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1.
Emerg Microbes Infect ; 11(1): 1537-1549, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-1860764

ABSTRACT

There is a limited understanding of the pathophysiology of postacute pulmonary sequelae in severe COVID-19. The aim of current study was to define the circulating microRNA (miRNA) profiles associated with pulmonary function and radiologic features in survivors of SARS-CoV-2-induced ARDS. The study included patients who developed ARDS secondary to SARS-CoV-2 infection (n = 167) and a group of infected patients who did not develop ARDS (n = 33). Patients were evaluated 3 months after hospital discharge. The follow-up included a complete pulmonary evaluation and chest computed tomography. Plasma miRNA profiling was performed using RT-qPCR. Random forest was used to construct miRNA signatures associated with lung diffusing capacity for carbon monoxide (DLCO) and total severity score (TSS). Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses were conducted. DLCO < 80% predicted was observed in 81.8% of the patients. TSS showed a median [P25;P75] of 5 [2;8]. The miRNA model associated with DLCO comprised miR-17-5p, miR-27a-3p, miR-126-3p, miR-146a-5p and miR-495-3p. Concerning radiologic features, a miRNA signature composed by miR-9-5p, miR-21-5p, miR-24-3p and miR-221-3p correlated with TSS values. These associations were not observed in the non-ARDS group. KEGG pathway and GO enrichment analyses provided evidence of molecular mechanisms related not only to profibrotic or anti-inflammatory states but also to cell death, immune response, hypoxia, vascularization, coagulation and viral infection. In conclusion, diffusing capacity and radiological features in survivors from SARS-CoV-2-induced ARDS are associated with specific miRNA profiles. These findings provide novel insights into the possible molecular pathways underlying the pathogenesis of pulmonary sequelae.Trial registration: ClinicalTrials.gov identifier: NCT04457505..Trial registration: ISRCTN.org identifier: ISRCTN16865246..


Subject(s)
COVID-19 , Circulating MicroRNA , Respiratory Distress Syndrome , COVID-19/complications , Circulating MicroRNA/genetics , Humans , Lung , Respiratory Distress Syndrome/diagnostic imaging , Respiratory Distress Syndrome/virology , SARS-CoV-2 , Survivors
2.
Sci Rep ; 12(1): 6929, 2022 04 28.
Article in English | MEDLINE | ID: covidwho-1815599

ABSTRACT

One of the hallmarks of SARS-CoV-2 infection is an induced immune dysregulation, in some cases resulting in cytokine storm syndrome and acute respiratory distress syndrome (ARDS). Several physiological parameters are altered as a result of infection and cytokine storm. Among them, microRNAs (miRNAs) might reflect this poor condition since they play a significant role in immune cellular performance including inflammatory responses. Circulating miRNAs in patients who underwent ARDS and needed mechanical ventilation (MV+; n = 15) were analyzed by next generation sequencing in comparison with patients who had COVID-19 poor symptoms but without intensive care unit requirement (MV-; n = 13). A comprehensive in silico analysis by integration with public gene expression dataset and pathway enrichment was performed. Whole miRNA sequencing identified 170 differentially expressed miRNAs between patient groups. After the validation step by qPCR in an independent sample set (MV+ = 10 vs. MV- = 10), the miR-369-3p was found significantly decreased in MV+ patients (Fold change - 2.7). After integrating with gene expression results from COVID-19 patients, the most significant GO enriched pathways were acute inflammatory response, regulation of transmembrane receptor protein Ser/Thr, fat cell differentiation, and regulation of biomineralization and ossification. In conclusion, miR-369-3p was altered in patients with mechanical ventilation requirement in comparison with COVID-19 patients without this requirement. This miRNA is involved in inflammatory response which it can be considered as a prognosis factor for ARDS in COVID-19 patients.


