Western diet increases COVID-19 disease severity in the Syrian hamster

  1. Julia R. Port
  2. Danielle R. Adney
  3. Benjamin Schwarz
  4. Jonathan E. Schulz
  5. Daniel E. Sturdevant
  6. Brian J. Smith
  7. Victoria A. Avanzato
  8. Myndi G. Holbrook
  9. Jyothi N. Purushotham
  10. Kaitlin A. Stromberg
  11. Ian Leighton
  12. Catharine M. Bosio
  13. Carl Shaia
  14. Vincent J. Munster

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Abstract

Pre-existing comorbidities such as obesity or metabolic diseases can adversely affect the clinical outcome of COVID-19. Chronic metabolic disorders are globally on the rise and often a consequence of an unhealthy diet, referred to as a Western Diet. For the first time in the Syrian hamster model, we demonstrate the detrimental impact of a continuous high-fat high-sugar diet on COVID-19 outcome. We observed increased weight loss and lung pathology, such as exudate, vasculitis, hemorrhage, fibrin, and edema, delayed viral clearance and functional lung recovery, and prolonged viral shedding. This was accompanied by an increased trend of systemic IL-10 and IL-6, as well as a dysregulated serum lipid response dominated by polyunsaturated fatty acid-containing phosphatidylethanolamine, recapitulating cytokine and lipid responses associated with severe human COVID-19. Our data support the hamster model for testing restrictive or targeted diets and immunomodulatory therapies to mediate the adverse effects of metabolic disease on COVID-19.

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  1. ScreenIT

    SciScore for 10.1101/2021.06.17.448814: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsIACUC: Ethics statement: Approval of animal experiments was obtained from the Institutional Animal Care and Use Committee of the Rocky Mountain Laboratories.
    Euthanasia Agents: Inoculation experiments: After 16 weeks, animals were then inoculated intranasally (I.N.) under isoflurane anaesthesia. I.N. inoculation was performed with 40 µL sterile Dulbecco’s Modified Eagle Medium (DMEM) containing 8×104 TCID50 SARS-CoV-2.
    Sex as a biological variableHigh-fat high-sugar diet: Four to six-week-old male Syrian Golden hamsters (ENVIGO) were randomly assigned to either regular rodent chow (Teklad Global 16%
    RandomizationHigh-fat high-sugar diet: Four to six-week-old male Syrian Golden hamsters (ENVIGO) were randomly assigned to either regular rodent chow (Teklad Global 16%
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    (Novus Biologicals #NBP2-38790) were detected using the Vector Laboratories ImPress VR anti-rabbit IgG polymer (# MP-6401) as the secondary antibody.
    anti-rabbit IgG
    suggested: None
    Spike-specific antibodies were detected with goat anti-hamster IgG Fc (horseradish peroxidase (HRP)-conjugated, Abcam) for 1 h at RT and visualized with KPL TMB 2-component peroxidase substrate kit (SeraCare, 5120-0047).
    anti-hamster IgG
    suggested: None
    Cytokine analysis: Cytokine concentrations were determined using a commercial hamster ELISA kit for TNF-α, INF-γ, IL-6, IL-4, and IL-10 available at antibodies.com, according to the manufacturer’s instructions (antibodies.com; A74292, A74590, A74291, A74027, A75096).
    TNF-α
    suggested: (Bio-Rad Cat# M6000007NY, RRID:AB_2784537)
    INF-γ
    suggested: None
    IL-6
    suggested: None
    IL-4
    suggested: None
    A74590
    suggested: None
    A74291
    suggested: None
    A75096
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    Virus propagation was performed in VeroE6 cells in DMEM supplemented with 2% foetal bovine serum (FBS), 2 mM L-glutamine, 100 U/mL penicillin and 100 μg/mL streptomycin.
    VeroE6
    suggested: JCRB Cat# JCRB1819, RRID:CVCL_YQ49)
    Software and Algorithms
    SentencesResources
    One hundred nanograms of RNA was used as input for rRNA depletion and NGS library preparation following the Illumina Stranded Total RNA Prep Ligation with Ribo-Zero Plus workflow (Illumina).
    NGS
    suggested: (PM4NGS, RRID:SCR_019164)
    Remaining reads were aligned to the Mesocricetus auratus genome assembly version 1.0 using Hisat2 (Kim et al., 2015).
    Hisat2
    suggested: (HISAT2, RRID:SCR_015530)
    Differential expression analysis was performed using the Bioconductor package DESeq2 (Love et al., 2014).
    Bioconductor
    suggested: (Bioconductor, RRID:SCR_006442)
    DESeq2
    suggested: (DESeq, RRID:SCR_000154)
    Pathway analysis was performed using Ingenuity Pathway Analysis (QIAGEN) and gene clustering was performed using Partek Genomics Suite (
    Ingenuity Pathway Analysis
    suggested: (Ingenuity Pathway Analysis, RRID:SCR_008653)
    Remaining reads were mapped to the SARS-CoV-2 2019-nCoV/USA-WA1/2020 genome (MN985325.1) using Bowtie2 version 2.2.928 with parameters --local --no-mixed -X 1500.
    Bowtie2
    suggested: (Bowtie 2, RRID:SCR_016368)
    PCR duplicates were removed using picard MarkDuplicates (Broad Institute) and variants were called using GATK HaplotypeCaller version 4.1.2.029 with parameter -ploidy 2.
    GATK
    suggested: (GATK, RRID:SCR_001876)
    Morphometric analysis: IHC stained tissue slides were scanned with an Aperio ScanScope XT (Aperio Technologies, Inc.) and analyzed using the ImageScope Positive Pixel Count algorithm (version 9.1).
    ImageScope
    suggested: (ImageScope, RRID:SCR_014311)
    All univariate and multivariate analysis was performed using GraphPad Prism or MarkerView (AB Sciex).
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    Statistical analysis: All graphs were designed in GraphPad Prism software (version 8.0.1; GraphPad Software).
    GraphPad
    suggested: (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:
    Taking the limitations of the model into account, our data further suggests the possible suitability of the Syrian hamster model to assess immunomodulatory therapies. While dietary advice for those suffering from metabolic diseases is proposed to reduce burden of severe COVID-19 (Demasi, 2021), it remains doubtful if any change in diet can impact disease outcome favorably after infection has occurred. Targeted immunomodulatory therapies, such as anti-IL-6 therapies, may be more efficient (Zhong et al., 2020). The Syrian hamster model may also be applied to further studies of selected aspects of NAFLD, which the model recapitulates. This model seems to present with an absences or limited amount of liver fibrosis; further work is needed to demonstrate how faithfully it assesses the direct effect of liver fibrosis on acute disease. However, it may be useful to assess long term post-COVID-19 NAFLD, to document further deterioration of liver damage (Portincasa et al., 2020) and the relation to infection sequelae.

    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.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2021.06.17.448814v1 on bioRxiv