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

EBioMedicine (Jul 2023)

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.

Journal volume & issue: Vol. 93
p. 104678

Abstract

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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).

Published in EBioMedicine

ISSN: 2352-3964 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General)
Website: http://www.journals.elsevier.com/ebiomedicine/

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