A global lipid map reveals host dependency factors conserved across SARS-CoV-2 variants

  1. Scotland E. Farley
  2. Jennifer E. Kyle
  3. Hans C. Leier
  4. Lisa M. Bramer
  5. Jules B. Weinstein
  6. Timothy A. Bates
  7. Joon-Yong Lee
  8. Thomas O. Metz
  9. Carsten Schultz
  10. Fikadu G. Tafesse

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Abstract

A comprehensive understanding of host dependency factors for SARS-CoV-2 remains elusive. Here, we map alterations in host lipids following SARS-CoV-2 infection using nontargeted lipidomics. We find that SARS-CoV-2 rewires host lipid metabolism, significantly altering hundreds of lipid species to effectively establish infection. We correlate these changes with viral protein activity by transfecting human cells with each viral protein and performing lipidomics. We find that lipid droplet plasticity is a key feature of infection and that viral propagation can be blocked by small-molecule glycerolipid biosynthesis inhibitors. We find that this inhibition was effective against the main variants of concern (alpha, beta, gamma, and delta), indicating that glycerolipid biosynthesis is a conserved host dependency factor that supports this evolving virus.

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  1. Version published to 10.1038/s41467-022-31097-7
  2. Rapid Reviews Infectious Diseases

    Dao Wen Wang

    Review 3: "A global lipid map reveals host dependency factors conserved across SARS-CoV-2 variants"

    This preprint examines lipid droplet plasticity as a feature of infection that can be stopped by glycolipid biosynthesis inhibitors and finds that they are a host dependency factor supporting COVID-19. Reviewers found this study reliable and informative for virus evolution.

  3. Rapid Reviews Infectious Diseases

    Aman Rajpal

    Review 2: "A global lipid map reveals host dependency factors conserved across SARS-CoV-2 variants"

    This preprint examines lipid droplet plasticity as a feature of infection that can be stopped by glycolipid biosynthesis inhibitors and finds that they are a host dependency factor supporting COVID-19. Reviewers found this study reliable and informative for virus evolution.

  4. Rapid Reviews Infectious Diseases

    Susmita Kaushik

    Review 1: "A global lipid map reveals host dependency factors conserved across SARS-CoV-2 variants"

    This preprint examines lipid droplet plasticity as a feature of infection that can be stopped by glycolipid biosynthesis inhibitors and finds that they are a host dependency factor supporting COVID-19. Reviewers found this study reliable and informative for virus evolution.

  6. ScreenIT

    SciScore for 10.1101/2022.02.14.480430: (What is this?)

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

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Anti-dsRNA antibody was obtained from Millipore (identifier MABE1134); anti-mouse IgG AlexaFluor 647 was obtained from Invitrogen (Identifier A32628); anti-llama secondary HRP, goat IgG was obtained from Novus (identifier NB7242).
    anti-mouse IgG
    suggested: None
    anti-llama secondary HRP, goat IgG
    suggested: (Thermo Fisher Scientific Cat# A16060, RRID:AB_2534733)
    Cells were stained overnight with an anti-dsRNA antibody diluted 1:50 in blocking buffer.
    anti-dsRNA
    suggested: None
    Cells were washed three times with PBS and then stained with an A647 secondary antibody for 1 hr.
    A647
    suggested: None
    Plates were permeabilized in perm buffer (0.1% saponin, 0.1% BSA in PBS) for 30 minutes, then incubated with 50 μL primary antibody (alpaca anti-SARS-CoV-2 serum, diluted 1:5,000 in perm buffer) for either 2hr room temperature or overnight at 4 °C.
    anti-SARS-CoV-2
    suggested: None
    Plates were incubated with 50 μL secondary antibody (anti-llama HRP, goat IgG) for either 2hr room temperature or overnight at 4 °C.
    anti-llama HRP, goat IgG
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    Materials: Cell lines: Cell lines (HEK293T, HEK293T-ACE2, Vero-E6, and Caco2) were obtained from ATCC.
    HEK293T
    suggested: None
    Viral strains: SARS-CoV-2 viral strains (isolate USA-WA1/2020: Identifier #NR-52281; isolate USA/CA_CDC_5574/2020: Identifier #NR-54011; isolate hCoV-19/South Africa/KRISP-K005325/2020: Identifier #NR-54009; hCoV-19/Japan/TY7-503/2021: Identifier #NR54982; isolate hCoV-19/USA/PHC658/2021: Identifier # NR-55611) were obtained from BEI resources and propagated in Vero E6 cells.
    Vero E6
    suggested: RRID:CVCL_XD71)
    Media for Vero-E6 cells, 293T (wt) and 293T-ACE2 cells was supplemented with 10% FBS while media for Caco2 cells was supplemented with 20% FBS.
    Vero-E6
    suggested: None
    293T-ACE2
    suggested: None
    Wild-type 293T cells were seeded in 6cm dishes and transfected with varying amounts viral plasmids (based on optimal expression for each plasmid, see Table S1), as well as a PLVX empty vector control, using Lipofectamine 3000 (ThermoFisher Scientific) as per manufacturer’s instructions.
    293T
    suggested: None
    Lipid droplet immunofluorescence — Infection: 293T-ACE2 or Caco2 cells were seeded at 70% cell density in 24-well plates and allowed to grow overnight.
    Caco2
    suggested: None

    Results from OddPub: Thank you for sharing your data.

    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 found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).

    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.

  7. Version published to 10.1101/2022.02.14.480430v1 on bioRxiv