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Clinical MedicineIn-Press PreviewInfectious disease Open Access | 10.1172/JCI188016

Mycobacterium tuberculosis resisters despite HIV exhibit activated T cells and macrophages in their pulmonary alveoli

Monica Dallmann-Sauer,1 Vinicius M. Fava,1 Stephanus T. Malherbe,2 Candice E. MacDonald,2 Marianna Orlova,1 Elouise E. Kroon,3 Aurélie Cobat,4 Stéphanie Boisson-Dupuis,4 Eileen G. Hoal,3 Laurent Abel,4 Marlo Möller,3 Jean-Laurent Casanova,4 Gerhard Walzl,2 Nelita Du Plessis,2 and Erwin Schurr1

1Program in Infectious Diseases and Global Health, The Research Institute of the McGill University Health Centre, Montréal, Canada

2outh African Medical Research Council Centre for Tuberculosis Research, Bio, Stellenbosch University, Cape Town, South Africa

3South African Medical Research Council Centre for Tuberculosis Research, Di, Stellenbosch University, Cape Town, South Africa

4St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller , The Rockefeller University, New York, United States of America

Find articles by Dallmann-Sauer, M. in: JCI | PubMed | Google Scholar

1Program in Infectious Diseases and Global Health, The Research Institute of the McGill University Health Centre, Montréal, Canada

2outh African Medical Research Council Centre for Tuberculosis Research, Bio, Stellenbosch University, Cape Town, South Africa

3South African Medical Research Council Centre for Tuberculosis Research, Di, Stellenbosch University, Cape Town, South Africa

4St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller , The Rockefeller University, New York, United States of America

Find articles by Fava, V. in: JCI | PubMed | Google Scholar |

1Program in Infectious Diseases and Global Health, The Research Institute of the McGill University Health Centre, Montréal, Canada

2outh African Medical Research Council Centre for Tuberculosis Research, Bio, Stellenbosch University, Cape Town, South Africa

3South African Medical Research Council Centre for Tuberculosis Research, Di, Stellenbosch University, Cape Town, South Africa

4St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller , The Rockefeller University, New York, United States of America

Find articles by Malherbe, S. in: JCI | PubMed | Google Scholar

1Program in Infectious Diseases and Global Health, The Research Institute of the McGill University Health Centre, Montréal, Canada

2outh African Medical Research Council Centre for Tuberculosis Research, Bio, Stellenbosch University, Cape Town, South Africa

3South African Medical Research Council Centre for Tuberculosis Research, Di, Stellenbosch University, Cape Town, South Africa

4St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller , The Rockefeller University, New York, United States of America

Find articles by MacDonald, C. in: JCI | PubMed | Google Scholar

1Program in Infectious Diseases and Global Health, The Research Institute of the McGill University Health Centre, Montréal, Canada

2outh African Medical Research Council Centre for Tuberculosis Research, Bio, Stellenbosch University, Cape Town, South Africa

3South African Medical Research Council Centre for Tuberculosis Research, Di, Stellenbosch University, Cape Town, South Africa

4St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller , The Rockefeller University, New York, United States of America

Find articles by Orlova, M. in: JCI | PubMed | Google Scholar |

1Program in Infectious Diseases and Global Health, The Research Institute of the McGill University Health Centre, Montréal, Canada

2outh African Medical Research Council Centre for Tuberculosis Research, Bio, Stellenbosch University, Cape Town, South Africa

3South African Medical Research Council Centre for Tuberculosis Research, Di, Stellenbosch University, Cape Town, South Africa

4St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller , The Rockefeller University, New York, United States of America

Find articles by Kroon, E. in: JCI | PubMed | Google Scholar

1Program in Infectious Diseases and Global Health, The Research Institute of the McGill University Health Centre, Montréal, Canada

2outh African Medical Research Council Centre for Tuberculosis Research, Bio, Stellenbosch University, Cape Town, South Africa

3South African Medical Research Council Centre for Tuberculosis Research, Di, Stellenbosch University, Cape Town, South Africa

4St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller , The Rockefeller University, New York, United States of America

Find articles by Cobat, A. in: JCI | PubMed | Google Scholar |

1Program in Infectious Diseases and Global Health, The Research Institute of the McGill University Health Centre, Montréal, Canada

2outh African Medical Research Council Centre for Tuberculosis Research, Bio, Stellenbosch University, Cape Town, South Africa

3South African Medical Research Council Centre for Tuberculosis Research, Di, Stellenbosch University, Cape Town, South Africa

4St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller , The Rockefeller University, New York, United States of America

Find articles by Boisson-Dupuis, S. in: JCI | PubMed | Google Scholar

1Program in Infectious Diseases and Global Health, The Research Institute of the McGill University Health Centre, Montréal, Canada

