Dissecting the selective vulnerability of dopamine neurons to SARS-CoV-2 infection using human stem cell models

Project lead:  Dr Oliver Harschnitz, The Center of Stem Cell Biology, Developmental Biology Program
                    Memorial Sloan Kettering Cancer Center (New York, USA)

Awarded: 2020, "Seed funding: Covid-19 and encephalitis"

As a neuroimmunologist in the research group of Lorenz Studer at the Sloan Kettering Institute in New York, my work is focused on the development and application of human stem cell models to study encephalitis. Our pilot study aims to dissect the mechanisms through which subsets of neurons, specifically dopamine neurons, are susceptible to SARS-CoV-2 infection.

The present COVID-19 pandemic is a global health crisis of which we are yet to see the full effects. While infection with SARS-CoV-2 can cause severe respiratory disease and may lead to death, the late-stage pathology following SARS-CoV-2 infection remains unknown.

There is increasing evidence that viral infection may lead to neurological complications, either directly or indirectly by systemic inflammation, rendering neurons vulnerable to future stressors. One of the most famous examples is the parkinsonism that occurred subsequent to viral encephalopathy that developed following the 1918 influenza pandemic.

Human stem cell technology offers a unique opportunity to study encephalitis in a human background. Recent progress in our lab has established methods to obtain both neuronal (cortical neurons and dopamine neurons) and nonneuronal (astrocytes and microglia) cells at high purity from human pluripotent stem cells. These technological advances enable us to study the susceptibility of human brain cells to SARS-CoV-2 infection. Furthermore, it allows us to understand the SARS-CoV-2 induced interaction between neuronal and nonneuronal cells that may lead to long-term neurological damage.

The work that will be performed in this pilot study is aimed at understanding the molecular mechanisms underlying the differential susceptibility to SARS-CoV-2 in the CNS and the effect of SARS-CoV-2 infection on the function and survival of dopamine neurons. This will provide insight into the potential long-term neurological effects of COVID-19 and helps identify therapeutic targets that require additional focus for the development of neuroprotective drugs for SARS-CoV-2 infected patients.