Tuberculosis (TB) continues to pose a formidable challenge to global health, infecting roughly a quarter of the world’s population with Mycobacterium tuberculosis. Despite the latent nature of most infections, individuals harboring latent TB infection (LTBI) face the ever-present risk of developing active TB, which escalates the potential for disease transmission within communities. This evolving spectrum from latent carriage to active disease underscores the urgency for diagnostic tools that do more than merely identify infection; these tools must predict progression to enable timely intervention and curb the spread of TB. However, current biomarkers effectively differentiate latent infection from active disease but fall short in dynamically monitoring disease progression—highlighting a critical gap in TB control strategies.
Emerging research has spotlighted alternative RNA splicing as a highly responsive mechanism attuned to cellular microenvironmental changes, positioning it as a promising biomarker for disease development. Among alternative splicing modalities, intron retention (IR) is particularly pervasive, influencing the expression of nearly 80% of protein-coding genes. IR represents a finely tuned post-transcriptional regulatory mechanism, capable of altering transcriptomes and proteomes in response to physiological and pathological cues. This biological process plays substantial roles across disease contexts, including cancer progression and aging; yet its function within the complex interplay of TB pathogenesis remained unexplored until recently.
In an innovative study published in the Chinese Medical Journal, researchers systematically charted the molecular landscape of IR-driven splicing reprogramming throughout TB progression. Their work reveals the dynamic functional significance of IR events, focusing on the intron retention of the DNASE1L2 gene (referred to as DNASE1L2-IR) as a novel biomarker and mechanistic player. This gene encodes a deoxyribonuclease involved in nucleic acid degradation, an essential step in modulating host innate immune responses to pathogen DNA. Through their analysis, the authors unveiled the dual role of DNASE1L2-IR in controlling TB progression by balancing microbial DNA clearance and inflammation regulation.
The investigation harnessed high-throughput sequencing data from an extensive cohort of 1,729 human clinical samples, encompassing healthy controls, individuals with LTBI, and patients diagnosed with active TB. This comprehensive analysis illuminated genome-wide patterns of intron splicing reprogramming, underscoring the dynamic shifting of IR events as infection progresses. Among these, four IR events emerged as significantly correlated with latent infection and disease advancement, with the DNASE1L2 intron retention event demonstrating the most prominent and characteristic rise-and-fall fluctuation aligned with disease stages.
Intriguingly, DNASE1L2-IR levels were elevated in individuals with LTBI compared to healthy controls, diminished markedly in patients experiencing active TB, and were even higher in “progressors” —those LTBI cases transitioning to active disease— versus “non-progressors.” This biphasic pattern was consistently corroborated in multiple antigen-stimulated cell models mimicking M. tuberculosis infection, reflecting a robust association with host immune status transitions under infectious stress. This dynamic indicates that DNASE1L2-IR not only marks infection status but actively participates in modulating immunological responses.
Delving deeper, molecular and cellular studies revealed that DNASE1L2-IR gives rise to two functionally distinct transcript isoforms: a long isoform (DNASE1L2-L) and a short isoform (DNASE1L2-S). Upon stimulation with M. tuberculosis, the long isoform predominantly localizes to the cytoplasm, positioning it advantageously for accessing and degrading microbial DNA. Conversely, the short isoform remains tethered to the cell membrane, likely limiting its interaction with intracellular substrates. Functional assays demonstrated that DNASE1L2-L boasts substantially higher DNase enzymatic activity, efficiently degrading M. tuberculosis genomic DNA as well as supercoiled plasmid DNA. This heightened catalytic function positions the long isoform as a critical modulator of host-pathogen interaction dynamics.
Crucially, cellular experiments showed that overexpression of DNASE1L2-L curtailed the secretion of pro-inflammatory cytokines such as TNF-α and IL-1β, which are widely recognized as mediators driving immunopathology in TB. In contrast, knockout of DNASE1L2 amplified inflammatory responses, underscoring the protective, inflammation-regulating function of this IR event. This mechanistic insight bridges molecular splicing changes with functional immunological outcomes, marking DNASE1L2-IR as a fine-tuner of host inflammation and bacterial clearance.
Collectively, these findings frame DNASE1L2-IR upregulation early in TB progression as a host defense strategy aimed at enhancing the production of the catalytically potent DNASE1L2-L isoform. This isoform facilitates the degradation of persistent mycobacterial DNA, thereby attenuating excessive inflammatory damage while promoting pathogen clearance. Conversely, downregulation of DNASE1L2-IR in certain individuals predisposes them to diminished DNase activity, allowing the pathogen to persist and amplify disease severity by inciting uncontrolled inflammation.
This seminal study is the first to link intron retention—a post-transcriptional regulatory mechanism—with dynamic biomarkers for monitoring TB progression. It elucidates a nuanced splicing-mediated host-pathogen crosstalk, revealing how M. tuberculosis may alter host RNA splicing patterns to its advantage, influencing disease outcomes. These insights pave the way for developing innovative RNA splicing-based diagnostic tools capable of predicting disease progression with temporal precision, offering new avenues for early intervention.
Moreover, the therapeutic implications are profound. By harnessing or modulating DNASE1L2 splicing events, future treatments may augment host defense mechanisms to limit disease advancement or attenuate damaging inflammation. The identification of this RNA splicing signature opens an untapped frontier in TB research, challenging conventional paradigms and heralding a new era of precision medicine in combating one of humanity’s oldest and deadliest infectious diseases.
Led by Professor Ying Binwu and colleagues at West China Hospital of Sichuan University, this work exemplifies cutting-edge molecular medicine integrating genomics, immunology, and infectious disease biology. Professor Ying’s expertise in molecular diagnostics and his team’s rigorous multi-model approach underpin the robustness and translational potential of these discoveries. The profound societal benefits of such research underscore the urgent need to integrate molecular splicing biomarkers into global TB control efforts.
As TB continues to claim millions of lives annually, innovative strategies that combine early detection, dynamic monitoring, and targeted molecular interventions offer renewed hope. The unveiling of DNASE1L2 intron retention dynamics not only advances scientific understanding but also charts a compelling course toward conquering TB through molecular precision, potentially reshaping public health landscapes worldwide.
Subject of Research: Human tissue samples
Article Title: Elucidating the functional dynamics of DNASE1L2 intron retention in tuberculosis progression
News Publication Date: 5-Mar-2026
Web References: DOI: 10.1097/CM9.0000000000003974
References:
DOI: 10.1097/CM9.0000000000003974
Image Credits: Bingwu Ying, West China Hospital of Sichuan University, China
Keywords: Tuberculosis, Mycobacterium tuberculosis, intron retention, RNA splicing, DNASE1L2, biomarker, disease progression, immune regulation, molecular diagnostics, inflammation
