Mycobacterium tuberculosis esx-3 genes into the IKE strain resulted in a strain, designated IKEPLUS, that remained susceptible to innate immune killing and was highly attenuated in mice but had a marked ability to stimulate bactericidal immunity against challenge with virulent M. tuberculosis. Analysis of these adaptive immune responses indicated that the highly protective bactericidal immunity elicited by IKEPLUS was dependent on CD4(+) memory T cells and involved a distinct shift in the pattern of cytokine responses by CD4(+) cells. Our results establish a role for the esx-3 locus in promoting mycobacterial virulence and also identify the IKE strain as a potentially powerful candidate vaccine vector for eliciting protective immunity to M. tuberculosis.
authors: Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, New York, USA.
authors: Kari A
authors: KA
authors: Sweeney
authors: Dee N
authors: DN
authors: Dao
authors: Michael F
authors: MF
authors: Goldberg
authors: Tsungda
authors: T
authors: Hsu
authors: Manjunatha M
authors: MM
authors: Venkataswamy
authors: Marcela
authors: M
authors: Henao-Tamayo
authors: Diane
authors: D
authors: Ordway
authors: Rani S
authors: RS
authors: Sellers
authors: Paras
authors: P
authors: Jain
authors: Bing
authors: B
authors: Chen
authors: Mei
authors: M
authors: Chen
authors: John
authors: J
authors: Kim
authors: Regy
authors: R
authors: Lukose
authors: John
authors: J
authors: Chan
authors: Ian M
authors: IM
authors: Orme
authors: Steven A
authors: SA
authors: Porcelli
authors: William R
authors: WR
authors: Jacobs
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology*; D019264:Adoptive Transfer; D000818:Animals; D001428:Bacterial Vaccines / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000097:blood; D005434:Flow Cytometry; D018014:Gene Transfer Techniques; D005798:Genes, Bacterial / Q000276:immunology*; D006652:Histological Techniques; D007113:Immunity, Innate / Q000276:immunology*; D051379:Mice; D020102:Mycobacterium smegmatis / Q000235:genetics / Q000276:immunology*; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D014376:Tuberculosis / Q000276:immunology* / Q000473:pathology
chemical_list: D001428:Bacterial Vaccines; D016207:Cytokines; D053594:Myeloid Differentiation Factor 88