Mycobacterium tuberculosis rewires host RNA splicing through effector-driven spliceosome remodeling.

Mycobacterium tuberculosis (Mtb) reshapes host immunity not only by rewiring signaling pathways but also by perturbing post-transcriptional control. Alternative splicing (AS) provides a switch-like layer that can reconfigure protein function without changing gene abundance, making it a plausible driver of infection-induced immune state transitions. Here, we synthesize emerging evidence that Mtb effectors promote isoform remodeling in macrophages and lymphocytes, with the resulting splicing programs further shaped by host inflammatory context and damage-associated signals. Selected AS events directly tune phagosome maturation, cell-death programs, cytokine signaling, and inflammatory lipid amplification, thereby influencing bacterial persistence, lesion evolution, and the balance between antimicrobial immunity and immune-mediated pathology. Structuring the field around a causal chain that links Mtb effectors and host splicing machinery to isoform-level events and immune consequences, this article proposes three controllable entry points for effector-driven remodeling: spliceosome supply (e.g., snRNP biogenesis), splicing-factor availability, and splicing-factor activity states. Current findings are further stratified by causal depth to distinguish mechanistically closed loops from associative cohort signatures. Finally, the discussion addresses context dependence across cell states and lesion microdomains, highlights enabling technologies for isoform-resolved studies, and outlines a roadmap for validating splicing events as tuberculosis biomarkers and therapeutic targets that integrate pathogen control with preservation of lung function.