MicroRNA-guided drug discovery for mitigating persistent pulmonary complications in critical COVID-19 survivors: A
María C García-Hidalgo1,2, Iván D Benítez1,2, Manel Perez-Pons1,2
1Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, Lleida, Spain.
Background And Purpose:
The post-acute sequelae of SARS-CoV-2 infection pose a significant global challenge, with nearly 50% of critical COVID-19 survivors manifesting persistent lung abnormalities. The lack of understanding about the molecular mechanisms and effective treatments hampers their management. Here, we employed microRNA (miRNA) profiling to decipher the systemic molecular underpinnings of the persistent pulmonary complications.
Experimental Approach:
We conducted a longitudinal investigation including 119 critical COVID-19 survivors. A comprehensive pulmonary evaluation was performed in the short-term (median = 94.0 days after hospital discharge) and long-term (median = 358 days after hospital discharge). Plasma miRNAs were quantified at the short-term evaluation using the gold-standard technique, RT-qPCR. The analyses combined machine learning feature selection techniques with bioinformatic investigations. Two additional datasets were incorporated for validation.
Key Results:
In the short-term, 84% of the survivors exhibited impaired lung diffusion (DLCO < 80% of predicted). One year post-discharge, 54.4% of this patient subgroup still presented abnormal DLCO. Four feature selection methods identified two specific miRNAs, miR-9-5p and miR-486-5p, linked to persistent lung dysfunction. The downstream experimentally validated targetome included 1473 genes, with heterogeneous enriched pathways associated with inflammation, angiogenesis and cell senescence. Validation studies using RNA-sequencing and proteomic datasets emphasized the pivotal roles of cell migration and tissue repair in persistent lung dysfunction. The repositioning potential of the miRNA targets was limited.
Conclusion And Implications:
Our study reveals early mechanistic pathways contributing to persistent lung dysfunction in critical COVID-19 survivors, offering a promising approach for the development of targeted disease-modifying agents.
Linked Articles:
This article is part of a themed issue Non-coding RNA Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.2/issuetoc.
Insights
Persistent lung dysfunction affects over half of critical COVID-19 survivors. This study identifies two microRNAs (miRNAs) linked to this condition, offering potential targets for new treatments for long COVID lung complications.
Area of Science:
- Molecular biology
- Pulmonology
- Virology
Background:
- Post-acute sequelae of SARS-CoV-2 infection (PASC) present a global health challenge.
- Nearly 50% of critical COVID-19 survivors experience persistent lung abnormalities.
- Understanding molecular mechanisms and treatments for PASC lung complications is limited.
Purpose of the Study:
- To investigate the molecular underpinnings of persistent pulmonary complications in critical COVID-19 survivors.
- To identify specific microRNAs (miRNAs) associated with long-term lung dysfunction.
- To explore potential therapeutic targets for PASC-related lung disease.
Main Methods:
- Longitudinal study of 119 critical COVID-19 survivors with pulmonary evaluations at short-term and long-term follow-up.
- Plasma miRNA profiling using RT-qPCR, combined with machine learning feature selection and bioinformatic analyses.
- Validation using independent RNA-sequencing and proteomic datasets.
Main Results:
- 84% of survivors had impaired lung diffusion short-term; 54.4% still affected at one year.
- Two miRNAs, miR-9-5p and miR-486-5p, were identified as key players in persistent lung dysfunction.
- Downstream analysis revealed enriched pathways in inflammation, angiogenesis, cell senescence, migration, and tissue repair.
Conclusions:
- Early mechanistic pathways contributing to persistent lung dysfunction in critical COVID-19 survivors were revealed.
- Identified miRNAs and pathways offer promising targets for developing disease-modifying agents for PASC.
- Further research into miRNA-based therapeutics for long COVID lung complications is warranted.
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