MicroRNA-1246 regulates macrophage lipid metabolism and is involved in resistance to human Mycobacterium tuberculosis infection 2259565

Abstract Introduction Resistance to Mycobacterium tuberculosis (Mtb) infection despite known exposure varies among individuals, but the molecular mechanisms underlying this resistance remain poorly understood. It is unclear whether microRNAs (miRNAs) influence the development of resistance to tuberculosis (TB) among individuals exposed to Mtb who remain uninfected or do not progress to active disease. Methods We analyzed blood samples from healthy household contacts (HHCs) of patients with active pulmonary TB. As reported in our previous study, 460 HHCs were recruited from 443 index TB cases, of which 293 (64.8%) remained interferon gamma release assay negative during a two-year follow-up period. Whole-transcriptome sequencing was performed at baseline (0 months) and at follow-up (24 months) to identify differentially expressed miRNAs between nonconverters, converters, and progressors. Candidate miRNAs were validated through confirmation studies, and mechanistic investigations were conducted using proteomics and computational analyses in macrophage models. Results Differential expression analysis revealed that hsa-miR-1246 (downregulated) and hsa-miR-125b (upregulated) were associated with resistance to Mtb infection in nonconverters compared with converters and progressors. Functional assays demonstrated that inhibition of hsa-miR-1246 reduced Mtb growth in macrophages by enhancing lipase activity through its target, alpha/beta hydrolase domain-containing protein 2 (ABHD2). Moreover, hsa-miR-1246 inhibition promoted glycolytic reprogramming and metabolic activation of macrophages, creating a cellular environment favorable for bacterial clearance. Conclusion Our findings identify hsa-miR-1246 as aa important regulator of macrophage metabolism and host resistance to Mtb infection. These results provide mechanistic insight into miRNA-driven immune protection and suggest potential miRNA-based therapeutic strategies to enhance resistance against tuberculosis. Funding Source CRDF Global, the Cain Foundation for Infectious Disease Research, the Department of Pulmonary Immunology, and the Department of Biotechnology (BT/PR9622/MED/15/109/2013 to VLV), New Delhi, India. Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)