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

Autor:	Delgobo M; Laboratório de Imunobiologia, Departmento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Florianópolis, Brazil., Mendes DA; Laboratório de Imunobiologia, Departmento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Florianópolis, Brazil., Kozlova E; Laboratório de Imunobiologia, Departmento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Florianópolis, Brazil., Rocha EL; Laboratório de Imunobiologia, Departmento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Florianópolis, Brazil.; Boston Children's Hospital, Boston, United States., Rodrigues-Luiz GF; Laboratório de Imunobiologia, Departmento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Florianópolis, Brazil., Mascarin L; Laboratório de Imunobiologia, Departmento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Florianópolis, Brazil., Dias G; Laboratório de Imunobiologia, Departmento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Florianópolis, Brazil., Patrício DO; Laboratório de Imunobiologia, Departmento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Florianópolis, Brazil., Dierckx T; Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory for Clinical and Epidemiological Virology, KU Leuven, Leuven, Belgium., Bicca MA; Laboratório de Imunobiologia, Departmento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Florianópolis, Brazil., Bretton G; Laboratory of Molecular Immunology, The Rockefeller University, New York, United States., Tenório de Menezes YK; Laboratório de Imunobiologia, Departmento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Florianópolis, Brazil., Starick MR; Laboratório de Imunobiologia, Departmento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Florianópolis, Brazil., Rovaris D; Laboratório Central do Estado de Santa Catarina/LACEN, Florianópolis, Brazil., Del Moral J; Serviço de Hematologia, Hospital Universitário, Universidade Federal de Santa Catarina, Florianópolis, Brazil., Mansur DS; Laboratório de Imunobiologia, Departmento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Florianópolis, Brazil., Van Weyenbergh J; Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory for Clinical and Epidemiological Virology, KU Leuven, Leuven, Belgium., Báfica A; Laboratório de Imunobiologia, Departmento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Florianópolis, Brazil.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2019 Oct 22; Vol. 8. Date of Electronic Publication: 2019 Oct 22.
DOI:	10.7554/eLife.47013
Abstrakt:	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.)
Databáze:	MEDLINE
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