Regulatory Noncoding and Predicted Pathogenic Coding Variants of CCR5 Predispose to Severe COVID-19

Cantalupo, Sueva; Lasorsa, Vito Alessandro; Russo, Roberta; Andolfo, Immacolata; D'Alterio, Giuseppe; Rosato, Barbara Eleni; Frisso, Giulia; Abete, Pasquale; Cassese, Gian Marco; Servillo, Giuseppe; Gentile, Ivan; Piscopo, Carmelo; Monica, Matteo Della; Fiorentino, Giuseppe; Russo, Giuseppe; Pellegrino, C.; Buonerba, Carlo; Pierri, Biancamaria; Zollo, Massimo; Iolascon, Achille; Capasso, Mario

doi:10.3390/ijms22105372

Cited by 24 publications

(22 citation statements)

References 53 publications

(54 reference statements)

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“…Furthermore, this miRNA targeted the C-C motif chemokine receptor 5 (CCR5) [69]. CCR5 is a chemokine receptor involved in host responses and host susceptibility, especially to viruses, and is highly expressed in lung tissue [70]. Of interest, CCR5 is involved in severe COVID-19 and has been proposed as anti-inflammatory treatment target [70][71][72].…”

Section: Discussionmentioning

confidence: 99%

“…CCR5 is a chemokine receptor involved in host responses and host susceptibility, especially to viruses, and is highly expressed in lung tissue [70]. Of interest, CCR5 is involved in severe COVID-19 and has been proposed as anti-inflammatory treatment target [70][71][72]. hsa-miR-455-5p was reported to have an anti-inflammatory role in multiple sclerosis [73].…”

Section: Discussionmentioning

confidence: 99%

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Altered microRNA expression in severe COVID-19: potential prognostic and pathophysiological role

Garnier

Pollet

Fourcot

et al. 2022

Preprint

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Background The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is ongoing. The pathophysiology of SARS-CoV-2 infection is beginning to be elucidated but the role of microRNAs (miRNAs), small non-coding RNAs that regulate gene expression, remains incompletely understood. They play a role in the pathophysiology of viral infections with potential use as biomarkers. The objective of this study was to identify miRNAs as biomarkers of severe COVID-19 and to analyze their role in the pathophysiology of SARS-CoV-2 infection. Methods miRNA expression was measured in nasopharyngeal swabs from 20 patients with severe COVID-19, 21 patients with non-severe COVID-19 and 20 controls. Promising miRNAs to differentiate non-severe from severe COVID-19 patients were identified by differential expression analysis and sparse Partial Least Squares-Discriminant Analysis (sPLS-DA). ROC analysis, target prediction, GO enrichment and pathway analysis were used to analyze the role and the pertinence of these miRNAs in severe COVID-19. Results The number of expressed miRNAs was lower in severe COVID-19 patients compared to non-severe COVID-19 patients and controls. Among the differentially expressed miRNAs between severe COVID-19 and controls, 5 miRNAs were also differentially expressed between severe and non-severe COVID-19. sPLS-DA analysis highlighted 8 miRNAs, that allowed to discriminate the severe and non-severe COVID-19 cases. Target and functional analysis revealed enrichment for genes involved in viral infections and the cellular response to infection as well as one miRNA, hsa-miR-15b-5p, that targeted the SARS-CoV-2 RNA. The comparison of results of differential expression analysis and discriminant analysis revealed three miRNAs, namely hsa-miR-125a-5p, hsa-miR-491-5p and hsa-miR-200b-3p. These discriminated severe from non-severe cases with areas under the curve ranging from 0.76 to 0.80. Conclusions Our analysis of miRNA expression in nasopharyngeal swabs revealed several miRNAs of interest to discriminate severe and non-severe COVID-19. These miRNAs represent promising biomarkers and possibly targets for antiviral or anti-inflammatory treatment strategies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Altered microRNA expression in severe COVID-19: potential prognostic and pathophysiological role

Garnier

Pollet

Fourcot

et al. 2022

Preprint

View full text Add to dashboard Cite

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“… 78 Data from GWAS are now pointing towards monocyte and macrophage cell homing molecules such as chemokines and chemokine receptors, as potentially increasing susceptibility to severe disease. 79 , 80 However, further entities may not be identified quickly, given that prior to the pandemic, it was difficult to identify more than 50% of gene defects underlying presumed monogenic PIDs. 81 Low identification rates can reflect pathogenic variants in non‐coding regions of known genes that require different sequencing technologies to identify them, 82 or variants in novel genes which, because of their rarity, do not give a statistical signal even within large populations, and where the process of proving pathogenesis through molecular modelling may take years.…”

Section: Where To Look For Other Rare Immune Defects Impacting Covid‐...mentioning

confidence: 99%

“…This approach can be successful because, even though the low relative risk of variants associated with GWAS informs little about why a given patient suffered bad disease, 84 the signal from the GWAS may actually reflect much rarer variants carrying a far greater risk and relevance, travelling in linkage disequilibrium with the common variant identified in the GWAS. This strategy has revealed rare variants in CCR5 in severe COVID‐19 patients, 80 although further molecular validation of this latter association is needed before it can be added to the list of COVID‐19‐predisposing gene defects.…”

