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IFN-γ independent markers of Mycobacterium tuberculosis exposure among male South African gold miners
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”...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10320233/ https://www.ncbi.nlm.nih.gov/pubmed/37379655 http://dx.doi.org/10.1016/j.ebiom.2023.104678 |
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author | Davies, Leela R.L. Smith, Malisa T. Cizmeci, Deniz Fischinger, Stephanie Shih-Lu Lee, Jessica Lu, Lenette L. Layton, Erik D. Grant, Alison D. Fielding, Katherine Stein, Catherine M. Boom, W. Henry Hawn, Thomas R. Fortune, Sarah M. Wallis, Robert S. Churchyard, Gavin J. Alter, Galit Seshadri, Chetan |
author_facet | Davies, Leela R.L. Smith, Malisa T. Cizmeci, Deniz Fischinger, Stephanie Shih-Lu Lee, Jessica Lu, Lenette L. Layton, Erik D. Grant, Alison D. Fielding, Katherine Stein, Catherine M. Boom, W. Henry Hawn, Thomas R. Fortune, Sarah M. Wallis, Robert S. Churchyard, Gavin J. Alter, Galit Seshadri, Chetan |
author_sort | Davies, Leela R.L. |
collection | PubMed |
description | 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 10.13039/100000002US 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 10.13039/100000862Doris Duke Charitable Foundation (Davies), the 10.13039/100000865Bill & Melinda Gates Foundation (OPP1151836 and OPP1109001 to Hawn; and OPP1151840 to Alter), Mass Life Science Foundation (Fortune), and Good Ventures Fund (Fortune). |
format | Online Article Text |
id | pubmed-10320233 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-103202332023-07-06 IFN-γ independent markers of Mycobacterium tuberculosis exposure among male South African gold miners Davies, Leela R.L. Smith, Malisa T. Cizmeci, Deniz Fischinger, Stephanie Shih-Lu Lee, Jessica Lu, Lenette L. Layton, Erik D. Grant, Alison D. Fielding, Katherine Stein, Catherine M. Boom, W. Henry Hawn, Thomas R. Fortune, Sarah M. Wallis, Robert S. Churchyard, Gavin J. Alter, Galit Seshadri, Chetan eBioMedicine Articles 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 10.13039/100000002US 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 10.13039/100000862Doris Duke Charitable Foundation (Davies), the 10.13039/100000865Bill & Melinda Gates Foundation (OPP1151836 and OPP1109001 to Hawn; and OPP1151840 to Alter), Mass Life Science Foundation (Fortune), and Good Ventures Fund (Fortune). Elsevier 2023-06-26 /pmc/articles/PMC10320233/ /pubmed/37379655 http://dx.doi.org/10.1016/j.ebiom.2023.104678 Text en © 2023 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Articles Davies, Leela R.L. Smith, Malisa T. Cizmeci, Deniz Fischinger, Stephanie Shih-Lu Lee, Jessica Lu, Lenette L. Layton, Erik D. Grant, Alison D. Fielding, Katherine Stein, Catherine M. Boom, W. Henry Hawn, Thomas R. Fortune, Sarah M. Wallis, Robert S. Churchyard, Gavin J. Alter, Galit Seshadri, Chetan IFN-γ independent markers of Mycobacterium tuberculosis exposure among male South African gold miners |
title | IFN-γ independent markers of Mycobacterium tuberculosis exposure among male South African gold miners |
title_full | IFN-γ independent markers of Mycobacterium tuberculosis exposure among male South African gold miners |
title_fullStr | IFN-γ independent markers of Mycobacterium tuberculosis exposure among male South African gold miners |
title_full_unstemmed | IFN-γ independent markers of Mycobacterium tuberculosis exposure among male South African gold miners |
title_short | IFN-γ independent markers of Mycobacterium tuberculosis exposure among male South African gold miners |
title_sort | ifn-γ independent markers of mycobacterium tuberculosis exposure among male south african gold miners |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10320233/ https://www.ncbi.nlm.nih.gov/pubmed/37379655 http://dx.doi.org/10.1016/j.ebiom.2023.104678 |
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