Human M1 macrophages express unique innate immune response genes after mycobacterial infection to defend against tuberculosis

Arshad Khan, Kangling Zhang, Vipul K. Singh, Abhishek Mishra, Priyanka Kachroo, Tian Bing, Jong Hak Won, Arunmani Mani, Ramesha Papanna, Lovepreet K. Mann, Eder Ledezma-Campos, Genesis Aguillon-Duran, David H. Canaday, Sunil A. David, Blanca I. Restrepo, Nhung Nguyen Viet, Ha Phan, Edward A. Graviss, James M. Musser, Deepak KaushalMarie Claire Gauduin, Chinnaswamy Jagannath

Research output: Contribution to journalArticlepeer-review


Mycobacterium tuberculosis (Mtb) is responsible for approximately 1.5 million deaths each year. Though 10% of patients develop tuberculosis (TB) after infection, 90% of these infections are latent. Further, mice are nearly uniformly susceptible to Mtb but their M1-polarized macrophages (M1-MΦs) can inhibit Mtb in vitro, suggesting that M1-MΦs may be able to regulate anti-TB immunity. We sought to determine whether human MΦ heterogeneity contributes to TB immunity. Here we show that IFN-γ-programmed M1-MΦs degrade Mtb through increased expression of innate immunity regulatory genes (Inregs). In contrast, IL-4-programmed M2-polarized MΦs (M2-MΦs) are permissive for Mtb proliferation and exhibit reduced Inregs expression. M1-MΦs and M2-MΦs express pro- and anti-inflammatory cytokine-chemokines, respectively, and M1-MΦs show nitric oxide and autophagy-dependent degradation of Mtb, leading to increased antigen presentation to T cells through an ATG-RAB7-cathepsin pathway. Despite Mtb infection, M1-MΦs show increased histone acetylation at the ATG5 promoter and pro-autophagy phenotypes, while increased histone deacetylases lead to decreased autophagy in M2-MΦs. Finally, Mtb-infected neonatal macaques express human Inregs in their lymph nodes and macrophages, suggesting that M1 and M2 phenotypes can mediate immunity to 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. These genes could serve as targets for diagnosis and immunotherapy of TB.

Original languageEnglish (US)
Article number480
JournalCommunications Biology
Issue number1
StatePublished - Dec 2022

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • General Biochemistry, Genetics and Molecular Biology
  • General Agricultural and Biological Sciences


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