Human M1 Macrophages Express Unique Innate Immune Response Genes After Mycobacterial Infection to Defend Against Tuberculosis

Mycobacterium TB (Mtb) is responsible for approximately 1.5 million TB (TB) deaths each year. Though 10% of patients develop TB after infection, 90% only develop latent infection. Mouse models of tuberculosis show near uniform susceptibility although their M1-polarized macrophages (M1-MΦs) can inhibit growth of Mtb in vitro. Our main objective was to determine if human macrophage (MΦ) heterogeneity contributes to active TB prevention. We found that IFN-γ-programmed M1-MΦs degraded Mtb through increased expression of innate immunity regulatory genes (Inregs). In contrast, IL-4-programmed M2-polarized MΦs (M2-MΦs) were permissive for Mtb proliferation and exhibited reduced expression of Inregs. M1-MΦs and M2-MΦs expressed pro- and anti-inflammatory cytokine-chemokines, respectively, and M1-MΦs showed a nitric oxide and autophagy dependent killing of Mtb which led to an increased antigen presentation to T cells through an ATG-RAB7 -cathepsin pathway. M1-MΦs showed increased histone acetylation of ATG5 and a pro-autophagy phenotype despite Mtb infection, whereas, increased histone deacetylases including Sirtuin led to decreased autophagy in Mtb infected M2-MΦs. Mtb-infected neonatal macaques expressed comparable Inregs in their lymph nodes and macrophages, suggesting that M1 and M2 phenotypes can exert differential control over TB in both humans and macaques. We conclude that human MФ subsets show unique patterns of gene expression that enable differential control of TB after infection. Funding Statement: Funding support from NIH RO1 AI-1220709 (PI CJ) & R01 AI-138587 (PIs CJ, DK) and HMRI for support funds. Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: All studies were conducted under approved institutional HSC and IRB protocols.