SARS-CoV2 infection triggers reactive astrocyte states and inflammatory conditions in long-term 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 long-term human stem cell-derived cortical organoids 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 of astrocytes, deep projection neurons, upper callosal neurons and inhibitory neurons in 6 months human cortical organoids. 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 cell metabolism, astrocyte activation and, inflammation and further, upregulation of cell survival pathways. Thus, local and minor infectivity of SARS-CoV2 in the brain may induce widespread adverse effects and may lead to resilience of dysregulated neurons and astrocytes within an inflammatory environment.