Morphological, cellular, and molecular basis of brain infection in COVID-19 patients, 2022, Crunfli et al

[Andy]

Significance

Neurological symptoms are among the most prevalent of the extrapulmonary complications of COVID-19, affecting more than 30% of patients. In this study, we provide evidence that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is found in the human brain, where it infects astrocytes and to a lesser extent, neurons. We also show that astrocytes are susceptible to SARS-CoV-2 infection through a noncanonical mechanism that involves spike–NRP1 interaction and respond to the infection by remodeling energy metabolism, which in turn, alters the levels of 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 observed in the brains of COVID-19 patients.

Abstract

Although increasing evidence confirms neuropsychiatric manifestations associated mainly with severe COVID-19 infection, long-term neuropsychiatric dysfunction (recently characterized as part of “long COVID-19” syndrome) has been frequently observed after mild infection.

We show the spectrum of cerebral impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, ranging from long-term alterations in mildly infected individuals (orbitofrontal cortical atrophy, neurocognitive impairment, excessive fatigue and anxiety symptoms) to severe acute damage confirmed in brain tissue samples extracted from the orbitofrontal region (via endonasal transethmoidal access) from individuals who died of COVID-19.

In an independent cohort of 26 individuals who died of COVID-19, we used histopathological signs of brain damage as a guide for possible SARS-CoV-2 brain infection and found that among the 5 individuals who exhibited those signs, all of them had genetic material of the virus in the brain. Brain tissue samples from these five patients also exhibited foci of SARS-CoV-2 infection and replication, particularly in astrocytes. Supporting the hypothesis of astrocyte infection, neural stem cell–derived human astrocytes in vitro are susceptible to SARS-CoV-2 infection through a noncanonical mechanism that involves spike–NRP1 interaction. SARS-CoV-2–infected astrocytes manifested changes in energy metabolism and in key proteins and metabolites used to fuel neurons, as well as in the biogenesis of neurotransmitters. Moreover, human astrocyte infection elicits a secretory phenotype that reduces neuronal viability. Our data support the model in which SARS-CoV-2 reaches the brain, infects astrocytes, and consequently, leads to neuronal death or dysfunction. These deregulated processes could contribute to the structural and functional alterations seen in the brains of COVID-19 patients.

Open access, https://www.pnas.org/doi/full/10.1073/pnas.2200960119

 

[SNT Gatchaman]

They looked at both mildly affected patients, with MRI and questionnaire assessments, but the postmortem evaluation seems the most impactful. Selected quotes, with added Wikipedia and S4ME links —

We also observed that higher levels of anxiety symptoms correlated with atrophy of the orbitofrontal cortex, a region previously linked with anxiety disorders. Our results suggest that anxiety and depression symptoms are at least partially associated with SARS-CoV-2 infection, a hypothesis supported by a recently discovered association between anxiety and reactive astrogliosis in patients after COVID-19.

More specifically, proteins found differentially expressed in SARS-CoV-2–infected astrocytes and in COVID-19 postmortem brain tissue samples belonged to glycolysis/gluconeogenesis, carbon metabolism, and the pentose phosphate pathway. Collectively, these data reinforce that SARS-CoV-2 infects astrocytes in the CNS, possibly affecting energy metabolism pathways and modulating proteins associated with neurodegeneration.

SARS-CoV-2–infected astrocytes showed pronounced changes in metabolic intermediates of glycolysis and anaplerotic reactions, indicating alterations in the pathways of astrocyte metabolism. This phenomenon was marked by a decrease in pyruvate and lactate, which are downstream metabolites of the glycolytic pathway, as well as a reduction in glutamine and intermediates of glutamine metabolism, such as glutamate, GABA, and alpha-ketoglutarate

Astrocytes also play a vital role in glutamate-level homeostasis and neurotransmitter recycling, crucial processes for the maintenance of synaptic transmission and neuronal excitability. At glutamatergic synapses, glutamate uptake by astroglia prevents excitotoxicity, whereupon glutamine synthetase converts glutamate to glutamine, which can then be transferred back to neurons, thus closing the glutamate–glutamine cycle. At GABAergic synapses, GABA is taken up by astrocytes and first metabolized to glutamate before being converted to glutamine. Given the importance of the metabolic coupling between astrocytes and neurons, alterations in astrocytic glucose and glutamine metabolism are expected to compromise neuronal metabolism and plasticity and synaptic function.

By 18F-FDG PET analysis, Guedj et al. reported hypometabolism in four different clusters of brain regions in patients suffering from long COVID-19, including the bilateral rectal/orbital gyrus and the olfactory gyrus. As key regulators of CNS metabolism, alterations in astrocyte metabolism contribute to the 18F-FDG PET signal. Therefore, dysfunctions in astrocyte energy metabolism, like those observed here, could explain, at least partially, the brain hypometabolism in COVID-19 patients.