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

Abstract

Monocyte counts are increased during human tuberculosis (TB) but it has not been determined whether <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) directly regulates myeloid commitment. We demonstrated that exposure to <i>Mtb</i> 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, <i>Mtb</i> 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 <i>IL-6/IL6R/CEBP</i> gene module associated with disease severity. Furthermore, genetic and functional analysis revealed the <i>IL6/IL6R/CEBP</i> gene module has undergone recent evolutionary selection, including Neanderthal introgression and human pathogen adaptation, connected to systemic monocyte counts. These results suggest <i>Mtb</i> co-opts an evolutionary recent IFN-IL6-CEBP feed-forward loop, increasing myeloid differentiation linked to severe TB in humans.