Study shows astrocytes as breeding grounds for SARS-CoV-2 during brain infection

In a recent study published in PNASresearchers have demonstrated the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the human brain, infecting astrocytes and impairing neuronal function and viability.

Background

Among all extrapulmonary effects reported in coronavirus disease 2019 (COVID-19) patients, the most prominent manifestations involve the central nervous system (CNS). Some of the long-term complications beyond 4 weeks of acute SARS-CoV-2 infection are neuropsychiatric. In affected patient populations, cognitive and neurological deficits are consistent with substantial damage to the CNS. Previous studies have shown the presence of SARS-CoV-2 ribonucleic acid (RNA) from the acute phase to as long as 3 months in patients with neurological symptoms. In addition, these patients had altered cortical areas and axonal damage and suffered from white matter loss.

Recent studies have also demonstrated the presence of SARS-CoV-2 protein in brain regions of COVID-19 patients. SARS-CoV-2 infection can cause astrogliosis, microgliosis, and accumulation of immune cells in the human brain. SARS-CoV-2 can also cross the blood-brain barrier (BBB) ​​and infect human brain organoid cells, as seen in mouse models. in vitro.

Despite increasing evidence of neurological and neuropsychiatric symptoms in COVID-19 patients, the molecular mechanisms governing SARS-CoV-2 brain infection and its subsequent impact on human brain structure and function remain elusive. I’m lacking understanding.

About research

In this study, researchers analyzed brain tissue samples from 26 individuals who died of COVID-19 using minimally invasive autopsy with intranasal transethmoid access. They used histopathological signs of brain injury as a guide for possible SARS-CoV-2 brain infection. In addition, researchers examined live patients and preclinical studies. in vitro When ex vivo model.

Moreover, they performed cortical surface-based morphometry on 81 subjects with mild COVID-19 within an average of 57 days after SARS-CoV-2 detection by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). performed the analysis. For this analysis, researchers prepared a control group consisting of 81 healthy volunteers without neuropsychiatric comorbidities.

In addition, the team assessed episodic verbal memory, sustained attention, alternating attention, and cognitive flexibility in subgroups of 61 participants. They also performed liquid chromatography-mass spectrometry (LC/MS) proteome analysis on her 12 postmortem brain samples from a COVID-19 patient and her eight SARS-CoV-2 negative controls. Finally, the researchers cultured neural stem cell (NSC)-derived neurons in a conditioned medium that allowed SARS-CoV-2-infected astrocytes to grow.

Survey results

in vitro Experiments have shown that NSC-derived human astrocytes are susceptible to SARS-CoV-2 infection through a non-canonical mechanism involving the spike (S)-neuropilin-1 (NRP1) interaction. it was done. These astrocytes also showed alterations in energy metabolism and key metabolites used to fuel neurons, as well as in the biosynthesis of neurotransmitters. Notably, infected astrocytes secreted unidentified factors leading to neuronal cell death.

Furthermore, conditioned medium increased the apoptotic rate of NSC-derived neurons by 22.7%. SARS-CoV-2 RNA was not detected in either cell type after exposure to conditioned media, thus ruling out the possibility of neuronal infection, and direct exposure to SARS-CoV-2 was not effective in NSC-derived neurons after 24 days. 48, or 72 hours that did not reduce survival. These results suggest that SARS-CoV-2-infected astrocytes release soluble factors that reduce neuronal viability.

Analysis of cortical thickness revealed areas of reduced cortical thickness only in the left hemisphere or orbitofrontal region due to proximity and communication with the nasal cavity. A neuropsychological assessment revealed that 70% and 36% of his individuals experienced fatigue and daytime sleepiness, respectively. Nearly 28% of participants exhibited impairments in immediate episodic verbal memory, with approximately 34% and 56% performance declines on color trails A and B, respectively. Notably, 77% of these COVID-19 patients also exhibited acute olfactory or dysgeusia, likely related to the observed changes in cortical thickness.

Histopathological analysis revealed changes consistent with necrosis and inflammation in 5 of 26 brain tissue samples. These five samples also contained SARS-CoV-2 RNA and S protein. Since SARS-CoV-2 preferentially infects astrocytes, astrocytes were the most highly expressed of the 656 differentially expressed proteins. In addition, LC/MS analysis of SARS-CoV-2-infected astrocytes showed significant alterations in metabolic intermediates of glycolysis such as pyruvate and lactate. Taken together, these results indicated a reduction in metabolites produced by SARS-CoV-2-infected astrocytes and supporting neuronal metabolism and function.

Conclusion

Astrocytes are the major energy reservoirs of the brain, are essential for brain homeostasis, and also play an important role in protecting brain cell damage caused by pathogenic infections and sterile inflammation. Current research results suggest that anxiety and depressive symptoms are also partially associated with SARS-CoV-2 infection. in vivo Findings showed cortical atrophy, neuropsychiatric symptoms, and cognitive dysfunction in brain tissue of COVID-19 patients. Interestingly, her mild COVID-19 patient also exhibited cortical atrophy of the superior temporal gyrus, previously reported in a group of severe SARS-CoV-2 infected patients.

This study therefore raised the possibility that the neural invasion observed in fatal COVID-19 cases may function in mild COVID-19. Therefore, COVID-19 treatment should include methods to prevent SARS-CoV-2 from entering the central nervous system.