Deregulated miRNA expression is associated with endothelial dysfunction in post-mortem lung biopsies of COVID-19 patients.

MicroRNAs (miRNAs) are critical modulators of endothelial homeostasis, which highlights their involvement in vascular diseases, including the ones caused by virus infections. Our main objective was to identify miRNAs involved in the endothelial function and determine their expression in post-mortem lung biopsies of COVID-19 patients with severe respiratory injuries and thrombotic events. Based on functional enrichment analysis, miR-26a-5p, miR-29b-3p, and miR-34a-5p were identified as regulators of mRNA targets involved in endothelial, and inflammatory signaling pathways as well as in viral diseases. A miRNA/mRNA network, constructed based on protein-protein interactions of the miRNA targets and the inflammatory biomarkers characterized in the patients, revealed a close interconnection of these miRNAs with relevance to the endothelial activation/dysfunction. Reduced expression levels of selected miRNAs were observed in the lung biopsies of COVID-19 patients (n=9) compared to the Controls (n=10)(P<0.01-0.0001). MiR-26a-5p and miR-29b-3p presented the best power to discriminate these groups (AUC=0.8286, and AUC=0.8125, respectively). The correlation analysis of the miRNAs with inflammatory biomarkers in the COVID-19 patients was significant for miR-26a-5p [IL-6 (r2=0.5414), and ICAM-1(r2=0.5624)], and miR-29b-3p [IL-4 (r2=0.8332), and IL-8 (r2=0.2654)]. Altogether, these findings demonstrate the relevance and the non-random involvement of miR-26a-5p, miR-29b-3p, and miR-34a-5p in endothelial dysfunction and inflammatory response in patients with SARS-CoV-2 infection and the occurrence of severe lung injury and immunothrombosis.

Cross-sectional study for COVID-19-related mortality predictors in a Brazilian state-wide landscape: the role of demographic factors, symptoms and comorbidities.

OBJECTIVE: The Brazilian state of Paraná has suffered from COVID-19 effects, understanding predictors of increased mortality in health system interventions prevent hospitalisation of patients. We selected the best models to evaluate the association of death with demographic characteristics, symptoms and comorbidities based on three levels of clinical severity for COVID-19: non-hospitalised, hospitalised non-ICU ward and ICU ward. DESIGN: Cross-sectional survey using binomial mixed models. SETTING: COVID-19-positive cases diagnosed by reverse transcription-PCR of municipalities located in Paraná State. PATIENTS: Cases of anonymous datasets of electronic medical records from 1 April 2020 to 31 December 2020. PRIMARY AND SECONDARY OUTCOME MEASURES: The best prediction factors were chosen based on criteria after a stepwise analysis using multicollinearity measure, lower Akaike information criterion and goodness-of-fit χ2 tests from univariate to multivariate contexts. RESULTS: Male sex was associated with increased mortality among non-hospitalised patients (OR 1.76, 95% CI 1.47 to 2.11) and non-ICU patients (OR 1.22, 95% CI 1.05 to 1.43) for symptoms and for comorbidities (OR 1.89, 95% CI 1.59 to 2.25, and OR 1.30, 95% CI 1.11 to 1.52, respectively). Higher mortality occurred in patients older than 35 years in non-hospitalised (for symptoms: OR 4.05, 95% CI 1.55 to 10.54; and for comorbidities: OR 3.00, 95% CI 1.24 to 7.27) and in hospitalised over 40 years (for symptoms: OR 2.72, 95% CI 1.08 to 6.87; and for comorbidities: OR 2.66, 95% CI 1.22 to 5.79). Dyspnoea was associated with increased mortality in non-hospitalised (OR 4.14, 95% CI 3.45 to 4.96), non-ICU (OR 2.41, 95% CI 2.04 to 2.84) and ICU (OR 1.38, 95% CI 1.10 to 1.72) patients. Neurological disorders (OR 2.16, 95% CI 1.35 to 3.46), neoplastic (OR 3.22, 95% CI 1.75 to 5.93) and kidney diseases (OR 2.13, 95% CI 1.36 to 3.35) showed the majority of increased mortality for ICU as well in the three levels of severity jointly with heart disease, diabetes and CPOD. CONCLUSIONS: These findings highlight the importance of the predictor's assessment for the implementation of public healthcare policy in response to the COVID-19 pandemic, mainly to understand how non-pharmaceutical measures could mitigate the virus impact over the population.

Genome interaction of the virus and the host genes and non-coding RNAs in SARS-CoV-2 infection.

In this review, we highlight the interaction of SARS-CoV-2 virus and host genomes, reporting the current studies on the sequence analysis of SARS-CoV-2 isolates and host genomes from diverse world populations. The main genetic variants that are present in both the virus and host genomes were particularly focused on the ACE2 and TMPRSS2 genes, and their impact on the patients' susceptibility to the virus infection and severity of the disease. Finally, the interaction of the virus and host non-coding RNAs is described in relation to their regulatory roles in target genes and/or signaling pathways critically associated with SARS-CoV-2 infection. Altogether, these studies provide a significant contribution to the knowledge of SARS-CoV-2 mechanisms of infection and COVID-19 pathogenesis. The described genetic variants and molecular factors involved in host/virus genome interactions have significantly contributed to defining patient risk groups, beyond those based on patients' age and comorbidities, and they are promising candidates to be potentially targeted in treatment strategies for COVID-19 and other viral infectious diseases.

The role of microRNAs in modulating SARS-CoV-2 infection in human cells: a systematic review.

MicroRNAs are gene expression regulators, associated with several human pathologies, including the ones caused by virus infections. Although their role in infection diseases is not completely known, they can exert double functions in the infected cell, by mediating the virus infection and/or regulating the immunity-related gene targets through complex networks of virus-host cell interactions. In this systematic review, the Pubmed, EMBASE, Scopus, Lilacs, Scielo, and EBSCO databases were searched for research articles published until October 22nd, 2020 that focused on describing the role, function, and/or association of miRNAs in SARS-CoV-2 human infection and COVID-19. Following the PRISMA 2009 protocol, 29 original research articles were selected. Most of the studies reported miRNA data based on the genome sequencing of SARS-CoV-2 isolates and computational prediction analysis. The latter predicted, by at least one independent study, 1266 host miRNAs to target the viral genome. Thirteen miRNAs were identified by four independent studies to target SARS-CoV-2 specific genes, suggested to act by interfering with their cleavage and/or translation process. The studies selected also reported on viral and host miRNAs that targeted host genes, on the expression levels of miRNAs in biological specimens of COVID-19 patients, and on the impact of viral genome mutations on miRNA function. Also, miRNAs that regulate the expression levels of the ACE2 and TMPRSS2 proteins, which are critical for the virus entrance in the host cells, were reported. In conclusion, despite the limited number of studies identified, based on the search terms and eligibility criteria applied, this systematic review provides evidence on the impact of miRNAs on SARS-CoV-2 infection and COVID-19. Although most of the reported viral/host miRNAs interactions were based on in silico prediction analysis, they demonstrate the relevance of the viral/host miRNA interaction for viral activity and host responses. In addition, the identified studies highlight the potential use of miRNAs as therapeutic targets against COVID-19, and other viral human diseases (This review was registered at the International Prospective Register of Systematic Reviews (PROSPERO) database (#CRD42020199290).