ApoE-Isoform-Dependent SARS-CoV-2 Neurotropism and Cellular Response.

Abstract

ApoE4, a strong genetic risk factor for Alzheimer disease, has been associated with increased risk for severe COVID-19. However, it is unclear whether ApoE4 alters COVID-19 susceptibility or severity, and the role of direct viral infection in brain cells remains obscure. We tested the neurotropism of SARS-CoV2 in human-induced pluripotent stem cell (hiPSC) models and observed low-grade infection of neurons and astrocytes that is boosted in neuron-astrocyte co-cultures and organoids. We then generated isogenic ApoE3/3 and ApoE4/4 hiPSCs and found an increased rate of SARS-CoV-2 infection in ApoE4/4 neurons and astrocytes. ApoE4 astrocytes exhibited enlarged size and elevated nuclear fragmentation upon SARS-CoV-2 infection. Finally, we show that remdesivir treatment inhibits SARS-CoV2 infection of hiPSC neurons and astrocytes. These findings suggest that ApoE4 may play a causal role in COVID-19 severity. Understanding how risk factors impact COVID-19 susceptibility and severity will help us understand the potential long-term effects in different patient populations.

• Authors: Cheng Wang, Mingzi Zhang, Gustavo Garcia Jr, E Tian, Qi Cui, Xianwei Chen, Guihua Sun, Jinhui Wang, Vaithilingaraja Arumugaswami, Yanhong Shi
• Journal: Cell stem cell (Cell Stem Cell) Vol. 28 Issue 2 Pg. 331-342.e5 (02 04 2021) ISSN: 1875-9777 [Electronic] United States
• PMID: 33450186 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Antiviral Agents
• Apolipoproteins E
• Protein Isoforms
• remdesivir
• Adenosine Monophosphate
• Alanine

Topics

• Adenosine Monophosphate (analogs & derivatives, pharmacology)
• Alanine (analogs & derivatives, pharmacology)
• Animals
• Antiviral Agents (pharmacology)
• Apolipoproteins E (metabolism)
• Astrocytes (drug effects, pathology, virology)
• Brain (pathology, virology)
• COVID-19 (virology)
• Cell Differentiation
• Chlorocebus aethiops
• Humans
• Induced Pluripotent Stem Cells (virology)
• Nerve Degeneration (pathology)
• Neurites (pathology)
• Neurons (drug effects, pathology, virology)
• Organoids (drug effects, pathology, virology)
• Protein Isoforms (metabolism)
• SARS-CoV-2 (physiology)
• Synapses (pathology)
• Tropism (physiology)
• Vero Cells