Subject(s)
COVID-19 , Circulating MicroRNA , MicroRNAs , Respiratory Distress Syndrome , COVID-19/complications , COVID-19/genetics , Circulating MicroRNA/genetics , Cytokine Release Syndrome , Humans , MicroRNAs/genetics , Respiratory Distress Syndrome/genetics , SARS-CoV-2
3.
Mech Ageing Dev ; 202: 111636, 2022 03.
Article in English | MEDLINE | ID: covidwho-1665255

ABSTRACT

The stratification of mortality risk in COVID-19 patients remains extremely challenging for physicians, especially in older patients. Innovative minimally invasive molecular biomarkers are needed to improve the prediction of mortality risk and better customize patient management. In this study, aimed at identifying circulating miRNAs associated with the risk of COVID-19 in-hospital mortality, we analyzed serum samples of 12 COVID-19 patients by small RNA-seq and validated the findings in an independent cohort of 116 COVID-19 patients by qRT-PCR. Thirty-four significantly deregulated miRNAs, 25 downregulated and 9 upregulated in deceased COVID-19 patients compared to survivors, were identified in the discovery cohort. Based on the highest fold-changes and on the highest expression levels, 5 of these 34 miRNAs were selected for the analysis in the validation cohort. MiR-320b and miR-483-5p were confirmed to be significantly hyper-expressed in deceased patients compared to survived ones. Kaplan-Meier and Cox regression models, adjusted for relevant confounders, confirmed that patients with the 20% highest miR-320b and miR-483-5p serum levels had three-fold increased risk to die during in-hospital stay for COVID-19. In conclusion, high levels of circulating miR-320b and miR-483-5p can be useful as minimally invasive biomarkers to stratify older COVID-19 patients with an increased risk of in-hospital mortality.


Subject(s)
COVID-19/blood , COVID-19/mortality , Circulating MicroRNA/blood , Hospital Mortality , Hospitalization , MicroRNAs/blood , Aged , Aged, 80 and over , Biomarkers/blood , COVID-19/diagnosis , COVID-19/genetics , Circulating MicroRNA/genetics , Female , Humans , Male , MicroRNAs/genetics , Predictive Value of Tests , Prognosis , RNA-Seq , Risk Assessment , Risk Factors , Time Factors , Up-Regulation
4.
Cells ; 10(12)2021 12 11.
Article in English | MEDLINE | ID: covidwho-1572377

ABSTRACT

The SARS-CoV-2 (COVID-19) pandemic has caused millions of deaths worldwide. Early risk assessment of COVID-19 cases can help direct early treatment measures that have been shown to improve the prognosis of severe cases. Currently, circulating miRNAs have not been evaluated as canonical COVID-19 biomarkers, and identifying biomarkers that have a causal relationship with COVID-19 is imperative. To bridge these gaps, we aim to examine the causal effects of miRNAs on COVID-19 severity in this study using two-sample Mendelian randomization approaches. Multiple studies with available GWAS summary statistics data were retrieved. Using circulating miRNA expression data as exposure, and severe COVID-19 cases as outcomes, we identified ten unique miRNAs that showed causality across three phenotype groups of COVID-19. Using expression data from an independent study, we validated and identified two high-confidence miRNAs, namely, hsa-miR-30a-3p and hsa-miR-139-5p, which have putative causal effects on developing cases of severe COVID-19. Using existing literature and publicly available databases, the potential causative roles of these miRNAs were investigated. This study provides a novel way of utilizing miRNA eQTL data to help us identify potential miRNA biomarkers to make better and early diagnoses and risk assessments of severe COVID-19 cases.


Subject(s)
COVID-19/genetics , Circulating MicroRNA/genetics , MicroRNAs/genetics , Patient Acuity , SARS-CoV-2/genetics , Biomarkers/blood , COVID-19/blood , Circulating MicroRNA/blood , Genome-Wide Association Study , Humans , Mendelian Randomization Analysis , MicroRNAs/blood , SARS-CoV-2/metabolism
5.
Signal Transduct Target Ther ; 6(1): 300, 2021 08 11.
Article in English | MEDLINE | ID: covidwho-1351933

