Disruption of the hypothalamic orexin system links SARS-CoV-2 infection to persistent cortical neuronal pathology
Yoon, G. Y.; Jeong, Y.-C.; Choi, J.-H.; Ha, Y.; Seo, S. Y.; Ku, K. B.; Kim, D. Y.; Hwang, W. Y.; Jeong, G. U.; Ahn, D.-G.; Kim, K.-D.; Rhee, J.-K.; Shin, W.-H.; Kwon, Y.-C.
Show abstract
Long COVID frequently presents with persistent neurological symptoms, including cognitive impairment, fatigue, and sleep disturbances; however, its underlying mechanisms remain unclear. Here, we show that SARS-CoV-2 infection induces lasting cortical neuronal injury and hypothalamic orexin (hypocretin) dysfunction in vivo. In K18-hACE2 and wild-type BALB/c mice, viral RNA persisted in the brain and coincided with focal loss of Neuronal Nuclei (NeuN)-positive cortical neurones beyond acute infection. SARS-CoV-2, but not the influenza A virus, triggered rapid and sustained suppression of hypothalamic orexin expression, defining a virus-specific neuropathological signature. Considering the downregulation of orexin and focal cortical NeuN expression, we showed that augmenting orexin signalling using recombinant orexin-A/B restored NeuN expression in vitro and in vivo. Overall, these findings identify the orexin system as a selective neural vulnerability to SARS-CoV-2 and define orexinergic circuit disruption as a mechanistic axis underlying the neurological manifestations of Long COVID.
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