An intestinal cell type in zebrafish is the nexus for the SARS-CoV-2 receptor and the Renin-Angiotensin-Aldosterone System that contributes to COVID-19 comorbidities
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Abstract
People with underlying conditions, including hypertension, obesity, and diabetes, are especially susceptible to negative outcomes after infection with the coronavirus SARS-CoV-2. These COVID-19 comorbidities are exacerbated by the Renin-Angiotensin-Aldosterone System (RAAS), which normally protects from rapidly dropping blood pressure or dehydration via the peptide Angiotensin II (Ang II) produced by the enzyme Ace. The Ace paralog Ace2 degrades Ang II, thus counteracting its chronic effects. Ace2 is also the SARS-CoV-2 receptor. Ace , the coronavirus, and COVID-19 comorbidities all regulate Ace2 , but we don’t yet understand how. To exploit zebrafish ( Danio rerio ) as a disease model to understand mechanisms regulating the RAAS and its relationship to COVID-19 comorbidities, we must first identify zebrafish orthologs and co-orthologs of human RAAS genes, and second, understand where and when these genes are expressed in specific cells in zebrafish development. To achieve these goals, we conducted genomic analyses and investigated single cell transcriptomes. Results showed that most human RAAS genes have an ortholog in zebrafish and some have two or more co-orthologs. Results further identified a specific intestinal cell type in zebrafish larvae as the site of expression for key RAAS components, including Ace, Ace2, the coronavirus co-receptor Slc6a19, and the Angiotensin-related peptide cleaving enzymes Anpep and Enpep. Results also identified specific vascular cell subtypes as expressing Ang II receptors, apelin , and apelin receptor genes. These results identify specific genes and cell types to exploit zebrafish as a disease model for understanding the mechanisms leading to COVID-19 comorbidities.
SUMMARY STATEMENT
Genomic analyses identify zebrafish orthologs of the Renin-Angiotensin-Aldosterone System that contribute to COVID-19 comorbidities and single-cell transcriptomics show that they act in a specialized intestinal cell type.
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SciScore for 10.1101/2020.09.01.278366: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IACUC: Work was conducted under the approval of the University of Oregon IACUC, Protocol # 18-31. Reagents: Dissociated cells were prepared for scRNA-seq using the 10X Chromium platform v.2 chemistry. cDNA libraries were amplified by 15 PCR cycles and sequenced on Illumina Hi-seq or Next-seq. Statistics: Sequencing data were analyzed by Cell Ranger version 2.2.0 (Zheng et al., 2017) and Seurat (Satija et al., 2015). Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources Phylogenies and conserved syntenies: To identify genes that encode zebrafish … SciScore for 10.1101/2020.09.01.278366: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IACUC: Work was conducted under the approval of the University of Oregon IACUC, Protocol # 18-31. Reagents: Dissociated cells were prepared for scRNA-seq using the 10X Chromium platform v.2 chemistry. cDNA libraries were amplified by 15 PCR cycles and sequenced on Illumina Hi-seq or Next-seq. Statistics: Sequencing data were analyzed by Cell Ranger version 2.2.0 (Zheng et al., 2017) and Seurat (Satija et al., 2015). Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources Phylogenies and conserved syntenies: To identify genes that encode zebrafish proteins related to the human RAAS, we utilized phylogenetic analysis embedded in the ComparaTree method at Ensembl (Flicek et al., 2010). Ensemblsuggested: (Ensembl, RRID:SCR_002344)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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