1. An evolutionary recent IFN/IL-6/CEBP axis is linked to monocyte expansion and tuberculosis severity in humans
- Author
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Murilo Delgobo, Johan Van Weyenbergh, Tim Dierckx, Joanita Ângela Gonzaga Del Moral, André Báfica, Gaëlle Breton, Darcita Rovaris, Yonne Karoline Tenório de Menezes, Daniel Augusto Gasparin Bueno Mendes, Gabriela F. Rodrigues-Luiz, Edroaldo Lummertz da Rocha, Maíra A. Bicca, Edgar Kozlova, Lucas Mascarin, Daniel O. Patricio, Greicy Dias, Daniel S. Mansur, and Márick R Starick
- Subjects
0301 basic medicine ,Proteomics ,Myeloid ,Hydrolases ,Antigens, CD34 ,Severity of Illness Index ,Monocytes ,immunology ,Transcriptome ,computational biology ,0302 clinical medicine ,Immunology and Inflammation ,Myeloid Cells ,Biology (General) ,0303 health sciences ,biology ,General Neuroscience ,systems biology ,Cell Differentiation ,General Medicine ,3. Good health ,interferons ,medicine.anatomical_structure ,tuberculosis ,Medicine ,Cytokines ,Research Article ,Computational and Systems Biology ,Tuberculosis ,QH301-705.5 ,Science ,General Biochemistry, Genetics and Molecular Biology ,Mycobacterium ,Mycobacterium tuberculosis ,03 medical and health sciences ,evolution ,medicine ,Humans ,human ,Interleukin 6 ,030304 developmental biology ,Cell Proliferation ,General Immunology and Microbiology ,Interleukin-6 ,Monocyte ,Macrophages ,biology.organism_classification ,medicine.disease ,Receptors, Interleukin-6 ,In vitro ,030104 developmental biology ,interleukins ,inflammation ,Cell culture ,Immunology ,biology.protein ,CCAAT-Enhancer-Binding Proteins ,030215 immunology ,Genome-Wide Association Study - Abstract
Monocyte counts are increased during human tuberculosis (TB) but it has not been determined whetherMycobacterium tuberculosis(Mtb) directly regulates myeloid commitment. We demonstrated that exposure toMtbdirects 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,Mtbenhanced 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 myeloidIL-6/IL6R/CEBPgene module associated with disease severity. Furthermore, genetic and functional analysis revealed theIL6/IL6R/CEBPgene module has undergone recent evolutionary selection, including Neanderthal introgression and human pathogen adaptation, connected to systemic monocyte counts. These results suggestMtbco-opts an evolutionary recent IFN-IL6-CEBP feed-forward loop, increasing myeloid differentiation linked to severe TB in humans.
- Published
- 2019