A recombinant Mycobacterium smegmatis induces potent bactericidal immunity against Mycobacterium tuberculosis

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Abstract
New vaccine candidates are urgently needed for the control and prevention of Mycobacterium tuberculosis (Mtb) infection. Kari Sweeney and her colleagues now report that an attenuated strain of Mycobacterium smegmatis expressing the esx-3 genes from Mtb induces effective CD4+ T cell dependent immunity against infection with Mtb in mice. The study offers a new avenue for the identification of protective immunogens in Mtb infection and a candidate vaccine platform warranting further study. 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.