Immunoregulatory roles of microRNAs in bacterial infections: A focus on tuberculosis and sepsis

Tuberculosis and sepsis represent opposing extremes of host immune regulation: one characterised by sustained immune adaptation that permits Mycobacterium tuberculosis persistence, the other by rapid immune collapse that precipitates life-threatening inflammation. Examining these divergent outcomes through a shared regulatory lens highlights microRNAs (miRNAs) as pivotal, yet context-dependent, modulators of antimicrobial defence and immunopathology. Rather than acting as linear switches, miRNAs operate within densely interconnected networks, simultaneously shaping inflammatory signalling, metabolic reprogramming, and programmed cell-death pathways. Across both chronic and acute bacterial infections recurrent miRNAs, miR-21, miR-125, miR-146a, and miR-155, emerge as regulatory hubs governing macrophage fate, cytokine signature, and tissue injury. However, their functional impact is highly contingent on infection stage, cellular compartmentalisation, and upstream regulation by competing endogenous RNAs and extracellular vesicle-mediated transfer. This complexity challenges simplistic interpretations of miRNA expression profiles and underscores the limitations of extrapolating findings across experimental models. By integrating mechanistic and translational evidence, this review presents shared and divergent miRNA-centred immune architectures in tuberculosis and sepsis, while critically assessing their value as biomarkers and therapeutic targets. Progress towards clinical translation will depend on context-resolved miRNA signatures and delivery strategies capable of accommodating the temporal and cellular complexity of RNA-mediated immune regulation in bacterial infections.