Neuropilin-1 Mediates SARS-CoV-2 Infection of Astrocytes in Brain Organoids, Inducing Inflammation Leading to Dysfunction and Death of Neurons

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Conflicts of Interest

Identified Weaknesses

Rating Explanation

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Paper Summary

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COVID Makes Brain 'Helper' Cells Go Rogue, Killing Neighboring Neurons (in Mini-Brains!)

This study, primarily using lab-grown mini-brains (organoids) and cultured human astrocytes, reveals that SARS-CoV-2 directly infects brain astrocytes using a novel receptor, Neuropilin-1 (NRP1), instead of the usual ACE2. This infection triggers severe inflammation in astrocytes, leading to a hostile brain environment that causes uninfected neighboring neurons to malfunction and die.

Possible Conflicts of Interest

One author (L.C.N.) serves as a scientific advisor to pharmaceutical companies Abbvie and ViiV and is on the board of Cytodyn; however, this work is stated as unrelated to the current study. Another author (W.C.G.) was appointed President and Chief Scientific Officer of InvisiShield Technologies Ltd. after the completion of the work, and this work is also stated as having no overlap with the paper's subject matter. These are noted but explicitly declared as unrelated to the study's content.

Identified Weaknesses

Model System Limitations (Brain Organoids and 2D Cultures)

The study relies on induced pluripotent stem cell (iPSC)-derived brain organoids and 2D cultures of primary human astrocytes. These in vitro models lack the full complexity, cellular diversity (e.g., no microglial cells in organoids), blood-brain barrier, and systemic immune interactions present in a living human brain, thus limiting the direct translatability of findings to in vivo human pathology.

Difficulty Identifying Live Virus in vivo

The introduction notes that it has been challenging to find live SARS-CoV-2 virus in actual human brain tissues. While this study demonstrates productive infection in in vitro models, this highlights a potential disconnect or more complex in vivo situation compared to the direct and robust infection observed in the models.

Variant Infectivity Differences

Delta and Omicron variants showed lower infectivity in astrocytes and brain organoids compared to the wild-type strain. Although they still induced similar inflammatory responses, this difference in infectivity in the model might not fully reflect their impact or prevalence in the human brain in vivo.

Rating Explanation

The study provides strong mechanistic evidence, using robust in vitro models (brain organoids, primary human astrocytes) to identify a novel SARS-CoV-2 entry receptor (NRP1) in astrocytes and elucidate a bystander effect leading to neuronal dysfunction and death. The methodology is comprehensive. However, the inherent limitations of in vitro models mean the findings, while significant, require further in vivo validation for direct human relevance, preventing a 'groundbreaking' rating.

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