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.
- André Báfica
- Daniel S Mansur
- Johan Van Weyenbergh
- André Báfica
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Human subjects: This study was approved by the institutional review boards of Universidade Federal de Santa Catarina and The University Hospital Prof. Polydoro Ernani de São Thiago (IRB# 89894417.8.0000.0121). Informed consent was obtained from all subjects.
- Bavesh D Kana, University of the Witwatersrand, South Africa
© 2019, Delgobo et al.
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