The neurobiology of SARS-CoV-2 infection

Worldwide, over 694 million people have been infected with SARS-CoV-2, with an estimated 55-60% of those infected developing COVID-19. Since the beginning of the pandemic in December 2019, different variants of concern have appeared and continue to occur. With the emergence of different variants, an increasing rate of vaccination and previous infections, the acute neurological symptomatology of COVID-19 changed. Moreover, 10-45% of individuals with a history of SARS-CoV-2 infection experience symptoms even 3 months after disease onset, a condition that has been defined as 'post-COVID-19' by the World Health Organization and that occurs independently of the virus variant. The pathomechanisms of COVID-19-related neurological complaints have become clearer during the past 3 years. To date, there is no overt - that is, truly convincing - evidence for SARS-CoV-2 particles in the brain. In this Review, we put special emphasis on discussing the  methodological difficulties of viral detection in CNS tissue and discuss immune-based (systemic and central) effects contributing to COVID-19-related CNS affection. We sequentially review the reported changes to CNS cells in COVID-19, starting with the blood-brain barrier and blood-cerebrospinal fluid barrier - as systemic factors from the periphery appear to primarily influence barriers and conduits - before we describe changes in brain parenchymal cells, including microglia, astrocytes, neurons and oligodendrocytes as well as cerebral lymphocytes. These findings are critical to understanding CNS affection in acute COVID-19 and post-COVID-19 in order to translate these findings into treatment options, which are still very limited.