Effect of statins on SARS-CoV-2 infection
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Abstract
The retrospective analysis of clinical data of patients suffering from COVID-19 has indicated that statin therapy, used to lower plasma cholesterol levels, is associated with a better clinical outcome. We therefore investigated the effect of statins on SARS-CoV-2 infection and found that selective statins reduced SARS-CoV-2 cell entry and inhibited high and low pathogenic coronavirus infection in human cells. A retrospective study on hospitalized patients with COVID-19 implies that reduced high density lipoprotein levels, which are typically counteracted by statin therapy, are associated with aggravated disease outcome. These results suggest that statin therapy poses no additional risk to individuals exposed to SARS-CoV-2 and that some statins may have a mild beneficial effect on COVID-19 outcome. Placebo controlled trials are required to clarify the role of statins in COVID-19 infected patients .
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SciScore for 10.1101/2020.07.13.20152272: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement Consent: Primary lung cell culture: Primary human bronchial epithelial cells (HBEC) were isolated with informed consent from lung tissue from three individual patients, who underwent thoracic surgery at the University hospital of Umeå, Sweden, with ethical permission approved by the local Ethics Review Board.
IRB: Primary lung cell culture: Primary human bronchial epithelial cells (HBEC) were isolated with informed consent from lung tissue from three individual patients, who underwent thoracic surgery at the University hospital of Umeå, Sweden, with ethical permission approved by the local Ethics Review Board.Randomization not detected. Blinding not detected. Power … SciScore for 10.1101/2020.07.13.20152272: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement Consent: Primary lung cell culture: Primary human bronchial epithelial cells (HBEC) were isolated with informed consent from lung tissue from three individual patients, who underwent thoracic surgery at the University hospital of Umeå, Sweden, with ethical permission approved by the local Ethics Review Board.
IRB: Primary lung cell culture: Primary human bronchial epithelial cells (HBEC) were isolated with informed consent from lung tissue from three individual patients, who underwent thoracic surgery at the University hospital of Umeå, Sweden, with ethical permission approved by the local Ethics Review Board.Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Cell Line Authentication Contamination: Each cell line was tested regularly for Mycoplasma contamination. Table 2: Resources
Antibodies Sentences Resources Presence of ciliated cells and goblet cells was also determined with IF using antibodies directed against acetylated-tubulin and muc5AC, respectively, as described under IF staining below. antibodies directed against acetylated-tubulinsuggested: Nonemuc5ACsuggested: NoneExperimental Models: Cell Lines Sentences Resources Cell lines and virus strains: HEK293T cells, Huh7.5 cells constitutively expressing a Firefly luciferase (Huh7.5 FLuc) and Calu-3 cells were maintained in DMEM supplemented with 10% fetal bovine serum, 2 mM glutamine, 0.1 mM non-essential amino acids and 1% Penicillin/Streptomycin at 37°C and 5% CO2. HEK293Tsuggested: NoneThe recombinant hCoV229E encoding a Renilla luciferase gene was produced in Huh7.5 cells at 33°C and titrated on Huh7.5 cells. Huh7.5suggested: RRID:CVCL_7927)Cells were pretreated with 10 μM fluvastatin, simvastatin, rosuvastatin or DMSO for 24 h and then infected with SARS-CoV-2 isolate at MOI 2.0×10−5 based on titration in Vero cells. Verosuggested: CLS Cat# 605372/p622_VERO, RRID:CVCL_0059)In brief, the viral stock was propagated in Vero E6 cells for 48 h and titrated by plaque assay. Vero E6suggested: NoneMass Spectrometry: Calu-3 cells were treated with statins and infected as described in section ‘SARS-2 infection and quantification by RT-qPCR’. Calu-3suggested: KCLB Cat# 30055, RRID:CVCL_0609)Software and Algorithms Sentences Resources MS/MS raw data files were processed by using Peaks X+ (Bioinformatics Solutions) and MaxQuant (1.6.17.0) software56 and UniProtKB databases (Homo sapiens: UP000005640/April 28, 2020; SARS-CoV-2: UP000464024/September 29, 2020). MaxQuantsuggested: (MaxQuant, RRID:SCR_014485)UniProtKBsuggested: (UniProtKB, RRID:SCR_004426)Protein-protein interaction network analysis of statistically dysregulated proteins (p-value cut-off = 0.05) was performed with STRING with a medium confidence threshold (0.4). STRINGsuggested: (STRING, RRID:SCR_005223)STRING analysis was exported to Cytoscape 3.8.2 and enrichment analysis executed with EnrichmentMap 3.1.0 plugin61. Cytoscapesuggested: (Cytoscape, RRID:SCR_003032)EnrichmentMapsuggested: (EnrichmentMap, RRID:SCR_016052)All statistical analyses were performed using one or two-way analysis of variance (ANOVA) followed by Dunnett or Sidak’s multiple comparison test using GraphPad Prism software version 8 (GraphPad). GraphPad Prismsuggested: (GraphPad Prism, RRID:SCR_002798)GraphPadsuggested: (GraphPad Prism, RRID:SCR_002798)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: We detected the following sentences addressing limitations in the study:However, given the limitations of retrospective studies, placebo-controlled trials are required to clarify the role of statins in COVID-19 infected patients. It is important to note that the inhibitory doses observed in our cell culture experiments are an order of magnitude higher than statin serum concentrations in patients, which are in the nM range27. This suggests that the observed direct effects on SARS-CoV-2 infection in tissue culture may not account for the clinical observations in the retrospective cohort studies. Unfortunately, fluvastatin, the only statin with anti-coronavirus activity in our study, is prescribed rarely and only one patient in the retrospective studies received this therapy12,13. In sum, we found no evidence for a direct aggravating effect of statins on SARS-CoV-2 infection of human lung cells. The known immunomodulatory effects of statins28–31 may ameliorate the outcome of hospitalized COVID-19 patients. In our study, statin treatment did not markedly affected SARS-CoV-2 immune sensing or cytokine-mediated cellular responses in comparison to solvent control (Fig. 4). However, the slight upregulation of interferon stimulated genes (ISGs) in uninfected cells and milder dysregulation of cytokine-regulated genes after infection (Fig. 4) indicates that fluvastatin may have a relevant immunomodulatory effect on lung epithelial cells, which could ultimately ameliorate COVID-19 immunopathology. Of note, our study does not address the effect of statins on ...
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.
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