Integrated miRNAome-transcriptome analyses identify an immuno-hematopoietic subcluster in patients with long COVID.

Publication date: Jun 23, 2026

Persistent symptoms following SARS-CoV-2 infection, termed post-COVID-19 condition or long COVID (LC), impose substantial psychological and socioeconomic burdens. However, miRNA-mRNA interactions underlying LC heterogeneity remain incompletely defined. To determine whether integrative blood miRNA-mRNA profiling identifies molecular LC subclusters linked to clinical and immune-hematopoietic features. We performed integrated miRNAome-transcriptome profiling of circulating blood RNA from individuals with LC and recovered controls. Differential miRNA and mRNA expression were assessed using LIMMA, and hierarchical clustering was used to define LC subclusters. Validated miRNA-mRNA interaction networks were constructed using miRNet. Clinical, functional, and biochemical parameters were compared between subclusters, and a random forest classifier was developed. Clustering identified an immune-hematopoietic LC subcluster, LC1, characterized by extensive miRNA-mRNA dysregulation, enrichment of erythropoietic, platelet, and immune pathways, and biochemical alterations including lower plasma sodium and elevated fibrin D-dimer and thrombin time. Compared with LC2, LC1 showed persistently greater symptom burden, functional impairment, reduced quality of life, lower resilience, and higher anxiety/depressive symptoms. Potential confounding by age, sex, comorbidities, and selected medication use was evaluated. Network and co-expression analyses identified regulatory nodes enriched for viral infection and natural killer cell activation pathways. A random forest classifier incorporating nine miRNAs and LRRFIP2 achieved an AUROC of 0. 91 for LC1, distinguishing LC1 from LC2 and recovered controls. LC comprises biologically and clinically distinct subclusters shaped by coordinated miRNA-mRNA remodeling. The immune-hematopoietic LC1 subtype supports biomarker-based stratification of patients with persistent physiological and clinical impairment.

Semantics

Original Article