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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.

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