ABSTRACT

Elderly people and patients with comorbidities are at higher risk of COVID-19 infection, resulting in severe complications and high mortality. However, the underlying mechanisms are unclear. In this study, we investigate whether miRNAs in serum exosomes can exert antiviral functions and affect the response to COVID-19 in the elderly and people with diabetes. First, we identified four miRNAs (miR-7-5p, miR-24-3p, miR-145-5p and miR-223-3p) through high-throughput sequencing and quantitative real-time PCR analysis, that are remarkably decreased in the elderly and diabetic groups. We further demonstrated that these miRNAs, either in the exosome or in the free form, can directly inhibit S protein expression and SARS-CoV-2 replication. Serum exosomes from young people can inhibit SARS-CoV-2 replication and S protein expression, while the inhibitory effect is markedly decreased in the elderly and diabetic patients. Moreover, three out of the four circulating miRNAs are significantly increased in the serum of healthy volunteers after 8-weeks' continuous physical exercise. Serum exosomes isolated from these volunteers also showed stronger inhibitory effects on S protein expression and SARS-CoV-2 replication. Our study demonstrates for the first time that circulating exosomal miRNAs can directly inhibit SARS-CoV-2 replication and may provide a possible explanation for the difference in response to COVID-19 between young people and the elderly or people with comorbidities.


Subject(s)
COVID-19/genetics , Diabetes Mellitus/genetics , MicroRNAs/genetics , Spike Glycoprotein, Coronavirus/genetics , Adult , Age Factors , Aged , COVID-19/blood , COVID-19/pathology , COVID-19/virology , China , Circulating MicroRNA/blood , Circulating MicroRNA/genetics , Cohort Studies , Diabetes Mellitus/blood , Diabetes Mellitus/pathology , Diabetes Mellitus/virology , Exercise , Exosomes/genetics , Exosomes/metabolism , Exosomes/virology , Female , Gene Expression Regulation , HEK293 Cells , Host-Pathogen Interactions/genetics , Humans , Male , MicroRNAs/blood , Middle Aged , SARS-CoV-2/genetics , SARS-CoV-2/growth & development , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/blood , Virus Replication
6.
Infect Genet Evol ; 94: 105020, 2021 10.
Article in English | MEDLINE | ID: covidwho-1331048

ABSTRACT

Nowadays, the coronavirus disease (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represents a major global health problem. Intensive efforts are being employed to better understand this pathology and develop strategies enabling its early diagnosis and efficient treatment. In this study, we compared the signature of circulating miRNAs in plasma of COVID-19 patients versus healthy donors. MiRCURY LNA miRNA miRNome qPCR Panels were performed for miRNA signature characterization. Individual quantitative real-time PCR (qRT-PCR) was carried out to validate miRNome qPCR results. Receiver-operator characteristic (ROC) curve analysis was applied to assess the diagnostic accuracy of the most significantly deregulated miRNA(s) as potential diagnostic biomarker(s). Eight miRNAs were identified to be differentially expressed with miR-17-5p and miR-142-5p being down-regulated whilst miR-15a-5p, miR-19a-3p, miR-19b-3p, miR-23a-3p, miR-92a-3p and miR-320a being up-regulated in SARS-CoV-2-infected patients. ROC curve analyses revealed an AUC (Areas Under the ROC Curve) of 0.815 (P = 0.031), 0.875 (P = 0.012), and 0.850 (P = 0.025) for miR-19a-3p, miR-19b-3p, and miR-92a-3p, respectively. Combined ROC analyses using these 3 miRNAs showed a greater AUC of 0.917 (P = 0.0001) indicating a robust diagnostic value of these 3 miRNAs. These results suggest that plasma miR-19a-3p, miR-19b-3p, and miR-92a-3p expression levels could serve as potential diagnostic biomarker and/or a putative therapeutic target during SARS-CoV-2-infection.


