New mechanistic insights into the origin of SARS-CoV-2-induced neurological disorders

In a recent study published in bioRxiv* Preprint server Researchers explored the effect of exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the brain.

Stady: The synaptic analgesic of SARS-CoV-2 molecules disrupts the regulation and function of the synapse. Image Credit: Illustration Forest / Shutterstock

background

Coronavirus disease (COVID) is a term that includes the short and long-term neurological and mental complications associated with SARS-CoV-2 infection. Accurate identification of the molecular processes underlying virus-induced brain changes is hampered by the heterogeneous and highly variable nature of these symptoms. Despite the limited infection, mere exposure of brain cells to SARS-CoV-2 particles is sufficient to cause significant changes in synapse regulation associated with dysfunctional electrical activity.

about studying

In this study, researchers explain virus-induced neurodegenerative diseases using a new model in which viral particles physically interfere with transsynaptic structures, resulting in local electrical disturbances.

The team created an organic model outside of vivo Culture using frontal and parietal cortex slices from postmortem brain resection of non-COVID patients to better regulate the effects of SARS-CoV-2 exposure on the human brain. The 3D microelectrode array measured the functional activity of the cultured brain slices because they showed marked spontaneous electrical activity. The team used a 3D system that copies the embryonic cortex without the microglia.

Mass spectrometry-based differential proteomics was performed on a single cortical organoid infected either in the presence or absence of SARS-CoV-2 to detect virus-induced molecular changes. This method allowed the team to interpret the varying permittivity of SARS-CoV-2 observed from semi-organic to organic. The team first compared the post-translational modifications (PTM) found in the proteins. A new analysis of the single organic proteomic data set was performed. using outside of vivo Organotyped brain slices, the team investigated whether such a phenotype could be detected in a model with limited synaptic plasticity.

consequences

Even in patients with viremia negative, the team detected a small amount of viral RNA in the temporal lobe, supporting the theory that some viruses may be able to enter and possibly survive in the brain. After cortical cutting, histopathological investigations revealed a reduced density of neurons, possibly due to the cutting process. Away from the slice edge, neuronal viability was mostly retained, and the general tissue architecture and cellular structure of the slice remained unchanged.

ex vivo Infection of frontal and parietal brain slices infected with SARS-CoV-2 reporter viruses showed that only a small percentage of cells could become infected, and the virus could not spread further in the slice after initial virus inoculation. SARS-CoV-2 did not result in significant tissue toxicity or disruption. These data showed that SARS-CoV-2 can only infect neurons to a limited extent. However, after the initial vaccination, the kinetics of viral replication were stabilized, making it unlikely that these cells could support the production of new infectious particles.

Brain organoids showed mature neurons, astrocytes, and neural progenitor cells. Confocal image quantification revealed the permissibility of this heterogeneous form of SARS-CoV-2, which ranged from mild to highly infectious cases. Thus, the study confirmed that mature neurons showed the highest amount of let

Cortical organelles infected with SARS-CoV-2 did not show significant cytotoxicity, apoptosis, or impaired organelle growth. While the organelles did not release any new infectious particles, further analysis of the cortical organelle infection showed replication-dependent expression of the viral protein N.-2 proliferation. Therefore, the team hypothesized that exposure to SARS-CoV-2 to the brain could lead to localized and transient disturbances, which correspond to the multidirectional and variable neurological symptoms observed in the majority of COVID-19 patients.

The team discovered that nearly a third of the 180 proteins that were upregulated after SARS-CoV-2 infection were related to the synapse. Also, the presynaptic bassoon showed significant hypertrophy and elongation after exposure to SARS-CoV-2, as shown by quantitative image analysis.

The high number of transsynaptic complexes in human primary neurons observed after exposure to UV-inactivated SARS-CoV-2 particles showed that viral replication was not necessary to induce perturbations. Remarkably, enlarged synapses have been reported with respect to the synaptic homeostasis observed after chronic blockade of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and N-methyl-D-aspartate receptors (NMDARs), termed It also has “Interlocked Upgrade”.

Based on local field potential, the team discovered that organisms susceptible to SARS-CoV-2 could be easily distinguished from their dummy counterparts. With an accuracy of over 97%, an algorithm developed by the team was able to determine if an organic member had been exposed to SARS-CoV-2. Moreover, before infection or 30 min after infection, the same infected organelles could not be distinguished from those of sham, which indicates the specificity of the algorithm. Altogether, the study concluded that SARS-CoV-2 caused an aberrant synaptic structure associated with perturbed electrical synaptic transmission.

conclusion

Overall, the study results showed that SARS-CoV-2 significantly altered the synapse environment and disturbed the local field potential. These results were related to the retention of viral particles in the synapse, which raised the possibility of a direct host-pathogen interference mechanism.

*Important note

bioRxiv publishes preliminary scientific reports that are not subject to peer review, and therefore should not be considered conclusive, guide clinical practice/health-related behavior, or be treated as established information.