Journal
NATURE MEDICINE
Volume 25, Issue 6, Pages 977-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41591-019-0441-3
Keywords
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Funding
- Gates Foundation [OPP1109001, OPP1151840, OPP1156795]
- Ragon Institute
- Samana Cay MGH scholar program
- [K08-AI130357]
- [U01-AI115642]
- [R01-AI124348]
- [P41GM103694]
- Bill and Melinda Gates Foundation [OPP1156795, OPP1151840, OPP1109001] Funding Source: Bill and Melinda Gates Foundation
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Exposure to Mycobacterium tuberculosis (Mtb) results in heterogeneous clinical outcomes including primary progressive tuberculosis and latent Mtb infection (LTBI). Mtb infection is identified using the tuberculin skin test and interferon-gamma (IFN-gamma) release assay IGRA, and a positive result may prompt chemoprophylaxis to prevent progression to tuberculosis. In the present study, we report on a cohort of Ugandan individuals who were household contacts of patients with TB. These individuals were highly exposed to Mtb but tested negative disease by IFN-gamma release assay and tuberculin skin test, 'resisting' development of classic LTBI. We show that 'resisters' possess IgM, class-switched IgG antibody responses and non-IFN-gamma T cell responses to the Mtb-specific proteins ESAT6 and CFP10, immunologic evidence of exposure to Mtb. Compared to subjects with classic LTBI, 'resisters' display enhanced antibody avidity and distinct Mtb-specific IgG Fc profiles. These data reveal a distinctive adaptive immune profile among Mtb-exposed subjects, supporting an expanded definition of the host response to Mtb exposure, with implications for public health and the design of clinical trials.
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