STAT2 signaling as double-edged sword restricting viral dissemination but driving severe pneumonia in SARS-CoV-2 infected hamsters
This article has been Reviewed by the following groups
Listed in
- Evaluated articles (ScreenIT)
Abstract
Since the emergence of SARS-CoV-2 causing COVID-19, the world is being shaken to its core with numerous hospitalizations and hundreds of thousands of deaths. In search for key targets of effective therapeutics, robust animal models mimicking COVID-19 in humans are urgently needed. Here, we show that productive SARS-CoV-2 infection in the lungs of mice is limited and restricted by early type I interferon responses. In contrast, we show that Syrian hamsters are highly permissive to SARS- CoV-2 and develop bronchopneumonia and a strong inflammatory response in the lungs with neutrophil infiltration and edema. Moreover, we identify an exuberant innate immune response as a key player in pathogenesis, in which STAT2 signaling plays a dual role, driving severe lung injury on the one hand, yet restricting systemic virus dissemination on the other. Finally, we assess SARS-CoV- 2-induced lung pathology in hamsters by micro-CT alike used in clinical practice. Our results reveal the importance of STAT2-dependent interferon responses in the pathogenesis and virus control during SARS-CoV-2 infection and may help rationalizing new strategies for the treatment of COVID-19 patients.
Article activity feed
-
-
SciScore for 10.1101/2020.04.23.056838: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IACUC: Housing conditions and experimental procedures were approved by the ethical committee of KU Leuven (license P015-2020), following institutional guidelines approved by the Federation of European Laboratory Animal Science Associations (FELASA).
Consent: Human convalescent serum (HCS) was donated under informed consent (Patient #1).Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable Six- to eight-weeks-old female mice and wild-type hamsters were used throughout the Cell Line Authentication Contamination: Prior to inoculation of animals, virus stocks were confirmed to be free of mycoplasma (PlasmoTest, InvivoGen) … SciScore for 10.1101/2020.04.23.056838: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IACUC: Housing conditions and experimental procedures were approved by the ethical committee of KU Leuven (license P015-2020), following institutional guidelines approved by the Federation of European Laboratory Animal Science Associations (FELASA).
Consent: Human convalescent serum (HCS) was donated under informed consent (Patient #1).Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable Six- to eight-weeks-old female mice and wild-type hamsters were used throughout the Cell Line Authentication Contamination: Prior to inoculation of animals, virus stocks were confirmed to be free of mycoplasma (PlasmoTest, InvivoGen) and other adventitious agents by deep sequencing on a MiSeq platform (Illumina) following an established metagenomics pipeline64,65. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources For maintenance of Calu-3 cells (human airway epithelium, kind gift from Lieve Naesens, KU Leuven, BE), the above medium was supplemented with 10mM HEPES (Gibco). Calu-3suggested: NoneInfectious virus was isolated by serial passaging on HuH7 and Vero E6 cells (see Fig. Vero E6suggested: RRID:CVCL_XD71)Experimental Models: Organisms/Strains Sentences Resources All other mouse (C57BL/6, Ifnar1-/-, Il28r-/-, BALB/c and SCID) and hamster (STAT2-/- and IL28R-a-/-) strains were bred in-house. C57BL/6suggested: NoneIl28r-/-suggested: NoneBALB/csuggested: NoneIfnar1-/- mouse breeding couples were a generous gift of Dr. Claude Libert, IRC/VIB, University of Ghent, Belgium. Il28r-/- mice [C57B/6N-A Ifnlr1/Wtsi, strain ID: EM:07988] were provided by the Wellcome Trust Sanger Institute Mouse Genetics Project (Sanger MGP)61. Ifnar1-/-suggested: NoneC57B/6N-A Ifnlr1/Wtsisuggested: NoneSTAT2-/- and IL28R-a-/- hamsters were generated by CRISPR/Cas-mediated gene targeting. STAT2-/-suggested: NoneSoftware and Algorithms Sentences Resources SARS-CoV-2 strain BetaCov/Belgium/GHB-03021/2020 (EPI ISL 407976|2020-02-03) recovered from a nasopharyngeal swab taken from a RT-qPCR-confirmed asymptomatic patient returning from Wuhan, China beginning of February 202062 was directly sequenced on a MinION platform (Oxford Nanopore) as described previously63. MinIONsuggested: (MinION, RRID:SCR_017985)Pathway, GO (Gene Ontology) and transcription factor target enrichment analysis was performed using GSEA ( GSEAsuggested: (SeqGSEA, RRID:SCR_005724)Principal component analysis, correlation matrices, unsupervised hierarchical clustering (Eucledian distance) were performed using XLSTAT and visualized using MORPHEUS (https://software.broadinstitute.org/morpheus) as described previously20. XLSTATsuggested: (XLSTAT, RRID:SCR_016299)MORPHEUSsuggested: (Morpheus, RRID:SCR_014975)Statistical analysis: GraphPad Prism Version 8 ( GraphPadsuggested: (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: 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: 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.
-