Alveolar macrophage transcriptional signatures associated with resistance to TST/IGRA conversion following Mycobacterium tuberculosis exposure.

Despite heavy exposure to Mycobacterium tuberculosis (Mtb), some individuals are resistant to TST and IGRA conversion (RSTRs). The functional and immunological mechanisms governing resistance are poorly understood. We hypothesized that RSTR and LTBI alveolar macrophages (AMs) respond differently to Mtb infection with transcriptional programs that are distinct from peripheral blood monocytes. We examined media and Mtb-infected AMs from bronchoalveolar lavage fluid collected from a RSTR cohort in Uganda with over 10 years of clinical follow-up. With transcriptional profiles of BAL cells analyzed immediately after collection, gene set enrichment analysis (GSEA) revealed 13 differentially expressed gene sets between RSTR (n = 19) and LTBI (n = 26) groups, including one (Hallmark E2F targets) which was positively enriched in the RSTR group (FDR < 0.3). In a subset of this cohort (n = 7 RSTR and 8 LTBI), AMs were examined with and without Mtb infection. When comparing the RSTR and LTBI groups, we identified 52 DEGs including 22 in the media condition, 15 with Mtb stimulation, and 11 with the interaction term (FDR < 0.2, Log 2-fold change > 1/<-1). Notably, RSTR AMs appear to upregulate inflammation more strongly than LTBI counterparts, including Hallmark inflammatory response (FDR < 0.2), IFNγ response (FDR < 0.1), and IFNα response (FDR < 0.1) while existing in a more non-inflammatory state at baseline (Hallmark TNF signaling via NF-kB (down, FDR < 0.1), inflammatory response (down, FDR < 0.1). In a comparison of peripheral blood monocyte gene expression profiles from the same cohort, there were both shared and AM-specific RSTR profiles detected. Together, these results suggest that RSTR and LTBI AMs have different basal and Mtb-induced transcriptional profiles, including some that differ from peripheral blood monocytes.