Hamsters with long Covid exhibits a neurodegenerative signature in the brainstem

Abstract

After infection with SARS-CoV-2, patients may present with one or more symptoms that appear or persist over time, including fatigue, respiratory, cardiovascular and neurological disorders. Neurological symptoms include anxiety, depression and impaired short-term memory. However, the exact underlying mechanisms of long Covid are not yet decrypted. Using the golden hamster as a model, we provide further evidence that SARS-CoV-2 is neuroinvasive and can persist in the central nervous system, as we found viral RNA and replicative virus in the brainstem after 80 days of infection. Infected hamsters presented a neurodegenerative signature in the brainstem, with overexpression of innate immunity genes, impacted dopaminergic and glutamatergic synapses, altered energy metabolism. Finally, the infected hamsters manifested persistent signs of depression and impaired short-term memory, as well as late-onset signs of anxiety, as a valuable model to study long Covid. Conclusively, we provide evidence that virus-related and neurodegenerative and immunometabolic mechanisms coexist in the brainstem of infected hamsters and contribute to the manifestation of neuropsychiatric and cognitive symptoms. HighlightsO_LISARS-CoV-2 infects and persists in the brainstem of intranasally-inoculated hamsters C_LIO_LIPersistent neuropsychiatric and cognitive consequences are observed in SARS-CoV-2-infected hamsters C_LIO_LIThe brainstem present distinct transcriptome profiles in acute and in long Covid C_LIO_LIThe dopaminergic and glutamatergic systems are affected in long Covid C_LIO_LIThe SARS-CoV-2 infection affects the expression of genes related to neurodegenerative processes in acute and in long Covid C_LI