biostudies-literatureGumas JNational Institute of Allergy and Infectious DiseasesAmerican Cancer SocietyNIAID NIH HHSNHLBI NIH HHSNational Institutes of HealthNational Heart Lung and Blood InstituteNational Institute of General Medical SciencesNIGMS NIH HHS102156https://www.ebi.ac.uk/biostudies/studies/S-EPMC10933579biostudies-literatureUnknown35(1)<i>Mycobacterium tuberculosis</i> (Mtb) infection is among the world's deadliest infectious diseases. Developing effective treatments and biomarkers for tuberculosis requires a deeper understanding of its pathobiology and host responses. Here, we report a comprehensive characterization of circulating short non-coding RNAs (sncRNAs) in plasma samples from Mtb-infected patients. We achieved this by pre-treating plasma RNAs with T4 polynucleotide kinase to convert all RNA ends to those compatible with sncRNA sequencing. We discovered a global and drastic upregulation of plasma sncRNAs in Mtb-infected patients, with tRNA-derived sncRNAs representing the most dramatically elevated class. Most of these tRNA-derived sncRNAs originated from a limited subset of tRNAs, specifically from three tRNA isoacceptors, and exhibited skewed patterns to 5'-derived fragments, such as 5' halves, 5' tRNA fragments (tRFs), and internal tRFs (i-tRFs) from the 5' regions. Further, Mtb-infected patients displayed markedly upregulated and distinct profiles of both rRNA- and mRNA-derived sncRNAs. Some of these sncRNAs, which are abundant and specific to Mtb-infected patients, robustly activated human macrophages via Toll-like receptor 7 and induced cytokine production. This drastic accumulation of circulating, immunostimulatory sncRNAs in the plasma of Mtb-infected patients offers insights into the sncRNA-driven aspects of host immune response against infectious diseases and suggests a pool of potential therapeutic targets and biomarkers.Molecular therapy. Nucleic acidsImmunostimulatory short non-coding RNAs in the circulation of patients with tuberculosis infection.PMC10933579R21 AI171366R01 HL150560AI168975R21 AI168975HL150560GM106047R01 GM106047R21 AI151641RSG-17-059-01-RMCAI151641AI171366Gumas JKirino YShigematsu MKawamura TfalseImmunostimulatory short non-coding RNAs in the circulation of patients with tuberculosis infection.<i>Mycobacterium tuberculosis</i> (Mtb) infection is among the world's deadliest infectious diseases. Developing effective treatments and biomarkers for tuberculosis requires a deeper understanding of its pathobiology and host responses. Here, we report a comprehensive characterization of circulating short non-coding RNAs (sncRNAs) in plasma samples from Mtb-infected patients. We achieved this by pre-treating plasma RNAs with T4 polynucleotide kinase to convert all RNA ends to those compatible with sncRNA sequencing. We discovered a global and drastic upregulation of plasma sncRNAs in Mtb-infected patients, with tRNA-derived sncRNAs representing the most dramatically elevated class. Most of these tRNA-derived sncRNAs originated from a limited subset of tRNAs, specifically from three tRNA isoacceptors, and exhibited skewed patterns to 5'-derived fragments, such as 5' halves, 5' tRNA fragments (tRFs), and internal tRFs (i-tRFs) from the 5' regions. Further, Mtb-infected patients displayed markedly upregulated and distinct profiles of both rRNA- and mRNA-derived sncRNAs. Some of these sncRNAs, which are abundant and specific to Mtb-infected patients, robustly activated human macrophages via Toll-like receptor 7 and induced cytokine production. This drastic accumulation of circulating, immunostimulatory sncRNAs in the plasma of Mtb-infected patients offers insights into the sncRNA-driven aspects of host immune response against infectious diseases and suggests a pool of potential therapeutic targets and biomarkers.2024-01-01T00:00:00Z2024 Mar2026-06-02T19:21:06.646Z2025-02-19T04:41:51.589ZS-EPMC109335793848193610.1016/j.omtn.2024.102156