Mycobacterium tuberculosis-dependent Monocyte Expression Quantitative Trait Loci and Tuberculosis Pathogenesis

Hyejeong Hong, Kimberly A. Dill-McFarland, Jason D. Simmons, Glenna J. Peterson, Penelope Benchek, Harriet Mayanja-Kizza, W. Henry Boom, Catherine M. Stein, Thomas R. Hawn

The heterogeneous outcomes after Mycobacterium tuberculosis (Mtb) exposure is a conundrum associated with millennia of host-pathogen co-evolution. We hypothesized that human myeloid cells contain genetically encoded, Mtb-dependent responses regulating critical steps in tuberculosis (TB) pathogenesis. Utilizing RNAseq from 80 Ugandan household contacts of pulmonary TB cases, we mapped genome-wide expression quantitative trait loci (eQTLs) in Mtb-infected monocytes. We identified 29 Mtb-dependent eQTLs, some associated with cytokine expression and clinical resistance to tuberculin skin test (TST) and interferon-γ release assay (IGRA) conversion. BMP6, an Mtb-dependent eQTL gene, correlated with IFNB1 induction in Mtb-infected and DNA ligand-induced cells. Network and enrichment analyses highlighted fatty acid metabolism as a pathway linked to eQTL genes. These findings suggest that monocyte genes contain Mtb-dependent eQTLs, including a subset associated with cytokine expression and/or clinical resistance to TST/IGRA conversion, offering insights into immunogenetic pathways regulating susceptibility to Mtb infection and TB pathogenesis.