Mycobacterium tuberculosis induced interferon pathways distinguish responses of Human Alveolar Macrophages from Monocyte-Derived Macrophages

Alveolar macrophages (AMs) and recruited monocyte-derived macrophages (MDMs) mediate early lung immune responses to Mycobacterium tuberculosis (Mtb). Using paired human AMs and MDMs from 6 healthy volunteers, we investigated transcriptional profiles in responses to Mtb. We found 681 genes that were Mtb-dependent in AMs compared to MDMs, 107 that were induced in both cell types but in different directions, and 4538 that were Mtb-dependent in MDMs but not AMs (FDR < 0.05). We found that IFNA Response and IFNG Response were the top two gene sets selectively induced in Mtb-infected AM. Thus, a second experiment utilized MDMs treated with IFNA1, IFNA8, IFNE, or IFNL1 found that IFNA8 modulated Mtb-induced pro-inflammatory cytokines and, compared to other interferons,stimulated unique transcriptional profiles. Overall design: Using paired human AMs and 5-day MCSF-derived MDMs from 6 healthy volunteers, we infected cells for 6 hours with Mtb H37Rv, isolated RNA, and analyzed transcriptomic profiles with RNASeq. A second experiment utilized MDMs treated with IFNA1, IFNA8, IFNE, or IFNL1 for 6 hours.