1. An evolutionary recent IFN/IL-6/CEBP axis is linked to monocyte expansion and tuberculosis severity in humans.
- Author
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Delgobo M, Mendes DA, Kozlova E, Rocha EL, Rodrigues-Luiz GF, Mascarin L, Dias G, Patrício DO, Dierckx T, Bicca MA, Bretton G, Tenório de Menezes YK, Starick MR, Rovaris D, Del Moral J, Mansur DS, Van Weyenbergh J, and Báfica A
- Subjects
- Antigens, CD34, CCAAT-Enhancer-Binding Proteins genetics, Cell Differentiation, Cell Proliferation, Cytokines genetics, Cytokines metabolism, Genome-Wide Association Study, Humans, Hydrolases, Interferons genetics, Interleukin-6 genetics, Macrophages microbiology, Monocytes microbiology, Mycobacterium tuberculosis pathogenicity, Myeloid Cells physiology, Proteomics, Receptors, Interleukin-6, Severity of Illness Index, Transcriptome, Tuberculosis metabolism, CCAAT-Enhancer-Binding Proteins metabolism, Interferons metabolism, Interleukin-6 metabolism, Monocytes metabolism, Mycobacterium tuberculosis immunology, Tuberculosis immunology
- 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., Competing Interests: MD, DM, EK, ER, GR, LM, GD, DP, TD, MB, GB, YT, MS, DR, JD, DM, JV, AB No competing interests declared, (© 2019, Delgobo et al.)- Published
- 2019
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