Neuroinvasion of SARS-CoV-2 in human and mouse brain
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Abstract
Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus on the consequences of CNS infections. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in infected and neighboring neurons. However, no evidence for type I interferon responses was detected. We demonstrate that neuronal infection can be prevented by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate SARS-CoV-2 neuroinvasion in vivo. Finally, in autopsies from patients who died of COVID-19, we detect SARS-CoV-2 in cortical neurons and note pathological features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV-2 and an unexpected consequence of direct infection of neurons by SARS-CoV-2.
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SciScore for 10.1101/2020.06.25.169946: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
No key resources detected.
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:However, a limitation of our study is that autopsy samples from only a small number of patients were examined. Future studies are needed to examine whether there are other cases of neuroinvasion in the CNS, and the predisposition …
SciScore for 10.1101/2020.06.25.169946: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
No key resources detected.
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:However, a limitation of our study is that autopsy samples from only a small number of patients were examined. Future studies are needed to examine whether there are other cases of neuroinvasion in the CNS, and the predisposition for such infection. Although we are unable to determine the exact relationship between neuroinvasion and ischemic infarcts, we pose a possible hypothesis from our findings in the patients, mice, and infections of human brain organoids; that SARS-CoV-2 neuroinvasion may cause locally hypoxic regions and disturbance of vasculature, and the disruption of brain vasculature can make vulnerable ischemic infarcts and regions more susceptible to viral invasion (Figure S10). Our findings expand the utility of human brain organoids, beyond modeling fetal brains, and highlight the importance of using a variety of approaches to best model physiology of the human brain. In future studies, identifying the route of SARS-CoV-2 invasion into the brain in addition to determining the sequence of infection in different cell types in the central nervous system will help validate the temporal relationship between SARS-CoV-2 and ischemic infarcts in patients. It may be through the nasal cavity to CNS connection through the cribriform plate, olfactory epithelium and nerve, or viremia, but regardless, the brain should be considered a high-risk organ system upon respiratory exposure (Baig and Sanders, 2020; Coolen et al., 2020). Altogether, our study provides clear demonstrat...
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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SciScore for 10.1101/2020.06.25.169946: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Cell Line Authentication S2C), we also observed infection of SOX2-positive neural stem cells with bipolar morphology and cells localized around the neural tube-like structures (Fig. 1B.1). Table 2: Resources
Antibodies Sentences Resources To test the requirement of ACE2 for SARS-CoV-2 infection , we incubated organoids with an anti-ACE2 blocking monoclonal antibody prior to infection with SARS-CoV-2 . anti-ACE2suggested: NoneFurther, we detected robust antiviral antibody … SciScore for 10.1101/2020.06.25.169946: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Cell Line Authentication S2C), we also observed infection of SOX2-positive neural stem cells with bipolar morphology and cells localized around the neural tube-like structures (Fig. 1B.1). Table 2: Resources
Antibodies Sentences Resources To test the requirement of ACE2 for SARS-CoV-2 infection , we incubated organoids with an anti-ACE2 blocking monoclonal antibody prior to infection with SARS-CoV-2 . anti-ACE2suggested: NoneFurther, we detected robust antiviral antibody presence in the CSF of a COVID-19 patient, who presented with acute neurologic symptoms. antiviralsuggested: (Antibodies-Online Cat# ABIN753133, AB_11206991)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 OddPub: We did not find a statement about open data. We also did not find a statement about open code. Researchers are encouraged to share open data when possible (see Nature blog).
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 is not a substitute for expert review. SciScore checks for the presence and correctness of RRIDs (research resource identifiers) in the manuscript, and detects sentences that appear to be missing RRIDs. SciScore also checks to make sure that rigor criteria are addressed by authors. It does this by detecting sentences that discuss criteria such as blinding or power analysis. SciScore does not guarantee that the rigor criteria that it detects are appropriate for the particular study. Instead it assists authors, editors, and reviewers by drawing attention to sections of the manuscript that contain or should contain various rigor criteria and key resources. For details on the results shown here, including references cited, please follow this link.
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