A new study has provided the most compelling evidence yet that the SARS-CoV-2 virus enters the human brain, where it infects neuronal support cells called astrocytes. Writing in the journal PNAS, researchers reveal how the pathogen alters the metabolism of these cells, causing them to secrete compounds that impair the viability of neurons and ultimately promote neuronal death.
“Neurological symptoms are among the most prevalent of the extrapulmonary complications of COVID-19, affecting more than 30 percent of patients,” write the authors. However, until now it has remained unclear whether these effects are the result of systemic changes produced by the virus or direct infection of the brain and central nervous system (CNS).
To investigate, the study authors began by assessing 81 individuals who had suffered from mild COVID-19 symptoms without the need for hospitalization. Compared to 81 healthy controls, these participants exhibited higher levels of anxiety and depression and greater atrophy in a brain region called the orbitofrontal cortex, which has previously been associated with anxiety disorders.
To determine how the virus triggers the destruction of brain cells within this key structure, the team analyzed brain tissue samples from 26 people who had died from COVID-19-related complications. The SARS-CoV-2 virus was found in the astrocytes of five of these individuals, leading the study authors to speculate that the pathogen may well have been present in the brains of the other 21 subjects, despite not being detected in the small samples used for the study.
Astrocytes provide metabolic support for neurons, supplying them with the energy they need to function. An analysis of the proteins expressed by SARS-CoV-2-infected astrocytes revealed key metabolic changes, including a decrease in the production of lactate, which is essential for neural activity and survival.
Based on this observation, the researchers state that “SARS-CoV-2 infection elicits a neurotoxic secretory phenotype in astrocytes that results in increased neuronal death.”
Taking their investigation a step further, the team sought to determine how the virus infects brain cells. In the lungs, SARS-CoV-2 infects cells by using its spike protein to dock onto receptors called ACE2 receptors, although these particular gateways are not expressed by astrocytes.
After introducing the virus to brain cells in a petri dish, the researchers found that the spike protein targets a different receptor, known as NRP1, in order to infect astrocytes. When NRP1 receptors were blocked with neutralizing antibodies, the virus lost its ability to invade these cells.
“In summary, our findings are consistent with a model in which SARS-CoV-2 is able to reach the CNS of COVID-19 patients, infect astrocytes via NRP1 interaction, and secondarily impair neuronal function and viability,” write the study authors.
“These features could explain the damage and structural changes observed in the brains of COVID-19 patients.”