An evolutionary recent IFN-IL-6-CEBP axis is linked to monocyte expansion and tuberculosis severity in humans

Abstract

Monocyte counts are increased during human tuberculosis (TB) but it has not been determined whether Mycobacterium tuberculosis (Mtb) directly regulates myeloid commitment. We demonstrated that exposure to Mtb directs primary human CD34+ cells to differentiate into monocytes/macrophages. In vitro myeloid conversion did not require type I or type II IFN signaling. In contrast, Mtb enhanced IL-6 responses by CD34+ cell cultures and IL-6R neutralization inhibited myeloid differentiation and decreased mycobacterial growth in vitro. Integrated systems biology analysis of transcriptomic, proteomic and genomic data of large data sets of healthy controls and TB patients established the existence of a myeloid IL-6/IL6R/CEBP gene module associated with disease severity. Furthermore, genetic and functional analysis revealed the IL6/IL6R/CEBP gene module has undergone recent evolutionary selection, including Neanderthal introgression and human pathogen adaptation, connected to systemic monocyte counts. These results suggest Mtb co-opts an evolutionary recent IFN-IL6-CEBP feed-forward loop, increasing myeloid differentiation linked to severe TB in humans.

Data availability

Sequencing data have been deposited in GEO under accession code GSE129270.

The following previously published data sets were used

Article and author information

Author details

  1. Murilo Delgobo

    Laboratório de Imunobiologia, Departmento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Florianópolis, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  2. Daniel A G B Mendes

    Laboratório de Imunobiologia, Departmento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Florianópolis, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  3. Edgar Kozlova

    Laboratório de Imunobiologia, Departmento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Florianópolis, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  4. Edroaldo Lummertz Rocha

    Laboratório de Imunobiologia, Departmento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Florianópolis, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  5. Gabriela F Rodrigues-Luiz

    Laboratório de Imunobiologia, Departmento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Florianópolis, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  6. Lucas Mascarin

    Laboratório de Imunobiologia, Departmento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Florianópolis, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  7. Greicy Dias

    Laboratório de Imunobiologia, Departmento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Florianópolis, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  8. Daniel O Patrício

    Laboratório de Imunobiologia, Departmento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Florianópolis, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  9. Tim Dierckx

    Department of Microbiology, Immunology and Transplantation, University of Leuven, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  10. Maira A Bicca

    Laboratório de Imunobiologia, Departmento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Florianópolis, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  11. Gaelle Bretton

    Laboratory of Molecular Immunology, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Yonne Karoline Tenório de Menezes

    Laboratório de Imunobiologia, Departmento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Florianópolis, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  13. Márick R Starick

    Laboratório de Imunobiologia, Departmento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Florianópolis, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  14. Darcita Rovaris

    Tuberculosis Unit, Laboratório Central do Estado de Santa Catarina, Florianópolis, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  15. Joanita Del Moral

    Serviço de Hematologia, Hospital Universitário, Universidade Federal de Santa Catarina, Florianópolis, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  16. Daniel S Mansur

    Laboratório de Imunobiologia, Departmento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Florianopolis, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  17. Johan Van Weyenbergh

    Department of Microbiology, Immunology and Transplantation, University of Leuven, Leuven, Belgium
    For correspondence
    j.vw@live.be
    Competing interests
    The authors declare that no competing interests exist.
  18. André Báfica

    Laboratório de Imunobiologia, Departmento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Florianópolis, Brazil
    For correspondence
    andre.bafica@ufsc.br
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5148-600X

Funding

Howard Hughes Medical Institute (Early Career Scientist 55007412)

  • André Báfica

CAPES (23038.010048/2013-27)

  • Daniel S Mansur

FWO (G0D6817N)

  • Johan Van Weyenbergh

National Institutes of Health (Global Research Initiative Program TW008276)

  • André Báfica

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: This study was approved by the institutional review boards of Universidade Federal de Santa Catarina and The University Hospital Prof. Polydoro Ernani de São Thiago (IRB# 89894417.8.0000.0121). Informed consent was obtained from all subjects.

Reviewing Editor

  1. Bavesh D Kana, University of the Witwatersrand, South Africa

Version history

  1. Received: March 20, 2019
  2. Accepted: October 8, 2019
  3. Accepted Manuscript published: October 22, 2019 (version 1)
  4. Version of Record published: October 29, 2019 (version 2)

Copyright

© 2019, Delgobo et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Murilo Delgobo
  2. Daniel A G B Mendes
  3. Edgar Kozlova
  4. Edroaldo Lummertz Rocha
  5. Gabriela F Rodrigues-Luiz
  6. Lucas Mascarin
  7. Greicy Dias
  8. Daniel O Patrício
  9. Tim Dierckx
  10. Maira A Bicca
  11. Gaelle Bretton
  12. Yonne Karoline Tenório de Menezes
  13. Márick R Starick
  14. Darcita Rovaris
  15. Joanita Del Moral
  16. Daniel S Mansur
  17. Johan Van Weyenbergh
  18. André Báfica
(2019)
An evolutionary recent IFN-IL-6-CEBP axis is linked to monocyte expansion and tuberculosis severity in humans
eLife 8:e47013.
https://doi.org/10.7554/eLife.47013

Share this article

https://doi.org/10.7554/eLife.47013

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