TY - JOUR T1 - <em>Mycobacterium tuberculosis</em> hijacks an evolutionary recent IFN-IL-6-CEBP axis linked to monocyte development and disease severity in humans JF - bioRxiv DO - 10.1101/514943 SP - 514943 AU - Murilo Delgobo AU - Edgar Kozlova AU - Edroaldo Lummertz Rocha AU - Gabriela F. Rodrigues-Luiz AU - Daniel A. G. B. Mendes AU - Lucas Mascarin AU - Greicy Dias AU - Daniel O. Patricio AU - Tim Dierckx AU - Maíra A. Bicca AU - Gaëlle Breton AU - Darcita Rovaris AU - Joanita Del Moral AU - Daniel S. Mansur AU - Johan Van Weyenbergh AU - André Báfica Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/01/09/514943.abstract N2 - Following pathogen-induced injury, multicellular organisms enhance production and differentiation of leukocytes, which are important players maintaining the body homeostasis. Monocyte counts are increased during human tuberculosis but it has not been determined whether Mycobacterium tuberculosis (Mtb) can regulate myeloid commitment. We demonstrated that following exposure to laboratory or clinical Mtb strains, primary CD34+ cells preferentially differentiated into monocytes/macrophages, and to lesser extent granulocytes. This process required pathogen viability and while Mtb induced type I IFN expression and STAT1 phosphorylation in CD34+ cells, myeloid conversion did not require type I or type II IFN signaling. In contrast, Mtb enhanced IL-6 production by CD34+ cell cultures and IL-6R blockade abolished myeloid differentiation and decreased mycobacterial growth. Integrated systems biology analysis of transcriptomic, proteomic and genomic data of &gt; 1,500 individuals from cohorts of healthy controls, latent and active tuberculosis (TB) patients confirmed the existence of a myeloid IL-6/IL-6R/CEBP axis associated with disease severity in vivo. Furthermore, genetic and functional analysis revealed the IL6/IL6R/CEBP gene module has undergone recent evolutionary selection, including Neandertal introgression, linked to systemic monocyte counts. Together, these results suggest Mtb hijacks an evolutionary recent IFN-IL6-CEBP feed-forward loop, increasing myeloid differentiation linked to severe TB in humans.Authors’ contributionMD, EK, ELR, GL, TD, DSM, JVW andAB designed experiments and analyzed data; MD, EK, JVW, DGM, LM, GD, DP, EK, GL, TD, MAB, ELR and AB performed experiments;GB, DR, JDM contributed with critical reagents/tools/clinical samples; AB, MD andJVW wrote themanuscript ER -