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

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

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

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).

Original language	English (US)
Article number	104678
Journal	EBioMedicine
Volume	93
DOIs	https://doi.org/10.1016/j.ebiom.2023.104678
State	Published - Jul 2023
Externally published	Yes

Keywords

Antibody
B cell
Human
Immunology
Mycobacterium tuberculosis
Resister
T cell

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.ebiom.2023.104678

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Davies, L. R. L., Smith, M. T., Cizmeci, D., Fischinger, S., Shih-Lu Lee, J., Lu, L. L., Layton, E. D., Grant, A. D., Fielding, K., Stein, C. M., Boom, W. H., Hawn, T. R., Fortune, S. M., Wallis, R. S., Churchyard, G. J., Alter, G., & Seshadri, C. (2023). IFN-γ independent markers of Mycobacterium tuberculosis exposure among male South African gold miners. EBioMedicine, 93, Article 104678. https://doi.org/10.1016/j.ebiom.2023.104678

Davies, LRL, Smith, MT, Cizmeci, D, Fischinger, S, Shih-Lu Lee, J, Lu, LL, Layton, ED, Grant, AD, Fielding, K, Stein, CM, Boom, WH, Hawn, TR, Fortune, SM, Wallis, RS, Churchyard, GJ, Alter, G & Seshadri, C 2023, 'IFN-γ independent markers of Mycobacterium tuberculosis exposure among male South African gold miners', EBioMedicine, vol. 93, 104678. https://doi.org/10.1016/j.ebiom.2023.104678

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title = "IFN-γ independent markers of Mycobacterium tuberculosis exposure among male South African gold miners",

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",

author = "Davies, {Leela R.L.} and Smith, {Malisa T.} and Deniz Cizmeci and Stephanie Fischinger and {Shih-Lu Lee}, Jessica and Lu, {Lenette L.} and Layton, {Erik D.} and Grant, {Alison D.} and Katherine Fielding and Stein, {Catherine M.} and Boom, {W. Henry} and Hawn, {Thomas R.} and Fortune, {Sarah M.} and Wallis, {Robert S.} and Churchyard, {Gavin J.} and Galit Alter and Chetan Seshadri",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = jul,

doi = "10.1016/j.ebiom.2023.104678",

language = "English (US)",

volume = "93",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Elsevier BV",

}

TY - JOUR

T1 - IFN-γ independent markers of Mycobacterium tuberculosis exposure among male South African gold miners

AU - Davies, Leela R.L.

AU - Smith, Malisa T.

AU - Cizmeci, Deniz

AU - Fischinger, Stephanie

AU - Shih-Lu Lee, Jessica

AU - Lu, Lenette L.

AU - Layton, Erik D.

AU - Grant, Alison D.

AU - Fielding, Katherine

AU - Stein, Catherine M.

AU - Boom, W. Henry

AU - Hawn, Thomas R.

AU - Fortune, Sarah M.

AU - Wallis, Robert S.

AU - Churchyard, Gavin J.

AU - Alter, Galit

AU - Seshadri, Chetan

PY - 2023/7

Y1 - 2023/7

N2 - 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).

AB - 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).

KW - Antibody

KW - B cell

KW - Human

KW - Immunology

KW - Mycobacterium tuberculosis

KW - Resister

KW - T cell

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JO - EBioMedicine

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ER -

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

Abstract

Keywords

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