Section: Where To Look For Other Rare Immune Defects Impacting Covid‐...mentioning

confidence: 99%

Severe COVID‐19 represents an undiagnosed primary immunodeficiency in a high proportion of infected individuals

2022

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Since the emergence of the COVID‐19 pandemic in early 2020, a key challenge has been to define risk factors, other than age and pre‐existing comorbidities, that predispose some people to severe disease, while many other SARS‐CoV‐2‐infected individuals experience mild, if any, consequences. One explanation for intra‐individual differences in susceptibility to severe COVID‐19 may be that a growing percentage of otherwise healthy people have a pre‐existing asymptomatic primary immunodeficiency (PID) that is unmasked by SARS‐CoV‐2 infection. Germline genetic defects have been identified in individuals with life‐threatening COVID‐19 that compromise local type I interferon (IFN)‐mediated innate immune responses to SARS‐CoV‐2. Remarkably, these variants – which impact responses initiated through TLR3 and TLR7, as well as the response to type I IFN cytokines – may account for between 3% and 5% of severe COVID‐19 in people under 70 years of age. Similarly, autoantibodies against type I IFN cytokines (IFN‐α, IFN‐ω) have been detected in patients' serum prior to infection with SARS‐CoV‐2 and were found to cause c . 20% of severe COVID‐19 in the above 70s and 20% of total COVID‐19 deaths. These autoantibodies, which are more common in the elderly, neutralise type I IFNs, thereby impeding innate antiviral immunity and phenocopying an inborn error of immunity. The discovery of PIDs underlying a significant percentage of severe COVID‐19 may go some way to explain disease susceptibility, may allow for the application of targeted therapies such as plasma exchange, IFN‐α or IFN‐β, and may facilitate better management of social distancing, vaccination and early post‐exposure prophylaxis.

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“…Besides, several minor symptoms such as gastrointestinal complications, including nausea, vomiting, and diarrhea, have also been reported [19]. In severe cases, breathing di culties with dyspnea occur, with acute respiratory distress syndrome (ARDS) being the most serious complication [20]. SARS-CoV-2 infection exhibits varied infectivity and mortality rates in different worldwide populations [21,22].…”

Section: Introductionmentioning

confidence: 99%

Evaluation and Limitations of Different Approaches Among COVID-19 Fatal Cases Using Whole-exome Sequencing Data

Forgacova

Holesova

Hekel

et al. 2022

Preprint

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Background: COVID-19 caused by SARS-CoV-2 infection may result in various disease symptoms and severity, ranging from asymptomatic, through mild, up to very severe and fatal cases. Although environmental, clinical, and social factors play important roles in both susceptibility to SARS-CoV-2 infection and COVID-19 disease progress, it is becoming evident that both pathogen and host genetic factors are important too. Here we report whole-exome sequencing (WES) findings of 27 individuals who died as a result of COVID-19 infection, especially focusing on frequencies of DNA variants in genes previously associated with SARS-CoV-2 infection and COVID-19 severity. Results: We selected risk DNA variants/alleles or target genes using four different approaches: 1) aggregated GWAS results from the GWAS Catalog; 2) selected publications from PubMed; 3) the aggregated results of the Host Genetics Initiative database; and 4) a commercial DNA variant annotation/interpretation tool providing its own knowledgebase. We divided these variants/genes into those reported to influence the susceptibility to SARS-CoV-2 infection and those influencing COVID-19 severity. Based on these, we compared frequencies of alleles among the fatal COVID-19 cases to frequencies identified in two population control datasets (non-Finnish European population from the gnomAD database and genomic frequencies specific for the Slovak population from our own database). Our comparisons delineated a trend of higher frequencies of severe COVID-19 associated risk alleles among fatal COVID-19 cases, when compared to both control population datasets. This trend reached statistical significance specifically when using the HGI derived variant list. We also analyzed other approaches to WES data evaluation, where we showed their usage as well as limitations. Conclusions: Although our results proved the likely involvement of host genetic factors pinned out by previous studies for COVID-19 disease severity, careful considerations about the molecular-testing strategies and the evaluated genomic positions may have a strong impact on the utility of genomic testing.

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Regulatory Noncoding and Predicted Pathogenic Coding Variants of CCR5 Predispose to Severe COVID-19

Cited by 24 publications

References 53 publications

Altered microRNA expression in severe COVID-19: potential prognostic and pathophysiological role

Altered microRNA expression in severe COVID-19: potential prognostic and pathophysiological role

Severe COVID‐19 represents an undiagnosed primary immunodeficiency in a high proportion of infected individuals

Evaluation and Limitations of Different Approaches Among COVID-19 Fatal Cases Using Whole-exome Sequencing Data

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