Type I Interferon Limits Viral Dissemination-Driven Clinical Heterogeneity in a Native Murine Betacoronavirus Model of COVID-19

  1. Hua Qing
  2. Lokesh Sharma
  3. Brandon K. Hilliard
  4. Xiaohua Peng
  5. Anush Swaminathan
  6. Justin Tian
  7. Kavita Israni-Winger
  8. Cuiling Zhang
  9. Delva Leão
  10. Seungjin Ryu
  11. Victoria Habet
  12. Lin Wang
  13. Xuefei Tian
  14. Yina Ma
  15. Shuta Ishibe
  16. Lawrence H. Young
  17. Sergei Kotenko
  18. Susan Compton
  19. Carmen J. Booth
  20. Aaron M. Ring
  21. Vishwa Deep Dixit
  22. Craig B. Wilen
  23. João P. Pereira
  24. Charles S. Dela Cruz
  25. Andrew Wang

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Abstract

Emerging clinical data demonstrates that COVID-19, the disease caused by SARS-CoV2, is a syndrome that variably affects nearly every organ system. Indeed, the clinical heterogeneity of COVID-19 ranges from relatively asymptomatic to severe disease with death resultant from multiple constellations of organ failures. In addition to genetics and host characteristics, it is likely that viral dissemination is a key determinant of disease manifestation. Given the complexity of disease expression, one major limitation in current animal models is the ability to capture this clinical heterogeneity due to technical limitations related to murinizing SARS-CoV2 or humanizing mice to render susceptible to infection. Here we describe a murine model of COVID-19 using respiratory infection with the native mouse betacoronavirus MHV-A59. We find that whereas high viral inoculums uniformly led to hypoxemic respiratory failure and death, lethal dose 50% (LD 50 ) inoculums led to a recapitulation of most hallmark clinical features of COVID-19, including lymphocytopenias, heart and liver damage, and autonomic dysfunction. We find that extrapulmonary manifestations are due to viral metastasis and identify a critical role for type-I but not type-III interferons in preventing systemic viral dissemination. Early, but not late treatment with intrapulmonary type-I interferon, as well as convalescent serum, provided significant protection from lethality by limiting viral dissemination. We thus establish a Biosafety Level II model that may be a useful addition to the current pre-clinical animal models of COVID-19 for understanding disease pathogenesis and facilitating therapeutic development for human translation.

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  1. ScreenIT

    SciScore for 10.1101/2020.09.11.294231: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    BlindingHematoxylin and Eosin (H&E), or Martius, Scarlet and Blue (MSB) staining was applied, then slides were assessed by a blinded pathologist.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Capture antibodies were anti-IL-6 (14-7061-85,
    anti-IL-6
    suggested: (Thermo Fisher Scientific Cat# 14-7061-85, RRID:AB_468423)
    Detection antibodies conjugated with biotin were anti-mouse-IL-6 (554402, BD Pharmingen)
    anti-mouse-IL-6
    suggested: None
    Plates were afterwards incubated with HRP-conjugated secondary goat anti-mouse IgGs, IgM, or IgA antibodies (abcam) with 10,000 dilution in PBS with 1% BSA.
    anti-mouse IgGs, IgM
    suggested: None
    IgA
    suggested: None
    Software and Algorithms
    SentencesResources
    Following the incubation with HRP-conjugated streptavidin (554066, BD Biosciences) and TMB substrate reagent (555214, BD Biosciences), color of the plates were closely monitored every minute and plates were read at 450nm instantly after the addition of stop solution (1N HCL).
    BD Biosciences
    suggested: (BD Biosciences, RRID:SCR_013311)
    Single-cell RNA sequencing: Sequence data was obtained from Gene Expression Omnibus, accession code GSE74672 (Romanov et al., 2017).
    Gene Expression Omnibus
    suggested: (Gene Expression Omnibus (GEO, RRID:SCR_005012)

    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:
    The major limitations of MHV-A59 is that it 1) does not capture all SARS-CoV-2-intrinsic pathogenic factors and that 2) the entry receptor of MHV-A59 CEACAM1 is not co-localized exactly with that of ACE2-expressing cells. However, we argue that, teleologically, our approach may not be that disparate from the ongoing efforts attempting to humanize mice and murinize SARS-CoV-2 to recapitulate human disease. Indeed, the only models that currently recapitulate severe disease using SARS-CoV-2 require the forced expression (using K18 or Hfh4 promoters) of human ACE2 in tissues which do not endogenously express ACE2 (Jiang et al., 2020; McCray et al., 2007). Likewise, based on the published data and previous experience with MERS-CoV, it is highly likely that murinization of SARS-CoV-2 will be required in order to produce COVID-19-like disease in mice where endogenous ACE2 expression is maintained. Therefore, while our model may lack certain features important for SARS-CoV-2-specific host-pathogen interactions, it is unlikely that any host other than a human will capture SARS-CoV-2-specific host-pathogen interactions. On the other hand, the MHV-A59 mouse model, which is the species-appropriate pathogen in its corresponding host, recapitulates a surprising number of characteristics of COVID-19. Perhaps the most astonishing feature COVID-19 is the wide breadth of clinical manifestations. A confounding factor in these clinical epidemiologic studies is that the time and dose of viral ino...

    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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  2. Version published to 10.1101/2020.09.11.294231v1 on bioRxiv