Researchers Identify Novel RNA Splicing Biomarker to Predict Tuberculosis Progression and Regulate Inflammation

Researchers uncover how the DNASE1L2-IR biomarker monitors TB progression and regulates the host's inflammatory response using specific RNA isoforms.

By: AXL Media

Published: Mar 30, 2026, 7:22 AM EDT

Source: Information for this report was sourced from Chinese Medical Journals Publishing House Co., Ltd. via EurekAlert!

The Challenge of Predicting Tuberculosis Progression

Tuberculosis (TB) remains a premier global health threat, with nearly two billion people carrying a latent infection (LTBI). The primary clinical challenge lies in identifying which of these individuals will remain asymptomatic and which will progress to active, transmissible disease. Current diagnostic tools are effective at distinguishing between healthy individuals and those with active TB, but they lack the sensitivity to monitor the high-risk "progression" phase. Researchers led by Professor Bingwu Ying have addressed this gap by looking into the post-transcriptional landscape of host cells.

Mapping the Landscape of Intron Retention

The research team focused on Intron Retention (IR), a form of alternative splicing where non-coding sequences (introns) are retained in the final messenger RNA. By analyzing 1,729 clinical samples, the team discovered that IR events are highly sensitive to the intracellular microenvironment of TB-infected cells. Among the thousands of events analyzed, the IR of the DNASE1L2 gene stood out. Levels of DNASE1L2-IR showed a distinct "rise-and-fall" pattern: rising during latent infection and in those progressing toward active disease, but falling sharply once the disease becomes fully active.

The Functional Roles of DNASE1L2 Isoforms

The study identified that DNASE1L2-IR generates two distinct protein isoforms: a long version (DNASE1L2-L) and a short version (DNASE1L2-S). These isoforms serve very different tactical roles within the host cell's defense system. DNASE1L2-L localizes in the cytoplasm and possesses significantly higher efficiency in degrading M. tuberculosis genomic DNA. In contrast, the shorter DNASE1L2-S remains anchored to the cell membrane and exhibits much lower enzymatic activity. This suggests that the host intentionally shifts splicing toward the long isoform during early infection to clear pathogen DNA.