Circulating miRNAs in the Plasma of Post-COVID-19 Patients with Typical Recovery and Those with Long-COVID Symptoms: Regulation of Immune Response-Associated Pathways

Abstract

Following the acute phase of SARS-CoV-2 infection, certain individuals experience persistent symptoms referred to as long COVID. This study analyzed the patients categorized into three distinct groups: (1) individuals presenting rheumatological symptoms associated with long COVID, (2) patients who have successfully recovered from COVID-19, and (3) donors who have never contracted COVID-19. A notable decline in the expression of miR-200c-3p, miR-766-3p, and miR-142-3p was identified among patients exhibiting rheumatological symptoms of long COVID. The highest concentration of miR-142-3p was found in healthy donors. One potential way to reduce miRNA concentrations is through antibody-mediated hydrolysis. Not only can antibodies possessing RNA-hydrolyzing activity recognize the miRNA substrate specifically, but they also catalyze its hydrolysis. The analysis of the catalytic activity of plasma antibodies revealed that antibodies from patients with long COVID demonstrated lower hydrolysis activity against five fluorescently labeled oligonucleotide sequences corresponding to the Flu-miR-146b-5p, Flu-miR-766-3p, Flu-miR-4742-3p, and Flu-miR-142-3p miRNAs and increased activity against the Flu-miR-378a-3p miRNA compared to other patient groups. The changes in miRNA concentrations and antibody-mediated hydrolysis of miRNAs are assumed to have a complex regulatory mechanism that is linked to gene pathways associated with the immune system. We demonstrate that all six miRNAs under analysis are associated with a large number of signaling pathways associated with immune response-associated pathways.

Keywords: COVID-19; RNA hydrolysis; SARS-CoV-2; antibodies; catalytic antibodies; long COVID; miR-142-3p; miR-200c-3p; miR-766-3p; miRNA; pathways; regulatory network; rheumatologically.

Figure 1

Examination of miRNA levels in the plasma of individuals within the three study cohorts: Lon refers to patients who experienced persistent rheumatologic symptoms alongside COVID-19, Cov denotes patients who successfully recovered from COVID-19 without any lingering complaints, and Neg represents disease-free donors. *—p-value < 0.05; **—p-value < 0.01; ***—p-value < 0.001, ****—p-value < 0.0001, ns—not significant.

Figure 2

The comparative activity of Flu-miRNA hydrolysis by plasma IgG preparations of patients in the three study groups. Lon refers to patients who experienced persistent rheumatologic symptoms alongside COVID-19, Cov denotes patients who successfully recovered from COVID-19 without any lingering complaints, and Neg represents disease-free donors. *—p-value < 0.05; **—p-value < 0.01; ***—p-value < 0.001, ns—not significant.

Figure 3

The network diagram of the interactions between target genes (highlighted in green) and six miRNAs (miR-200c-3p, miR-766-3p, miR-142-3p, miR-146b-5p, miR-4742-3p, miR-378a-3p) (highlighted in gray). The information is based on miRTarBase [90] and TargetScan [91] (accessed on 15 June 2024). The representation is limited to genes that regulate the immune response. Purple indicates the ontology of genes. The network is visualized using Cytoscape version 3.10.2.