Review 1: "SARS-CoV-2 Spike Protein Accumulation in the Skull-Meninges-Brain Axis: Potential Implications for Long-Term Neurological Complications in post-COVID-1"

The authors rate this study reliable to strong, as its main claims are supported by the methods and data, and they suggest the authors explore additional components of the brain to elucidate the mechanisms of viral entry.

by Edward Goetzl

Published onMay 18, 2023

1 of 2

This Pub is a Review of

SARS-CoV-2 Spike Protein Accumulation in the Skull-Meninges-Brain Axis: Potential Implications for Long-Term Neurological Complications in post-COVID-19

by Zhouyi Rong, Hongcheng Mai, Saketh Kapoor, Victor G. Puelles, Jan Czogalla, Julia Schädler, Jessica Vering, Claire Delbridge, Hanno Steinke, Hannah Frenzel, Katja Schmidt, Özüm Sehnaz Caliskan, Jochen Martin Wettengel, Fatma Cherif, Mayar Ali, Zeynep Ilgin Kolabas, Selin Ulukaya, Izabela Horvath, Shan Zhao, Natalie Krahmer, Sabina Tahirovic, Ali Önder Yildirim, Tobias B. Huber, Benjamin Ondruschka, Ingo Bechmann, Gregor Ebert, Ulrike Protzer, Harsharan Singh Bhatia, Farida Hellal, and Ali Ertürk

Show Description
Published on Apr 05, 2023
www.biorxiv.org

Description

ABSTRACT Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), has been associated mainly with a range of neurological symptoms, including brain fog and brain tissue loss, raising concerns about the virus’s acute and potential chronic impact on the central nervous system. In this study, we utilized mouse models and human post-mortem tissues to investigate the presence and distribution of the SARS-CoV-2 spike protein in the skull-meninges-brain axis. Our results revealed the accumulation of the spike protein in the skull marrow, brain meninges, and brain parenchyma. The injection of the spike protein alone caused cell death in the brain, highlighting a direct effect on brain tissue. Furthermore, we observed the presence of spike protein in the skull of deceased long after their COVID-19 infection, suggesting that the spike’s persistence may contribute to long-term neurological symptoms. The spike protein was associated with neutrophil-related pathways and dysregulation of the proteins involved in the PI3K-AKT as well as complement and coagulation pathway. Overall, our findings suggest that SARS-CoV-2 spike protein trafficking from CNS borders into the brain parenchyma and identified differentially regulated pathways may present insights into mechanisms underlying immediate and long-term consequences of SARS-CoV-2 and present diagnostic and therapeutic opportunities.Graphical Summary Short Summary The accumulation of SARS-CoV-2 spike protein in the skull-meninges-brain axis presents potential molecular mechanisms and therapeutic targets for neurological complications in long-COVID-19 patients.

RR:C19 Evidence Scale rating by reviewer:

Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

***************************************

Review:

Dr. Rong and colleagues clearly describe their findings of S1 and N proteins and RNAs in human post-mortem skull, meninges and brain tissues of COVID-19 patients and uninfected controls, inflammatory and coagulation factors associated with S1 deposit, and similar pathology in mouse tissues after injection of S1 protein.

1) These data definitively link COVID-19 pathology to the acute and sustained presence of S1 protein.

2)These data also definitively show involvement of immune/inflammatory/coagulation mediators in the S1-evoked CNS pathogenesis of COVID-19. The co-localization of SARS-CoV-2 proteins and immune/inflammatory/coagulation mediators in human brain tissue is the most important new finding of this study.

3) Although the data suggest a possible transmission of SARS-CoV-2 RNAs and proteins from skull marrow to CNS parenchyma, the actual occurrence of such transfers and any role they have in COVID-19 are only weakly supported. Finding S1 protein in two locations does not prove effective transmission from one to the other site. If the mouse model could be used to quantitatively assess transfer of labeled S1 protein from skull marrow to brain parenchyma, blood to brain parenchyma and CSF to brain parenchyma in parallel, this would be better proof of an actual axis that meaningfully participates in movement of S1 protein in COVID-19 infection.

4) Demonstration of multi-organ system involvement in mice injected with S1 protein has little value in this report. There are already many descriptions of such multi-organ system distribution of SARS-CoV-2 proteins in COVID-19 infection in the literature. Unless a new dimension is explored - such as detailed kinetics of distribution - or the model is used to directly and quantitatively assess a skull marrow-brain parenchyma axis, then the findings described don't add to any understanding of COVID-19 pathogenesis.

5) All human findings are in post-mortem tissues, although others have demonstrated S1 and N RNAs and proteins in living humans. These reports are not cited in references.

Review 1: "SARS-CoV-2 Spike Protein Accumulation in the Skull-Meninges-Brain Axis: Potential Implications for Long-Term Neurological Complications in post-COVID-1"

Connections