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Review 1: "SARS-CoV-2 Infects Neurons, Astrocytes, Choroid Plexus Epithelial Cells and Pericytes of the Human Central Nervous System"

The reviewer found the study potentially informative, addressing the important question of neural cell tropism for various SARS-CoV-2 strains. However, they noted that the manuscript lacks critical information and the claims are not fully supported by the presented results.

Published onJul 01, 2024
Review 1: "SARS-CoV-2 Infects Neurons, Astrocytes, Choroid Plexus Epithelial Cells and Pericytes of the Human Central Nervous System"
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SARS-CoV-2 infects neurons, astrocytes, choroid plexus epithelial cells and pericytes of the human central nervous system
SARS-CoV-2 infects neurons, astrocytes, choroid plexus epithelial cells and pericytes of the human central nervous system
Description

Abstract SARS-CoV-2, the coronavirus responsible for the COVID-19 pandemic, is associated with a range of neurological manifestations including haemorrhage, thrombosis and ischaemic necrosis and encephalitits. However, the mechanism by which this occurs is unclear. Neurological disease associated with SARS-CoV-2 infection has been proposed to occur following direct infection of the central nervous system and/or indirect sequelae as a result of peripheral inflammation. We profiled ACE2 and TMPRSS2 in brain tissue from five healthy human donors, and observed expression of these proteins in astrocytes, neurons and choroid plexus epithelium within frontal cortex and medulla. Primary human astrocytes, neurons and choroid plexus epithelial cells supported productive SARS-CoV-2 infection in an ACE2- dependent manner. Infected cells supported the full viral lifecycle, releasing infectious virus particles. In contrast, primary brain microvascular endothelial cells, pericytes and microglia were refractory to SARS-CoV-2 infection. These data support a model whereby SARS-CoV-2 is neurotropic, and this may in part explain the neurological sequelae of infection.Importance A subset of patients with COVID-19 develop neurological symptoms, but the underlying cause is poorly understood. We observed that cells within normal human brain express the SARS-CoV-2 entry factors ACE-2 and TMPRRS2, with expression mainly observed within astrocytes, neurons and choroid plexus epithelium. Primary human astrocytes, neurons and choroid plexus epithelial cells cultured in vitro supported the full SARS-CoV-2 life cycle with a range of SARS-CoV-2 variants. This study demonstrates that cells of the human central nervous system express SARS-CoV-2 entry factors in vivo and support viral infection in vitro, thus supporting a model where neurological symptoms seen in some COVID-19 patients may be as a result of direct viral infection of the central nervous system. Furthermore, these data highlight the importance of investigating the ability of therapeutics to clear virus from this potential reservoir of infection.

RR:C19 Evidence Scale rating by reviewer:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.

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Review: This paper titled- SARS-CoV-2 infects neurons, astrocytes, choroid plexus epithelial cells and pericytes of the human central nervous system aims to answer a timely question of neural cell tropism for various strains of SARS-CoV2. Although the authors ask an important question, that can be leveraged to better therapeutics for neurotropic SARS-CoV2 infection, the manuscript lacks major information. This manuscript has a potential to be published in journals, but needs some major and minor revisions that may help authors do better justification for their data. Overall, the claims made by the authors, are not fully supported by the results mentioned in the manuscript.

  1. Major: In the result section 3.1; the authors claim that "ACE-2 expression was predominantly observed in astrocytes, with expression also observed in neurons. In contrast, TMPRSS2 expression was predominant in neurons, with expression also observed in astrocytes". However, it should be noted that this claim cannot be made without quantification data of the expression level or signal intensity. Moreover, histological analysis of the tissue does not always guarantee that correct cell types are being looked at. Thus it would better if the authors used cell specific markers like Tuj1 (neurons) and GFAP (astrocytes) to conclude their claims.

  2. Major: In result section3.2; the authors state that "Astrocytes supported the highest levels of infection, with 235 approximately 25-fold higher levels of infected cells than that of pericytes". It should be noted, although the graphs indicate that astrocytes are higher, this comparison cannot be done with proper statistical analysis. Based on the figure legends and the figure itself, it does not seem that the authors has applied any statistical test. It would be good to see if the authors can compare the results statically by one-way ANOVA and then add this result in this section. This would make the publication stronger. As mentioned, it does not support their claim.

  3. Major: In the result section 3.5; The authors write "Neurons supported the highest levels of infection by all variants, and astrocytes and choroid plexus epithelial cells were infected at similar levels (Figure 4A)". The way the data is presented in the manuscript, the only conclusions that can be made is that neurons are shown to be infected by the variants of SARS-CoV2. Similarly astrocytes and choroid plexus are also shown to be infected by the variants. However, this graph is not correct to make conclusions that neurons support higher levels of infection and that astrocytes and choroid plexus support similar levels. If the authors wish to make statements on the level of infection, the neurons, astrocytes, and choroid plexus must be compared to one another and must not be graphed separately as done currently. Overall the results in this section are not fully supported by the data shown.

  4. Minor: Methods section needs to be more detailed about various techniques, controls used, antibodies used, and dilutions of the antibodies used for various experiments in the manuscript.

  5. Minor: It would be informative if the authors could label the images shown in the manuscript to better inform the reader.

  6. Minor: The introduction section needs to include more details about ACE2 and TMPRSS2 and to inform the reader as to what the rationale was for selecting anti-ACE2 neutralizing technique.

  7. Discussion: Overall, the manuscript can be informative to the field to better understand neurological disease after CoV2 infection albeit not in the current form as the authors claims are not fully supported by their data.

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