IFN-γ independent markers of Mycobacterium tuberculosis exposure among male South African gold miners

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

doi:10.1016/j.ebiom.2023.104678

IFN-γ independent markers of Mycobacterium tuberculosis exposure among male South African gold miners

EBioMedicine. 2023 Jul:93:104678. doi: 10.1016/j.ebiom.2023.104678. Epub 2023 Jun 26.

Authors

Leela R L Davies¹, Malisa T Smith², Deniz Cizmeci³, Stephanie Fischinger⁴, Jessica Shih-Lu Lee⁴, Lenette L Lu⁴, Erik D Layton², Alison D Grant⁵, Katherine Fielding⁵, Catherine M Stein⁶, W Henry Boom⁷, Thomas R Hawn², Sarah M Fortune⁸, Robert S Wallis⁹, Gavin J Churchyard¹⁰, Galit Alter¹¹, Chetan Seshadri¹²

Affiliations

¹ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Brigham and Women's Hospital, Boston, MA, USA.
² Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.
³ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁴ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA.
⁵ TB Centre, London School of Hygiene and Tropical Medicine, London, UK.
⁶ Department of Medicine, Case Western Reserve University, Cleveland, OH, USA; Department of Population & Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.
⁷ Department of Medicine, Case Western Reserve University, Cleveland, OH, USA.
⁸ 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.
⁹ Department of Medicine, Case Western Reserve University, Cleveland, OH, USA; The Aurum Institute, Parktown, South Africa.
¹⁰ The Aurum Institute, Parktown, South Africa; Department of Medicine, Vanderbilt University, Nashville, TN, USA.
¹¹ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Moderna Therapeutics, Cambridge, MA, USA.
¹² Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA; Seattle Tuberculosis Research Advancement Center, Seattle, WA, USA. Electronic address: seshadri@u.washington.edu.

Abstract

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).

Keywords: Antibody; B cell; Human; Immunology; Mycobacterium tuberculosis; Resister; T cell.

MeSH terms

Antigens, Bacterial
Humans
Interferon-gamma
Male
Mycobacterium tuberculosis*
South Africa / epidemiology
Tuberculin Test
Tuberculosis* / diagnosis
Tuberculosis* / epidemiology

Substances

Antigens, Bacterial
Interferon-gamma

Abstract

MeSH terms

Substances

Grants and funding