Neuroproteomic Analysis after SARS-CoV-2 Infection Reveals Overrepresented Neurodegeneration Pathways and Disrupted...

Area of Science:

• Neuroscience
• Virology
• Molecular Biology

Background:

• Severe acute respiratory syndrome-associated coronavirus 2 (SARS-CoV-2), the virus causing COVID-19, is linked to neurological symptoms beyond respiratory illness.
• The precise molecular mechanisms underlying SARS-CoV-2-induced neuropathology remain largely uninvestigated.

Purpose of the Study:

• To investigate the susceptibility of human neurons to SARS-CoV-2 infection.
• To explore the neuroproteomic changes induced by direct viral infection and by inflammatory mediators from infected lung cells.

Main Methods:

• Utilized human-induced pluripotent stem cell-derived neurons expressing key SARS-CoV-2 receptors (ACE-2, TMPRSS2, TMEM106B).
• Exposed neurons to SARS-CoV-2 and analyzed infection rates, viral replication, and cellular morphology using RT-qPCR, immunocytochemistry, and proteomics.
• Treated neurons with conditioned media from SARS-CoV-2-infected lung cells to assess inflammatory effects on neuroproteomics.

Main Results:

• SARS-CoV-2 infected neurons, albeit at a lower rate than other human cells, with no evidence of viral replication or infectious virion production.
• Infected neurons exhibited irregular nuclear morphology.
• Exposure to conditioned media from infected lung cells and limited viral infection altered neuronal proteomic profiles, impacting mitochondrial proteins, apoptosis, and metabolic pathways.

Conclusions:

• SARS-CoV-2 can directly infect human neurons, causing morphological changes and altering key cellular pathways.
• Inflammatory mediators from infected lung cells, alongside direct viral effects, contribute to neuroproteomic alterations.
• These findings suggest a potential mechanism for SARS-CoV-2-associated neuropathology and lingering neurological effects observed in COVID-19 patients.