A study shows how SARS-COV-2 infects brain cells called astrocytes and causes structural changes in the brain. SARS-CoV-2 infection can result in brain changes and neurocognitive dysfunction, particularly in long-term COVID-19 syndrome, but the underlying mechanisms are elusive.
Daniel Martins-de-Souza and colleagues used MRI to compare the brain structure of 81 study participants who recovered from mild COVID-19 infection and 81 healthy individuals. The authors found that the former group exhibited reduced cortical thickness, which correlated with cognitive impairment and symptoms such as anxiety and depression.
The authors analyzed brain samples from 26 people who had died from COVID-19 and found that samples from five of those people showed tissue damage.
Another analysis of damaged brain samples revealed that astrocytes, i.e. brain cells that maintain neuronal metabolism, are particularly likely to be infected with SARS-CoV-2 and that the virus enters these cells via the NRP1 receptor.
After infection, astrocytes showed altered levels of metabolites used to power neurons and neurotransmitter production, and the infected cells secreted neurotoxic molecules. According to the authors, the results reveal structural changes observed in the brains of people with COVID-19.
The importance of the study points to the neurological symptoms, which are among the most prevalent extrapulmonary complications of COVID-19, affecting more than 30 percent of patients. In this study, we provide evidence that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is present in the human brain, where it infects astrocytes and, to a lesser extent, neurons.
We also show that astrocytes are vulnerable to SARS-CoV-2 infection through a non-canonical mechanism involving spike-NRP1 interaction and respond to infection by remodeling energy metabolism, which in turn increases levels of the Metabolites used to fuel neurons and support neurotransmitter synthesis. The altered secretory phenotype of infected astrocytes then impairs neuronal viability. These features could explain the damage and structural changes seen in the brains of COVID-19 patients.
Although increasing evidence confirms neuropsychiatric manifestations mainly associated with severe COVID-19 infection, long-term neuropsychiatric dysfunction (recently referred to as part of “long COVID-19” syndrome) has been commonly observed after mild infection.
The study shows the spectrum of cerebral effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, ranging from long-term changes in mildly infected individuals (orbitofrontal cortical atrophy, neurocognitive impairment, excessive fatigue and anxiety symptoms) to severe ones ranges from acute damage confirmed in brain tissue samples obtained from the orbitofrontal region (via an endonasal transethmoid approach) of individuals who have died from COVID-19.
In an independent cohort of 26 people who died from COVID-19, we used histopathological signs of brain damage as a guide to possible SARS-CoV-2 brain infection and found that among the 5 people who had these signs, all were genetic material of the virus was in the brain.
Brain tissue samples from these five patients also showed foci of SARS-CoV-2 infection and replication, particularly in astrocytes. To support the hypothesis of astrocyte infection, neural stem cell-derived human astrocytes are susceptible to SARS-CoV-2 infection in vitro through a non-canonical mechanism involving spike-NRP1 interaction.
SARS-CoV-2-infected astrocytes showed alterations in energy metabolism and in key proteins and metabolites used to fuel neurons, as well as in neurotransmitter biogenesis. In addition, human astrocyte infection produces a secretory phenotype that reduces neuronal viability.
The study results show that cognitive impairment and neuropsychiatric symptoms correlate with altered cerebral cortical thickness in convalescent COVID-19 patients. A cortical surface-based morphometric analysis (using high-resolution 3T MRI) in 81 subjects diagnosed with mild COVID-19 infection (62 self-reported anosmias or dysgeusia) who did not require oxygen support (Methodological details and patient demographics are presented in SI -Appendix).
Analysis was performed within a mean (SD) interval of 57 (26) days after SARS-CoV-2 detection by qRT-PCR, and subjects were compared to 81 healthy volunteers (without neuropsychiatric comorbidities) who were hospitalized during COVID -19 pandemic (age appropriate [P = 0.97] and sex [P = 0.3]). The COVID-19 group showed higher levels of anxiety and depression symptoms, fatigue and excessive daytime sleepiness (SI Appendix, Table S1 shows epidemiological and clinical data).
Analysis of cortical thickness (adjusted for multiple comparisons using the Holm-Bonferroni method) revealed areas of reduced cortical thickness in the left hemisphere exclusively, including the left rectus gyrus (P = 0.01), superior temporal gyrus (P = 0.036 ) and the inferior temporal sulcus (P = 0.02) and posterior lateral sulcus (P = 0.003) (Fig. 1A). No increase in cortical thickness was observed.