Subject(s)
COVID-19/blood , Circulating MicroRNA/blood , Adult , Biomarkers/blood , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/physiopathology , Circulating MicroRNA/genetics , Down-Regulation , Female , Humans , Male , Middle Aged , Severity of Illness Index
7.
Iran J Immunol ; 18(1): 65-73, 2021 03.
Article in English | MEDLINE | ID: covidwho-1159031

ABSTRACT

BACKGROUND: The role of cytokine storm in the immunopathogenesis of coronavirus disease 2019 (COVID-19) has been implicated. OBJECTIVE: To determine the association of microRNA (miRNA)-10b and serum levels of IL-2 and IL-8 in patients with COVID-19. METHODS: Blood samples were obtained from 33 COVID-19 patients and 29 healthy subjects. After RNA extraction and cDNA synthesis, the transcript level of miR-10b was determined by Real-time PCR. In addition, the serum levels of IL-2 and IL-8 were measured in subjects using ELISA. RESULTS: The patient group comprised of 33 patients with COVID-19 (62.4 ± 3.7 years old), 13 (39%) males and 20 (61%) females. In the control group, 29 subjects (56.6 ± 1.6 years old), 9 (31%) males and 20 (69%) females, were included. The expression of miR-10b was significantly downregulated in the peripheral blood of COVID-19 patients in comparison to the healthy controls (fold change= 0.12, P< 0.0001). The levels of IL-2 (P< 0.001) and IL-8 (P< 0.001) were significantly increased in the serum samples of COVID-19 patients compared to the healthy subjects. The expression level of miR-10b was correlated significantly with the serum levels of IL-2 and IL-8 as well as with the age of patients, ESR and CRP levels. CONCLUSIONS: miR-10b is downregulated in the COVID-19 patients and might result in increased levels of IL-2 and IL-8, hence contributing to cytokine storm.


Subject(s)
COVID-19/blood , Circulating MicroRNA/blood , Interleukin-2/blood , Interleukin-8/blood , MicroRNAs/blood , SARS-CoV-2/pathogenicity , Aged , Biomarkers/blood , COVID-19/genetics , COVID-19/immunology , COVID-19/virology , Case-Control Studies , Circulating MicroRNA/genetics , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/virology , Female , Host-Pathogen Interactions , Humans , Male , MicroRNAs/genetics , Middle Aged , SARS-CoV-2/immunology
8.
J Cell Mol Med ; 24(20): 12054-12064, 2020 10.
Article in English | MEDLINE | ID: covidwho-755303

ABSTRACT

Cell-free microRNAs (miRNAs) are transferred in disease state including inflammatory lung diseases and are often packed into extracellular vesicles (EVs). To assess their suitability as biomarkers for community-acquired pneumonia (CAP) and severe secondary complications such as sepsis, we studied patients with CAP (n = 30), sepsis (n = 65) and healthy volunteers (n = 47) subdivided into a training (n = 67) and a validation (n = 75) cohort. After precipitating crude EVs from sera, associated small RNA was profiled by next-generation sequencing (NGS) and evaluated in multivariate analyses. A subset of the thereby identified biomarker candidates was validated both technically and additionally by reverse transcription quantitative real-time PCR (RT-qPCR). Differential gene expression (DGE) analysis revealed 29 differentially expressed miRNAs in CAP patients when compared to volunteers, and 25 miRNAs in patients with CAP, compared to those with sepsis. Sparse partial-least discriminant analysis separated groups based on 12 miRNAs. Three miRNAs proved as a significant biomarker signature. While expression levels of miR-1246 showed significant changes with an increase in overall disease severity from volunteers to CAP and to sepsis, miR-193a-5p and miR-542-3p differentiated patients with an infectious disease (CAP or sepsis) from volunteers. Cell-free miRNAs are potentially novel biomarkers for CAP and may help to identify patients at risk for progress to sepsis, facilitating early intervention and treatment.


Subject(s)
Circulating MicroRNA/blood , Community-Acquired Infections/diagnosis , Community-Acquired Infections/genetics , Pneumonia/diagnosis , Pneumonia/genetics , Sepsis/blood , Sepsis/complications , Aged , Aged, 80 and over , Circulating MicroRNA/genetics , Community-Acquired Infections/blood , Gene Expression Regulation , Humans , Immunity, Humoral/genetics , Middle Aged , Multivariate Analysis , Pneumonia/blood , Pneumonia/complications , Reproducibility of Results , Reverse Transcription/genetics , Sepsis/genetics
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