An evolutionary recent IFN-IL-6-CEBP axis is linked to monocyte expansion and tuberculosis severity in humans
- Universidade Federal de Santa Catarina, Brazil
- University of Leuven, Belgium
- The Rockefeller University, United States
- Laboratório Central do Estado de Santa Catarina, Brazil
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.
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Blood Transcriptional Profiles of Active TB (UK Test Set Separated)NCBI Gene Expression Omnibus, GSE19443.
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Transcriptional profiles in Blood of patients with Tuberculosis - Longitudinal StudyNCBI Gene Expression Omnibus, GSE19435.
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Blood Transcriptional Profiles in Active and Latent Tuberculosis UK (Training Set)NCBI Gene Expression Omnibus, GSE19439.
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Blood Transcriptional Profiles of Active and Latent TB (UK Test Set)NCBI Gene Expression Omnibus, GSE19444.
Article and author information
Author details
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.
Reviewing Editor
- Bavesh D Kana, University of the Witwatersrand, South Africa
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.
Version history
- Received: March 20, 2019
- Accepted: October 8, 2019
- Accepted Manuscript published: October 22, 2019 (version 1)
- 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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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
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