SARS-CoV-2 infection is associated with hypothalamic orexin suppression and persistent cortical NeuN attenuation

  • J Neuroinflammation. 2026 May 5;23(1):216. doi: 10.1186/s12974-026-03842-y.
Gun Young Yoon  #  1 ,  Young Cheul Chung  #  2  3 ,  Ji Hyun Choi  1 ,  Yun Ha  4 ,  Se Yeon Seo  4 ,  Keun Bon Ku  1 ,  Do Yeon Kim  1  5 ,  Woo Yeon Hwang  1  5 ,  Gi Uk Jeong  1  6 ,  Dae-Gyun Ahn  1 ,  Kyun-Do Kim  1 ,  Je-Keun Rhee  4  7 ,  Won-Ho Shin  8  9 ,  Young-Chan Kwon  10  11
Affiliations
  • 1. Center for Infectious Diseases Vaccine and Diagnosis Innovation (CEVI), Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea.
  • 2. Division of Advanced Predictive Research, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea.
  • 3. Human and Environmental Toxicology, University of Science and Technology (UST), Daejeon, 34114, Republic of Korea.
  • 4. Department of Bioinformatics & Life Science, Soongsil University, Seoul, 06978, Republic of Korea.
  • 5. College of Pharmacy, Korea University, Sejong, 30019, Republic of Korea.
  • 6. Department of Microbiology, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea.
  • 7. AI-Bio Convergence Research Institute, Soongsil University, Seoul, 06978, Republic of Korea.
  • 8. Division of Advanced Predictive Research, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea. [email protected].
  • 9. Human and Environmental Toxicology, University of Science and Technology (UST), Daejeon, 34114, Republic of Korea. [email protected].
  • 10. Center for Infectious Diseases Vaccine and Diagnosis Innovation (CEVI), Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea. [email protected].
  • 11. Medical Chemistry and Pharmacology, University of Science and Technology (UST), Daejeon, 34114, Republic of Korea. [email protected].
  • # Contributed equally.
PMID: 42087199 DOI: 10.1186/s12974-026-03842-y
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 neurons 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 attenuation, we found that exogenous orexin-A/B supplementation increased NeuN abundance in vitro and in vivo under the tested conditions. Overall, these findings identify the orexin system as a candidate neural vulnerability to SARS-CoV-2 and suggest that orexinergic dysfunction may contribute to the neurological manifestations of Long COVID.

Keywords
Hcrt (Orexin); Long COVID; NeuN; Neurological pathogenesis; SARS-CoV-2.
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