Temporal omics analysis in Syrian hamsters unravel cellular effector responses to moderate COVID-19

  1. Geraldine Nouailles
  2. Emanuel Wyler
  3. Peter Pennitz
  4. Dylan Postmus
  5. Daria Vladimirova
  6. Julia Kazmierski
  7. Fabian Pott
  8. Kristina Dietert
  9. Michael Muelleder
  10. Vadim Farztdinov
  11. Benedikt Obermayer
  12. Sandra-Maria Wienhold
  13. Sandro Andreotti
  14. Thomas Hoefler
  15. Birgit Sawitzki
  16. Christian Drosten
  17. Leif E. Sander
  18. Norbert Suttorp
  19. Markus Ralser
  20. Dieter Beule
  21. Achim D. Gruber
  22. Christine Goffinet
  23. Markus Landthaler
  24. Jakob Trimpert
  25. Martin Witzenrath

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Abstract

In COVID-19, immune responses are key in determining disease severity. However, cellular mechanisms at the onset of inflammatory lung injury in SARS-CoV-2 infection, particularly involving endothelial cells, remain ill-defined. Using Syrian hamsters as a model for moderate COVID-19, we conduct a detailed longitudinal analysis of systemic and pulmonary cellular responses, and corroborate it with datasets from COVID-19 patients. Monocyte-derived macrophages in lungs exert the earliest and strongest transcriptional response to infection, including induction of pro-inflammatory genes, while epithelial cells show weak alterations. Without evidence for productive infection, endothelial cells react, depending on cell subtypes, by strong and early expression of anti-viral, pro-inflammatory, and T cell recruiting genes. Recruitment of cytotoxic T cells as well as emergence of IgM antibodies precede viral clearance at day 5 post infection. Investigating SARS-CoV-2 infected Syrian hamsters thus identifies cell type-specific effector functions, providing detailed insights into pathomechanisms of COVID-19 and informing therapeutic strategies.

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  1. Version published to 10.1038/s41467-021-25030-7
  2. Version published to 10.21203/rs.3.rs-148392/v1 on Research Square
  3. ScreenIT

    SciScore for 10.1101/2020.12.18.423524: (What is this?)

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

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    Virus stocks were propagated under BSL-3 conditions in Vero E6 cells (ATCC CRL-1586) in minimal essential medium (MEM; PAN Biotech, Aidenbach, Germany) supplemented with 10 % fetal bovine serum (PAN Biotech), 100 IU/mL penicillin G and 100 g/mL streptomycin (Carl Roth, Karlsruhe, Germany).
    Vero E6
    suggested: None
    Software and Algorithms
    SentencesResources
    Adjusted P values were calculated by DEseq2 using Benjamini-Hochberg corrections of Wald test P values.
    DEseq2
    suggested: (DESeq2, RRID:SCR_015687)
    Statistical Analyses of clinical data Graph-Pad Prism v8 (GraphPad Software Inc.
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)
    The Ensemble annotation was extended by mapping ENSEMBL gene ids without annotated gene names to entrez identifiers and to the homolog associated gene names using biomaRt (Durinck et al., 2009).
    ENSEMBL
    suggested: (Ensembl, RRID:SCR_002344)
    Analysis of bulk RNA-sequencing data Reads were aligned to the genome using hisat2 (Kim et al., 2019) and quantified using quasR (Gaidatzis et al., 2015).
    hisat2
    suggested: (HISAT2, RRID:SCR_015530)
    quasR
    suggested: (QUASR, RRID:SCR_006820)
    Integration with mouse data was performed using matching gene names between mouse and hamster, while gene names in the human data were converted to mouse using biomaRt.
    biomaRt
    suggested: (biomaRt, RRID:SCR_019214)

    Results from OddPub: Thank you for sharing your code and data.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Our study has several limitations, including limited disease spectrum by restriction to moderate disease, lack of detailed B cell response analysis beyond 14 dpi, and need for improvement of gene annotation in the current version hamster genomes. Furthermore, it does not recapitulate the various covariates and preexisting conditions that can affect disease outcome. Clearly, we are only at the beginning of matching the course of disease in hamsters and humans in greater detail. Nevertheless, we already provide clear evidence that Syrian hamsters recapitulate the course of moderate human SARS-CoV-2 infection. Hamsters displayed nearly prototypic antiviral immune responses starting with rapid, yet self-restricted neutrophilic response, along with a fast and strong monocytic innate immune response following activation after virus uptake, augmenting local anti-viral responses and pro- inflammatory CC chemokine production recruiting a potent type 1 T cell response that probably contributed to elimination of pulmonary residing virus via cytotoxic effector mechanisms. Neutralizing antibodies of IgM type aided in preventing viral spread and fostered cellular virus uptake. Viral infection and inflammatory response in and by lung epithelium is not predominant. Upon successful elimination of virus, alveolar epithelial repair mechanisms started, along with endothelial suppression of fibrotic programs, thus enabling pulmonary regeneration in convalesced hamsters. Hence, Syrian hamsters rep...

    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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  4. Version published to 10.1101/2020.12.18.423524v1 on bioRxiv