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

We determined whether microRNAs (miRNAs) regulate resistance to Mycobacterium tuberculosis (Mtb) infection in healthy household contacts (HHCs) of patients with tuberculosis (TB). As shown in our previously published study, we recruited 460 HHCs from 443 index cases of active pulmonary TB, with 293 (64.8%) remaining IGRA-negative throughout a two-year follow-up. Whole-transcriptome sequencing at baseline (0 months) and follow-up (24 months) and confirmation studies identified miRNA-1246 (downregulated) and miRNA-125b (upregulated) as potential candidates for the development of resistance in nonconverters compared with converters and progressors. Mechanistic studies using proteomics and computational analysis revealed that miRNA-1246 inhibitor reduce Mtb growth in macrophages by regulating lipase activity, specifically through targeting alpha/beta hydrolase domain-containing protein 2 (ABHD2). Inhibition of miRNA-1246 increased glycolytic activity and promoted a metabolic shift in macrophages conducive to pathogen clearance, suggesting its critical role in metabolic regulation and resistance to tuberculosis. These findings highlight potential miRNA-based therapeutic strategies to enhance immunity against Mtb.