Abstract
SARS-CoV-2 is the viral cause of the COVID-19 pandemic. Increasingly, significant neurological disorders have been associated with COVID-19. However, the pathogenesis of these neurological disorders remains unclear especially because only low or undetectable levels of SARS-CoV-2 have been reported in human brain specimens. Because SARS-CoV-2 S1 protein can be released from viral membranes, can cross the blood-brain barrier, and is present in brain cells including neurons, we tested the hypothesis that SARS-CoV-2 S1 protein can directly induce neuronal injury. Incubation of primary human cortical neurons with SARS-CoV-2 S1 protein resulted in accumulation of the S1 protein in endolysosomes as well as endolysosome de-acidification. Further, SARS-CoV-2 S1 protein induced aberrant endolysosome morphology and neuritic varicosities. Our findings suggest that SARS-CoV-2 S1 protein directly induces neuritic dystrophy, which could contribute to the high incidence of neurological disorders associated with COVID-19.
Highlights
COVID-19 caused by SARS-CoV-2 infection continues to be associated with significant neurological disorders; 10–35% of COVID-19 patients manifest neurological symptoms that include anosmia, loss of taste, and cognitive difficulties (Garrigues et al, 2020; Hornuss et al, 2020; Liotta et al, 2020; Tenforde et al, 2020; Varatharaj et al, 2020)
Even though SARS-CoV-2 can infect neurons directly (Song et al, 2021), the pathogenesis of the neurological disorders associated with SARS-CoV-2 infection remains unclear especially because only low or undetectable levels of SARS-CoV-2 virus have been reported in brain specimens (Matschke et al, 2020; Solomon et al, 2020; Lee et al, 2021)
Given that the receptor binding domain (RBD) necessary for SARS-CoV-2 viral entry into cells resides in the S1 protein (Huang et al, 2020), we determined whether S1 protein could enter and reside in neuronal endolysosomes following receptor-mediated endocytosis
Summary
COVID-19 caused by SARS-CoV-2 infection continues to be associated with significant neurological disorders; 10–35% of COVID-19 patients manifest neurological symptoms that include anosmia, loss of taste, and cognitive difficulties (Garrigues et al, 2020; Hornuss et al, 2020; Liotta et al, 2020; Tenforde et al, 2020; Varatharaj et al, 2020). Even though SARS-CoV-2 can infect neurons directly (Song et al, 2021), the pathogenesis of the neurological disorders associated with SARS-CoV-2 infection remains unclear especially because only low or undetectable levels of SARS-CoV-2 virus have been reported in brain specimens (Matschke et al, 2020; Solomon et al, 2020; Lee et al, 2021). Despite low levels of SARS-CoV-2 in brain specimens, SARS-CoV-2 viral proteins such as spiked glycoprotein (S protein) are present in brain tissues (Matschke et al, 2020; Meinhardt et al, 2021) and have been detected in brain neurons (Song et al, 2021). We tested the hypothesis that S1 protein induces endolysosome and neuritic dysfunction in neurons
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