Through the COVID-19 pandemic the scientific community has uncovered many aspects of SARS-CoV-2 biology. This includes the multi-organ tropism of SARS-CoV-2 and COVID-19 effects on multiple systems, including the central nervous system (CNS). From early in the pandemic a variety of CNS symptoms have been identified ranging from sensory loss to encephalitis/encephalopathies—with estimates of 30-80% of COVID-19 patients experiencing atleast one of these symptoms. However, there is still a large gap in knowledge in the biological consequences of SARS-CoV-2 infecting neural tissues. In order to investigate this further we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in infected and neighboring neurons. However, no evidence for type I interferon responses was detected. We demonstrate that neuronal infection can be prevented by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate SARS-CoV-2 neuroinvasion in vivo. In autopsies from patients who died of COVID-19, we detect SARS-CoV-2 in cortical neurons and note pathological features associated with infection with minimal immune cell infiltrates. Finally, utilizing single-cell RNA sequencing (scRNA-seq) of cerebrospinal fluid (CSF) and blood from individuals with COVID-19 with neurological symptoms, we find compartmentalized, CNS-specific B cell responses.All affected individuals had CSF anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies whose target epitopes diverged from serum antibodies. In an animal model, we find that intrathecal SARS-CoV-2 antibodies are present only during brain infection and not elicited by pulmonary infection.These results provide evidence for the neuroinvasive capacity of SARS-CoV-2 and an unexpected consequence of direct infection of neurons by SARS-CoV-2.

Learning Objectives: 

1. Explore the neuroinvasive potential of SARS-CoV-2

2. Learn about possible consequences of neuroinvasion of SARS-CoV-2

3. Identify neuroimmune responses against SARS-CoV-2