Simmons JD, Dill-McFarland KA, Stein CM, Van PT, Chihota V, Ntshiqa T, Maenetje P, Peterson GJ, Benchek P, Nsereko M, Velen K, Fielding KL, Grant AD, Gottardo R, Mayanja-Kizza H, Wallis RS, Churchyard G, Boom WH, Hawn TR. Monocyte transcriptional responses to Mycobacterium tuberculosis associate with resistance to tuberculin skin test and interferon gamma release assay conversion. mSphere. In press
Heavy exposure to Mycobacterium tuberculosis (Mtb), the etiologic agent of tuberculosis and among the top infectious killers worldwide, results in infection that is cleared, contained, or progresses to disease. Some heavily exposed tuberculosis contacts show no evidence of infection using the tuberculin skin test (TST) and interferon gamma release assay (IGRA) yet the mechanisms underlying this ‘resister’ (RSTR) phenotype are unclear. To identify transcriptional responses that distinguish RSTR monocytes, we performed RNAseq on monocytes isolated from heavily exposed household contacts in Uganda and gold miners in South Africa after ex vivo Mtb infection. Gene set enrichment analysis (GSEA) revealed several gene pathways that were consistently enriched in response to Mtb among RSTR subjects as compared to controls with positive TST/IGRA testing (LTBI) across Uganda and South Africa. The most significantly enriched gene set in which expression was increased in RSTR relative to LTBI Mtb-infected monocytes was the TNFα signaling pathway whose core enrichment (leading edge) substantially overlapped across RSTR populations. These leading edge genes included candidate resistance genes (ABCA1, DUSP2) with significantly increased expression among Uganda RSTRs (FDR <0.1). The distinct monocyte transcriptional response to Mtb among RSTR subjects, including increased expression of the TNF signaling pathway, highlights genes and inflammatory pathways that may mediate resistance to TST/IGRA conversion and provides therapeutic targets to enhance host restriction of Mtb intracellular infection. Importance
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