SARS-CoV-2 Infection Causes Dopaminergic Neuron Senescence

Abstract

COVID-19 patients commonly present with neurological signs of central nervous system (CNS) and/or peripheral nervous system dysfunction. However, which neural cells are permissive to infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been controversial. Here, we show that midbrain dopamine (DA) neurons derived from human pluripotent stem cells (hPSCs) are selectively permissive to SARS-CoV-2 infection both in vitro and upon transplantation in vivo, and that SARS-CoV-2 infection triggers a DA neuron inflammatory and cellular senescence response. A high-throughput screen in hPSC-derived DA neurons identified several FDA approved drugs, including riluzole, metformin, and imatinib, that can rescue the cellular senescence phenotype and prevent SARS-CoV-2 infection. RNA-seq analysis of human ventral midbrain tissue from COVID-19 patients, using formalin-fixed paraffin-embedded autopsy samples, confirmed the induction of an inflammatory and cellular senescence signature and identified low levels of SARS-CoV-2 transcripts. Our findings demonstrate that hPSC-derived DA neurons can serve as a disease model to study neuronal susceptibility to SARS-CoV-2 and to identify candidate neuroprotective drugs for COVID-19 patients. The susceptibility of hPSC-derived DA neurons to SARS-CoV-2 and the observed inflammatory and senescence transcriptional responses suggest the need for careful, long-term monitoring of neurological problems in COVID-19 patients.

Impact of Age and Sex on Antibody Response Following the Second Dose of COVID-19 BNT162b2 mRNA Vaccine in Greek Healthcare Workers

“…Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged as a pathogen in December 2019 and is responsible for coronavirus disease 2019 (COVID- 19) [1]. This novel virus causes symptoms that range from fever, dry cough, and dyspnea to the development of acute pneumonia, while neurological complications have also been reported [2], including damage in the dopaminergic system [3,4]. SARS-CoV-2-infection can be fatal for patients with underlying conditions regardless of their age, while healthy individuals that are treated can recover within 2-4 weeks [5].…”

Cellular and Molecular Effects of SARS-CoV-2 Linking Lung Infection to the Brain

“…Furthermore, recently in human 3D organoids, it was shown that SARS-CoV-2 is indeed able to infect and kill neurons (166). A preprint publication by Chen et al (101), claims that human pluripotent stem cell-derived midbrain dopamine neurons are selectively permissive to SARS-CoV-2 infection, with potential long-term implications for the risk of developing Parkinson's disease-related symptoms. Nevertheless, despite finding further proofs of SARS-CoV-2 protein expression in the brains of the deceased COVID-19 patients, so far, it was not successfully proven that the presence of the virus is directly associated with the neuropathological changes (100).…”

“…The authors found no evidence of CNS damage caused directly by SARS-CoV-2 but found strong microglia and astrocyte activation and infiltration of cytotoxic T-lymphocytes (100), which might be a consequence of the disrupted brain barrier. On the other hand, a new study revealed the selective susceptibility of dopaminergic cells to SARS-CoV-2 infection and observed inflammatory and senescence on the transcriptional level (101), indicating that this issue among COVID-19 patients might require special attention.…”

Can SARS-CoV-2 Infection Lead to Neurodegeneration and Parkinson’s Disease?

“…Another possible mechanism of inducing PD would be viral neurotropism resulting in direct neuronal damage in strategic areas. IPSC-derived midbrain dopaminergic neurons were shown to be submissive to SARS-CoV-2-infection, which triggered an inflammatory response and subsequently cellular senescence in vitro [ 89 ]. RNA-sequencing analysis of the ventral midbrain tissue of COVID-19 patients revealed a comparable phenotype of inflamed neurons and identified low levels of SARS-CoV-2 transcripts [ 89 ].…”

“…IPSC-derived midbrain dopaminergic neurons were shown to be submissive to SARS-CoV-2-infection, which triggered an inflammatory response and subsequently cellular senescence in vitro [ 89 ]. RNA-sequencing analysis of the ventral midbrain tissue of COVID-19 patients revealed a comparable phenotype of inflamed neurons and identified low levels of SARS-CoV-2 transcripts [ 89 ]. These data underline that there may be a special susceptibility to SARS-CoV-2 of particularly vulnerable midbrain regions involved in the development of PD.…”