MicroRNA-centered theranostics for pulmoprotection in critical COVID-19

Abstract

Elucidating the pathobiological mechanisms underlying post-acute pulmonary sequelae following SARS-CoV-2 infection is essential for early interventions and patient stratification. Here, we investigated the potential of microRNAs (miRNAs) as theranostic agents for pulmoprotection in critical illness survivors. Multicenter study including 172 ICU survivors. Diffusion impairment was defined as a lung diffusing capacity for carbon monoxide (DLCO)<80% within 12 months post-discharge. A disease-associated 16-miRNA panel was quantified in plasma samples collected at ICU admission. Bioinformatic analyses were conducted using KEGG, Reactome, GTEx and Drug-Gene Interaction databases. The results were validated using an external RNA-seq dataset. A 3-miRNA signature linked to diffusion impairment (miR-27a-3p, miR-93a-5p, and miR-199a-5p) was identified using Random Forest. Levels of miR-93a-5p and miR-199a-5p were independently associated with the outcome, improving patient classification provided by the electronic heatlh record. The experimentally-validated targets of these miRNAs exhibited enrichment across diverse pathways, with telomere length quantification in an additional set samples (n=83) supporting the role of cell senescence in sequelae. Analysis of an external dataset refined the pathobiological fingerprint of pulmonary sequelae. Gene-drug interaction analysis revealed four FDA-approved drugs. Overall, this study advances our understanding of lung recovery in post-acute respiratory infections, highlighting the potential of miRNAs and their targets for pulmonoprotection.