SARS-CoV2 infection triggers reactive astrocyte states and inflammatory conditions in Human Cortical Organoids

SARS-CoV2, severe acute respiratory syndrome coronavirus 2, is frequently associated with neurological manifestations. Despite the presence of mild to severe CNS-related symptoms in a cohort of patients, there is no consensus whether the virus can infect directly brain tissue or if the symptoms in patients are a consequence of peripheral infectivity of the virus. Here, we use a human stem cell-derived cortical organoid model to assess SARS-CoV2 infectivity of brain cells and unravel the cell-type tropism and its downstream pathological effects. Our results show consistent and reproducible low levels of SARS-CoV2 infection in human cortical organoids at different maturation stages in vitro. We found that astrocytes, deep projection neurons, upper callosal neurons and inhibitory neurons were infected by SARS-CoV2. Interestingly, astrocytes showed the highest infection rate among all infected cell populations that led to increased presence of reactive states. Further, transcriptomic analysis revealed overall changes in expression of genes related to oxidative phosphorylation, TNFA signaling, astrocyte activation and metabolic changes. Thus, local and minor infectivity of SARS-CoV2 in the brain may induce widespread adverse effects in brain cell populations.