Integrated miR-omics and proteomics reveal the regulatory role of miR in protein networks associated with COVID-19 disease progression.
While microRNA (miR) expression profiling has identified potential biomarkers in patients with COVID-19, the regulatory mechanisms by which miRs modulate disease severity remain poorly characterized. We performed integrated miR-proteome analysis to elucidate mechanistic relationships between miR regulation and COVID-19 severity.
Deidentified plasma samples from 93 participants with acute COVID-19 were categorized by severity using a 12-point symptom scoring system: mild (0-1), moderate (2-4), and severe (5-12). miR and proteomic profiles were analyzed using univariate statistics, pathway analysis, miR-target prediction, and correlation analysis. Differentially expressed miRNAs (DEMs) and differentially expressed proteins (DEPs) between the three severity groups from the original cohort were evaluated in a validation cohort of 94 participants.
We identified 365 unique miRs and 801 unique proteins that were significantly associated with COVID-19 severity in any of the three comparisons. Ingenuity pathway analysis revealed neutrophil degranulation, cytokine storm, interleukin-10 (IL-10) signaling, and wound healing signaling as top dysregulated pathways in severe versus mild cases, with IL-6 involved in 9 of the 10 most significant pathways. Correlation analysis between miRs and proteins from 93 participants identified 6,559 miR-protein pairs with |r| > 0.5, of which 83.6% were negative correlations, suggesting widespread miR-mediated downregulation of protein expression. A significant correlation (r = 0.43, p < 0.0001) was found between 122 predicted miR-protein pairs found in the discovery cohort and the same miR-protein pairs in the validation cohort.
To our knowledge, this represents the first integrated analysis of circulating miRs and proteins from the same COVID-19 participants and separately in a validation cohort. The high frequency of negative miR-protein correlations combined with target prediction analysis suggests that miRs play regulatory roles in COVID-19 severity-associated pathways. These findings provide mechanistic insights into miR regulation of host immune responses and identify potential biomarkers that could inform therapy of COVID-19.
Deidentified plasma samples from 93 participants with acute COVID-19 were categorized by severity using a 12-point symptom scoring system: mild (0-1), moderate (2-4), and severe (5-12). miR and proteomic profiles were analyzed using univariate statistics, pathway analysis, miR-target prediction, and correlation analysis. Differentially expressed miRNAs (DEMs) and differentially expressed proteins (DEPs) between the three severity groups from the original cohort were evaluated in a validation cohort of 94 participants.
We identified 365 unique miRs and 801 unique proteins that were significantly associated with COVID-19 severity in any of the three comparisons. Ingenuity pathway analysis revealed neutrophil degranulation, cytokine storm, interleukin-10 (IL-10) signaling, and wound healing signaling as top dysregulated pathways in severe versus mild cases, with IL-6 involved in 9 of the 10 most significant pathways. Correlation analysis between miRs and proteins from 93 participants identified 6,559 miR-protein pairs with |r| > 0.5, of which 83.6% were negative correlations, suggesting widespread miR-mediated downregulation of protein expression. A significant correlation (r = 0.43, p < 0.0001) was found between 122 predicted miR-protein pairs found in the discovery cohort and the same miR-protein pairs in the validation cohort.
To our knowledge, this represents the first integrated analysis of circulating miRs and proteins from the same COVID-19 participants and separately in a validation cohort. The high frequency of negative miR-protein correlations combined with target prediction analysis suggests that miRs play regulatory roles in COVID-19 severity-associated pathways. These findings provide mechanistic insights into miR regulation of host immune responses and identify potential biomarkers that could inform therapy of COVID-19.
Authors
Mercer Mercer, Vijay Vijay, Yu Yu, Han Han, Masters Masters, Sun Sun, Bidarimath Bidarimath, Ramey Ramey, Agrawal Agrawal, Flores-Torres Flores-Torres, Green Green, Burkhart Burkhart, Herzog Herzog, Dusio Dusio, Arthur Arthur, Oliphant Oliphant, Smallwood Smallwood, Beger Beger
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