2outh African Medical Research Council Centre for Tuberculosis Research, Bio, Stellenbosch University, Cape Town, South Africa

3South African Medical Research Council Centre for Tuberculosis Research, Di, Stellenbosch University, Cape Town, South Africa

4St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller , The Rockefeller University, New York, United States of America

Find articles by Hoal, E. in: JCI | PubMed | Google Scholar

1Program in Infectious Diseases and Global Health, The Research Institute of the McGill University Health Centre, Montréal, Canada

2outh African Medical Research Council Centre for Tuberculosis Research, Bio, Stellenbosch University, Cape Town, South Africa

3South African Medical Research Council Centre for Tuberculosis Research, Di, Stellenbosch University, Cape Town, South Africa

4St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller , The Rockefeller University, New York, United States of America

Find articles by Abel, L. in: JCI | PubMed | Google Scholar |

1Program in Infectious Diseases and Global Health, The Research Institute of the McGill University Health Centre, Montréal, Canada

2outh African Medical Research Council Centre for Tuberculosis Research, Bio, Stellenbosch University, Cape Town, South Africa

3South African Medical Research Council Centre for Tuberculosis Research, Di, Stellenbosch University, Cape Town, South Africa

4St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller , The Rockefeller University, New York, United States of America

Find articles by Möller, M. in: JCI | PubMed | Google Scholar

1Program in Infectious Diseases and Global Health, The Research Institute of the McGill University Health Centre, Montréal, Canada

2outh African Medical Research Council Centre for Tuberculosis Research, Bio, Stellenbosch University, Cape Town, South Africa

3South African Medical Research Council Centre for Tuberculosis Research, Di, Stellenbosch University, Cape Town, South Africa

4St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller , The Rockefeller University, New York, United States of America

Find articles by Casanova, J. in: JCI | PubMed | Google Scholar |

1Program in Infectious Diseases and Global Health, The Research Institute of the McGill University Health Centre, Montréal, Canada

2outh African Medical Research Council Centre for Tuberculosis Research, Bio, Stellenbosch University, Cape Town, South Africa

3South African Medical Research Council Centre for Tuberculosis Research, Di, Stellenbosch University, Cape Town, South Africa

4St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller , The Rockefeller University, New York, United States of America

Find articles by Walzl, G. in: JCI | PubMed | Google Scholar |

1Program in Infectious Diseases and Global Health, The Research Institute of the McGill University Health Centre, Montréal, Canada

2outh African Medical Research Council Centre for Tuberculosis Research, Bio, Stellenbosch University, Cape Town, South Africa

3South African Medical Research Council Centre for Tuberculosis Research, Di, Stellenbosch University, Cape Town, South Africa

4St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller , The Rockefeller University, New York, United States of America

Find articles by Du Plessis, N. in: JCI | PubMed | Google Scholar |

1Program in Infectious Diseases and Global Health, The Research Institute of the McGill University Health Centre, Montréal, Canada

2outh African Medical Research Council Centre for Tuberculosis Research, Bio, Stellenbosch University, Cape Town, South Africa

3South African Medical Research Council Centre for Tuberculosis Research, Di, Stellenbosch University, Cape Town, South Africa

4St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller , The Rockefeller University, New York, United States of America

Find articles by Schurr, E. in: JCI | PubMed | Google Scholar |

Published January 21, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI188016.
Copyright © 2025, Dallmann-Sauer et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 21, 2025 - Version history
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Abstract

Natural resistance to Mycobacterium tuberculosis (Mtb) infection in some people with HIV (PWH) is unexplained. We performed single cell RNA-sequencing of bronchoalveolar lavage cells, unstimulated or ex vivo stimulated with Mtb, for 7 PWH who were TST & IGRA positive (called LTBI) and 6 who were persistently TST & IGRA negative (called resisters). Alveolar macrophages (AM) from resisters displayed a baseline M1 macrophage phenotype while AM from LTBI did not. Resisters displayed alveolar lymphocytosis, with enrichment of all T cell subpopulations including IFNG-expressing cells. In both groups, mycobactericidal granulysin was expressed almost exclusively by a T cell subtype that co-expressed granzyme B, perforin and NK cell receptors. These poly-cytotoxic T lymphocytes (CTL) over-expressed activating NK cell receptors and were increased in resister BAL. Following challenge with Mtb, only Intraepithelial Lymphocytes-like cells from LTBI participants responded with increased transcription of IFNG. AM from resisters responded with a stronger TNF signature at 6h post-infection while at 24h post-infection AM from LTBI displayed a stronger IFN-γ signature. Conversely, at 24h post-infection only AM from resisters displayed a significant upregulation of MICA transcripts which encode an activating ligand for poly-CTL. These results suggest that poly-CTL and AM mediate the resister phenotype in PWH.

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  • Version 1 (January 21, 2025): In-Press Preview
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