Neuroinvasion and Encephalitis Following Intranasal Inoculation of SARS-CoV-2 in K18-hACE2 Mice
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Abstract
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection can cause neurological disease in humans, but little is known about the pathogenesis of SARS-CoV-2 infection in the central nervous system (CNS). Herein, using K18-hACE2 mice, we demonstrate that SARS-CoV-2 neuroinvasion and encephalitis is associated with mortality in these mice. Intranasal infection of K18-hACE2 mice with 105 plaque-forming units of SARS-CoV-2 resulted in 100% mortality by day 6 after infection. The highest virus titers in the lungs were observed on day 3 and declined on days 5 and 6 after infection. By contrast, very high levels of infectious virus were uniformly detected in the brains of all the animals on days 5 and 6. Onset of severe disease in infected mice correlated with peak viral levels in the brain. SARS-CoV-2-infected mice exhibited encephalitis hallmarks characterized by production of cytokines and chemokines, leukocyte infiltration, hemorrhage and neuronal cell death. SARS-CoV-2 was also found to productively infect cells within the nasal turbinate, eye and olfactory bulb, suggesting SARS-CoV-2 entry into the brain by this route after intranasal infection. Our data indicate that direct infection of CNS cells together with the induced inflammatory response in the brain resulted in the severe disease observed in SARS-CoV-2-infected K18-hACE2 mice.
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SciScore for 10.1101/2020.12.14.422714: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IACUC: The protocol was approved by the GSU IACUC (Protocol number A20044). Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable Roughly equal numbers of male and female mice were used. Cell Line Authentication not detected. Table 2: Resources
Antibodies Sentences Resources Additionally, tissue sections were incubated with anti-CD45, anti-NeuN and anti-SARS-CoV-2 spike protein antibodies (Thermo Fisher Scientific, Norcross anti-CD45suggested: Noneanti-NeuNsuggested: Noneanti-SARS-CoV-2 spike proteinsuggested: NoneExperimental Models: Cell Lines Sentences Resources Virus titers in tissue homogenates were measured by plaque … SciScore for 10.1101/2020.12.14.422714: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IACUC: The protocol was approved by the GSU IACUC (Protocol number A20044). Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable Roughly equal numbers of male and female mice were used. Cell Line Authentication not detected. Table 2: Resources
Antibodies Sentences Resources Additionally, tissue sections were incubated with anti-CD45, anti-NeuN and anti-SARS-CoV-2 spike protein antibodies (Thermo Fisher Scientific, Norcross anti-CD45suggested: Noneanti-NeuNsuggested: Noneanti-SARS-CoV-2 spike proteinsuggested: NoneExperimental Models: Cell Lines Sentences Resources Virus titers in tissue homogenates were measured by plaque assay using Vero cells. Verosuggested: CLS Cat# 605372/p622_VERO, RRID:CVCL_0059)Experimental Models: Organisms/Strains Sentences Resources Mice: Hemizygous K-18 hACE2 mice were purchased from the Jackson Laboratory (Bar Harbor, ME). K-18 hACE2suggested: RRID:IMSR_GPT:T037657)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 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.
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