Human Alveolar and Monocyte-derived Human Macrophage Responses to Mycobacterium tuberculosis

Rationale: Alveolar macrophages (AMs) and recruited monocyte-derived macrophages (MDMs) mediate early lung immune responses to Mycobacterium tuberculosis (Mtb). Differences in the response of these distinct cell types is poorly understood and may provide insight into mechanisms of TB pathogenesis. Objectives: To determine whether Mtb induces unique and essential anti-microbial pathways in human AMs compared to MDMs. Methods: Using paired human AMs and 5-day MCSF-derived MDMs from 6 healthy volunteers, we infected cells with Mtb H37Rv for 6 hours, isolated RNA, and analyzed transcriptomic profiles with RNASeq. Main Results: We found 681 genes that were Mtb-dependent in AMs compared to MDMs and 4538 that were Mtb-dependent in MDMs but not AMs (FDR < 0.05). Using hypergeometric enrichment of DEGs in Broad Hallmark gene sets, we found that Type I and II IFN Response were the only gene sets selectively induced in Mtb-infected AM (FDR <0.05). In contrast, MYC targets, unfolded protein response and MTORC1 signaling, were selectively enriched in MDMs (FDR < 0.05). IFNA1, IFNA8, IFNE, and IFNL1 were specifically and highly upregulated in AMs compared to MDMs at baseline and/or after Mtb infection. IFNA8 modulated Mtb-induced pro-inflammatory cytokines and, compared to other interferons, stimulated unique transcriptomes. Several DNA sensors and Interferon Regulatory Factors had higher expression at baseline and/or after Mtb infection in AMs compared to MDMs. Conclusions: These findings demonstrate that Mtb infection induced unique transcriptional responses in human AMs compared to MDMs, including upregulation of the IFN response pathway and specific DNA sensors. ### Competing Interest Statement The authors have declared no competing interest.