Neuroinvasion of SARS-CoV-2 in human and mouse brain

Abstract

Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Reports indicate that 30-60% of patients with COVID-19 suffer from CNS symptoms. Yet, there is no consensus whether the virus can infect the brain, or what the consequences of infection are. Following SARS-CoV-2 infection of human brain organoids, clear evidence of infection was observed, with accompanying metabolic changes in the infected and neighboring neurons. Further, no evidence for the type I interferon responses was detected. We demonstrate that neuronal infection can be prevented either by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Finally, using mice overexpressing human ACE2, we demonstrate in vivo that SARS-CoV-2 neuroinvasion, but not respiratory infection, is associated with mortality. These results provide evidence for the neuroinvasive capacity of SARS-CoV2, and an unexpected consequence of direct infection of neurons by SARS-CoV2.

Common genetic variation in humans impactsin vitrosusceptibility to SARS-CoV-2 infection

“…The neuroinvasion and neurotrophism by SARS-CoV-2 observed here is consistent with other pre-print studies, which include reports of infection of human neurons and astrocytes using monolayer and organoid approaches (Jacob et al, 2020;Ramani et al, 2020;Song et al, 2020), highlighting greater and productive infection in choroid plexus epithelial cells (Jacob et al, 2020) and less infection in NPCs (Ramani et al, 2020;Song et al, 2020). Consequences of neuronal infection include transcriptional dysregulation indicative of an inflammatory response (Jacob et al, 2020), missorted and phosphorylated Tau (Ramani et al, 2020), and increased cell death (Jacob et al, 2020;Ramani et al, 2020;Song et al, 2020).…”

Experimental Models for the Study of Central Nervous System Infection by SARS-CoV-2

“…Furthermore, this work tested the efficiency of Sofosbuvir, an FDA-approved brain-penetrant antiviral drug for positive-sense single-stranded RNA viruses ( 145 ), as a treatment for the SARS-CoV-2 infection and observed that this drug was able to rescue the altered synaptogenesis and decrease neuronal death and viral accumulation in these brain organoids ( 141 ). Song et al ( 117 ) also demonstrated that SARS-CoV-2 has neuroinvasive capacity in human brain organoids, particularly of NPCs and mature cortical neurons. Infected cells showed a hypermetabolic state and viral particles were accumulated within endoplasmic reticulum-like structures, indicating the virus ability to use the neural cell machinery to replicate ( 117 ).…”

“…Song et al ( 117 ) also demonstrated that SARS-CoV-2 has neuroinvasive capacity in human brain organoids, particularly of NPCs and mature cortical neurons. Infected cells showed a hypermetabolic state and viral particles were accumulated within endoplasmic reticulum-like structures, indicating the virus ability to use the neural cell machinery to replicate ( 117 ). In addition, a hypoxic environment and extensive neuronal cell death were observed in high density SARS-CoV-2 infected areas, suggesting that virus infection could promote death of nearby cells ( 117 ).…”

Possible routes of SARS‐CoV‐2 invasion in brain: In context of neurological symptoms in COVID‐19 patients

“…In a recent study, Song et al showed widespread expression of ACE2 protein in neurons and cells close to the lumen of the human brain organoids. They further showed SARS-CoV-2 can infect brain organoids, which can be blocked using ACE2 specific antibodies, or by administering cerebrospinal fluid from a COVID-19 patient, indicating the requirement of ACE2 for infection of brain organoids (Pavillet & Selvakumar, 2020;Song et al, 2020). Successful viral infection of brain tissue was also demonstrated in transgenic (Tg) mice expressing hACE2, following intranasal administration, which emphasized potentiality of olfactory route for SARS-CoV-2 entry in human brain (Pavillet & Selvakumar, 2020;Song et al, 2020).…”

“…(and also TMPRSS2) in brain/neural tissue ( Figure 1). Any neuronal expression of ACE2 protein and SARS-CoV-2 infectivity was only shown in human pluripotent stem cells (PSCs)-derived mixed neurons, or human brain organoids, and not directly in human brain tissue (Bullen et al, 2020;Pavillet & Selvakumar, 2020;Song et al, 2020). In a recent study, Song et al showed widespread expression of ACE2 protein in neurons and cells close to the lumen of the human brain organoids.…”