Journal
NATURE MEDICINE
Volume 17, Issue 10, Pages 1261-U292Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.2420
Keywords
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Funding
- US National Institutes of Health (NIH) (Einstein Center for AIDS Research) [AI063537, AI093649, AI092448, AI26170, AI051519]
- Bill and Melinda Gates Foundation
- Albert Einstein College of Medicine [T32-AI007501]
- Einstein Cancer Center (NIH/National Cancer Institute [CA013330]
- Einstein Center for AIDS Research [NIH AI051519]
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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 Delta esx-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.
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