Astroglia-mediated neuroinflammation as a putative mechanism of neurological outcomes in COVID-19? Insights from a Brazilian cohort

NeuroCOVID-19 has emerged as a significant global health concern, presenting a wide spectrum of neurological manifestations, including headaches, brain fog and anosmia. While mounting evidence indicates that SARS-CoV-2 infection compromises central nervous system (CNS) function, the precise processes underlying these effects remain incompletely understood. Although neurons have been extensively studied, astrocytes - critical regulators of brain homeostasis - have been largely overlooked in this context. In this study, we position astrocytes as central players in the neuropathological landscape of neuroCOVID-19, challenging their traditionally supportive role. We evaluated the frequent neurological symptoms in a Brazilian cohort of COVID-19 patients and investigated whether SARS-CoV-2 infection of cortical astrocytes induces neuroinflammation, glutamatergic imbalance, vasoregulatory disruption, and apoptosis as likely pathogenic processes. Among 162 COVID-19-positive patients, headache (53.09 %), brain fog (42.15 %), and anosmia (38.72 %) were the most commonly reported symptoms. Using human-induced pluripotent stem cell (hiPSC)-derived astrocytes, we found that SARS-CoV-2 infection promotes a pronounced pro-inflammatory response, evidenced by elevated levels of IL-6, IL-15, and IL-4 in the culture supernatant. Infected astrocytes also showed reduced mRNA expression of <i>KLK1</i> and <i>EAAT1</i>, key genes involved in vasodilation and glutamate clearance, respectively. Additionally, a significant increase in cleaved caspase-3-positive cells indicated enhanced apoptosis. Overall, these findings demonstrate that SARS-CoV-2 disrupts astrocyte homeostatic functions, leading to neuroinflammation, excitatory neurotransmission dysregulation, and cell death that may, hypothetically, underlie the neurological sequelae of COVID-19. By reframing astrocytes as active protagonists, this study highlights their essential role in CNS vulnerability. It also suggests potential targets for the future investigation in the development of therapies against the neurological complications of COVID-19.