The pigtail macaque (Macaca nemestrina) model of COVID-19 reproduces diverse clinical outcomes and reveals new and complex signatures of disease
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Abstract
The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 disease, has killed over five million people worldwide as of December 2021 with infections rising again due to the emergence of highly transmissible variants. Animal models that faithfully recapitulate human disease are critical for assessing SARS-CoV-2 viral and immune dynamics, for understanding mechanisms of disease, and for testing vaccines and therapeutics. Pigtail macaques (PTM, Macaca nemestrina ) demonstrate a rapid and severe disease course when infected with simian immunodeficiency virus (SIV), including the development of severe cardiovascular symptoms that are pertinent to COVID-19 manifestations in humans. We thus proposed this species may likewise exhibit severe COVID-19 disease upon infection with SARS-CoV-2. Here, we extensively studied a cohort of SARS-CoV-2-infected PTM euthanized either 6- or 21-days after respiratory viral challenge. We show that PTM demonstrate largely mild-to-moderate COVID-19 disease. Pulmonary infiltrates were dominated by T cells, including CD4+ T cells that upregulate CD8 and express cytotoxic molecules, as well as virus-targeting T cells that were predominantly CD4+. We also noted increases in inflammatory and coagulation markers in blood, pulmonary pathologic lesions, and the development of neutralizing antibodies. Together, our data demonstrate that SARS-CoV-2 infection of PTM recapitulates important features of COVID-19 and reveals new immune and viral dynamics and thus may serve as a useful animal model for studying pathogenesis and testing vaccines and therapeutics.
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SciScore for 10.1101/2021.08.28.458047: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IACUC: Animal experiments were approved by the Institutional Animal Care and Use Committee of Tulane University (protocol P0451).
Euthanasia Agents: Specifically, the animals were anesthetized with tiletamine/zolazepam (8 mg/kg IM) and given buprenorphine (0.01 mg/kg IM) followed by an overdose of pentobarbital sodium.Sex as a biological variable , viral inoculations, and procedures: Four male pigtail macaques (PTM), between the ages of 5 and 6 years old (Table S1), were exposed to 1×106 TCID50 of SARS-CoV-2 USA WA1/2020 ( Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
Antibodies Sentences Resources Mouse anti-Granzyme primary antibody (Table S6) was … SciScore for 10.1101/2021.08.28.458047: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IACUC: Animal experiments were approved by the Institutional Animal Care and Use Committee of Tulane University (protocol P0451).
Euthanasia Agents: Specifically, the animals were anesthetized with tiletamine/zolazepam (8 mg/kg IM) and given buprenorphine (0.01 mg/kg IM) followed by an overdose of pentobarbital sodium.Sex as a biological variable , viral inoculations, and procedures: Four male pigtail macaques (PTM), between the ages of 5 and 6 years old (Table S1), were exposed to 1×106 TCID50 of SARS-CoV-2 USA WA1/2020 ( Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
Antibodies Sentences Resources Mouse anti-Granzyme primary antibody (Table S6) was then added to the slides and allowed to bind for 60 minutes. anti-Granzymesuggested: NoneSoftware and Algorithms Sentences Resources Veterinarians in the TNPRC Division of Veterinary Medicine have established procedures to minimize pain and distress using several approaches. TNPRCsuggested: NonePlates were analyzed using the GloMax Explorer plate reader (Promega, Madison, WI) and GraphPad Prism (GraphPad Software version 9, LaJolla, California). GraphPadsuggested: (GraphPad Prism, RRID:SCR_002798)The GloMax Explorer plate reader (Promega, Madison, WI) along with GraphPad Prism v9 were used to analyze the plates. GraphPad Prismsuggested: (GraphPad Prism, RRID:SCR_002798)Quantification of Inflammatory Cytokines and Coagulation Biomarkers: BioLegend’s bead-based immunosorbent assays were used to measure inflammatory cytokines in serum (LegendPlex NHP Inflammation Panel, BioLegend Coagulation Biomarkerssuggested: (Monoclonal Antibody Index, RRID:SCR_013227)All samples were acquired on a LSRFortessa Cell Analyzer (BD Biosciences, Franklin Lakes, NJ) using BD FACSDIVA 8.0.1 software. BD FACSDIVAsuggested: (BD FACSDiva Software, RRID:SCR_001456)SARS-CoV-2 antigen specific T cell response figures (9A&B) were generated using the Matlab based tool cyt323. Matlabsuggested: (MATLAB, RRID:SCR_001622)Cytokine expression was measured in FlowJo and, when applicable, applied to cyt3 generated figures. t-distributed stochastic neighbor embedding (tSNE) analysis was performed in FlowJo 10.7.1, FlowJosuggested: (FlowJo, RRID:SCR_008520)nightingale rose plots were generated in R using the ggplot2 package, radial plots were generated in Microsoft Excel. ggplot2suggested: (ggplot2, RRID:SCR_014601)Microsoft Excelsuggested: (Microsoft Excel, RRID:SCR_016137)Statistical Analysis: GraphPad Prism (version 9 GraphPad Software, LaJolla California) was used for all graphing and statistical analyses. Statistical Analysis: GraphPad Prismsuggested: NoneResults 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: Please consider improving the rainbow (“jet”) colormap(s) used on page 58. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.
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.
Results from scite Reference Check: We found no unreliable references.
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