IFN-γ independent markers of Mycobacterium tuberculosis exposure among male South African gold minersResearch in context
Leela R.L. Davies,
Malisa T. Smith,
Deniz Cizmeci,
Stephanie Fischinger,
Jessica Shih-Lu Lee,
Lenette L. Lu,
Erik D. Layton,
Alison D. Grant,
Katherine Fielding,
Catherine M. Stein,
W. Henry Boom,
Thomas R. Hawn,
Sarah M. Fortune,
Robert S. Wallis,
Gavin J. Churchyard,
Galit Alter,
Chetan Seshadri
Affiliations
Leela R.L. Davies
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Brigham and Women's Hospital, Boston, MA, USA
Malisa T. Smith
Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
Deniz Cizmeci
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
Stephanie Fischinger
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA
Jessica Shih-Lu Lee
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA
Lenette L. Lu
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA
Erik D. Layton
Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
Alison D. Grant
TB Centre, London School of Hygiene and Tropical Medicine, London, UK
Katherine Fielding
TB Centre, London School of Hygiene and Tropical Medicine, London, UK
Catherine M. Stein
Department of Medicine, Case Western Reserve University, Cleveland, OH, USA; Department of Population & Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA
W. Henry Boom
Department of Medicine, Case Western Reserve University, Cleveland, OH, USA
Thomas R. Hawn
Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
Sarah M. Fortune
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Department of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Boston, MA, USA
Robert S. Wallis
Department of Medicine, Case Western Reserve University, Cleveland, OH, USA; The Aurum Institute, Parktown, South Africa
Gavin J. Churchyard
The Aurum Institute, Parktown, South Africa; Department of Medicine, Vanderbilt University, Nashville, TN, USA
Galit Alter
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Moderna Therapeutics, Cambridge, MA, USA
Chetan Seshadri
Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA; Seattle Tuberculosis Research Advancement Center, Seattle, WA, USA; Corresponding author. University of Washington School of Medicine, 750 Republican Street, Room F871, Seattle, WA 98109, USA.
Summary: Background: The prevalence of tuberculosis among men who work in the gold mines of South Africa is among the highest in the world, but a fraction of miners demonstrate consistently negative results upon tuberculin skin test (TST) and IFN-γ release assay (IGRA). We hypothesized that these “resisters” (RSTRs) may display unconventional immune signatures of exposure to M. tuberculosis (M.tb). Methods: In a cohort of RSTRs and matched controls with latent TB infection (LTBI), we profiled the functional breadth of M.tb antigen-specific T cell and antibody responses using multi-parameter flow cytometry and systems serology, respectively. Findings: RSTRs and LTBI controls both exhibited IFN-γ independent T-cell and IgG antibody responses to M.tb-specific antigens ESAT-6 and CFP-10. Antigen-specific antibody Fc galactosylation and sialylation were higher among RSTRs. In a combined T-cell and antibody analysis, M.tb lysate-stimulated TNF secretion by T cells correlated positively with levels of purified protein derivative-specific IgG. A multivariate model of the combined data was able to differentiate RSTR and LTBI subjects. Interpretation: IFN-γ independent immune signatures of exposure to M.tb, which are not detected by approved clinical diagnostics, are readily detectable in an occupational cohort uniquely characterized by intense and long-term infection pressure. Further, TNF may mediate a coordinated response between M.tb-specific T-cells and B-cells. Funding: This work was supported by the US National Institutes of Health (R01-AI124348 to Boom, Stein, and Hawn; R01-AI125189 and R01-AI146072 to Seshadri; and 75N93019C00071 to Fortune, Alter, Seshadri, and Boom), the Doris Duke Charitable Foundation (Davies), the Bill & Melinda Gates Foundation (OPP1151836 and OPP1109001 to Hawn; and OPP1151840 to Alter), Mass Life Science Foundation (Fortune), and Good Ventures Fund (Fortune).
