VIP plasma levels associate with survival in severe COVID-19 patients, correlating with protective effects in SARS-CoV-2-infected cells
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Abstract
Infection by SARS-CoV-2 may elicit uncontrolled and damaging inflammatory responses. Thus, it is critical to identify compounds able to inhibit virus replication and thwart the inflammatory reaction. Here, we show that the plasma levels of the immunoregulatory neuropeptide VIP are elevated in patients with severe COVID-19, correlating with reduced inflammatory mediators and with survival on those patients. In vitro, vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP), highly similar neuropeptides, decreased the SARS-CoV-2 RNA content in human monocytes and viral production in lung epithelial cells, also reducing cell death. Both neuropeptides inhibited the production of proinflammatory mediators in lung epithelial cells and in monocytes. VIP and PACAP prevented in monocytes the SARS-CoV-2-induced activation of NF-kB and SREBP1 and SREBP2, transcriptions factors involved in proinflammatory reactions and lipid metabolism, respectively. They also promoted CREB activation, a transcription factor with antiapoptotic activity and negative regulator of NF-kB. Specific inhibition of NF-kB and SREBP1/2 reproduced the anti-inflammatory, antiviral, and cell death protection effects of VIP and PACAP. Our results support further clinical investigations of these neuropeptides against COVID-19.
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SciScore for 10.1101/2020.07.25.220806: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement Consent: Ethics statement: Experimental procedures involving human cells from healthy donors were performed with samples obtained after written informed consent and were approved by the Institutional Review Board (IRB) of the Oswaldo Cruz Foundation/Fiocruz (Rio de Janeiro, RJ, Brazil) under the number 397-07.
IRB: The National Review Board approved the study protocol (CONEP 30650420.4.1001.0008), and informed consent was obtained from all participants or patients’ representatives.Randomization not detected. Blinding The reader was blind with respect to source of the supernatant. Power Analysis not detected. Sex as a biological variable PBMCs (2 × 106 cells) were plated … SciScore for 10.1101/2020.07.25.220806: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement Consent: Ethics statement: Experimental procedures involving human cells from healthy donors were performed with samples obtained after written informed consent and were approved by the Institutional Review Board (IRB) of the Oswaldo Cruz Foundation/Fiocruz (Rio de Janeiro, RJ, Brazil) under the number 397-07.
IRB: The National Review Board approved the study protocol (CONEP 30650420.4.1001.0008), and informed consent was obtained from all participants or patients’ representatives.Randomization not detected. Blinding The reader was blind with respect to source of the supernatant. Power Analysis not detected. Sex as a biological variable PBMCs (2 × 106 cells) were plated onto 48-well plates (NalgeNunc) in RPMI-1640 with 5% inactivated male human AB serum (Merck) for 3 hours. Cell Line Authentication not detected. Table 2: Resources
Antibodies Sentences Resources The purity of human monocytes was above 90%, as determined by flow cytometric analysis (FACScan; Becton Dickinson) using anti-CD3 (BD Biosciences) and anti-CD14 (BD Biosciences) monoclonal antibodies. anti-CD3suggested: (BioLegend Cat# 348805, RRID:AB_2889063)anti-CD14suggested: NoneExperimental Models: Cell Lines Sentences Resources SARS-CoV-2 was expanded in Vero E6 cells from an isolate contained on a nasopharyngeal swab obtained from a confirmed case in Rio de Janeiro, Brazil Vero E6suggested: RRID:CVCL_XD71)For viral titration, monolayers of Vero cells (2 × 104 cell/well) in 96-well plates were infected with serial dilutions of supernatants containing SARS-CoV-2 for 1 hour at 37°C. Verosuggested: RRID:CVCL_ZW93)Software and Algorithms Sentences Resources Statistical analysis: Statistics were performed using GraphPad Prism software version 8. GraphPad Prismsuggested: (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: 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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