1. A murine model of post-acute neurological sequelae following SARS-CoV-2 variant infection.
- Author
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Singh A, Adam A, Aditi, Peng BH, Yu X, Zou J, Kulkarni VV, Kan P, Jiang W, Shi PY, Samir P, Cisneros I, and Wang T
- Subjects
- Animals, Mice, Humans, Brain virology, Brain immunology, Antibodies, Neutralizing immunology, Antibodies, Viral blood, Antibodies, Viral immunology, Angiotensin-Converting Enzyme 2 genetics, Angiotensin-Converting Enzyme 2 metabolism, Female, COVID-19 immunology, SARS-CoV-2 immunology, Disease Models, Animal, Post-Acute COVID-19 Syndrome
- Abstract
Viral variant is one known risk factor associated with post-acute sequelae of COVID-19 (PASC), yet the pathogenesis is largely unknown. Here, we studied SARS-CoV-2 Delta variant-induced PASC in K18-hACE2 mice. The virus replicated productively, induced robust inflammatory responses in lung and brain tissues, and caused weight loss and mortality during the acute infection. Longitudinal behavior studies in surviving mice up to 4 months post-acute infection revealed persistent abnormalities in neuropsychiatric state and motor behaviors, while reflex and sensory functions recovered over time. In the brain, no detectable viral RNA and minimal residential immune cell activation was observed in the surviving mice post-acute infection. Transcriptome analysis revealed persistent activation of immune pathways, including humoral responses, complement, and phagocytosis, and gene expression levels associated with ataxia telangiectasia, impaired cognitive function and memory recall, and neuronal dysfunction and degeneration. Furthermore, surviving mice maintained potent systemic T helper 1 prone cellular immune responses and strong sera neutralizing antibodies against Delta and Omicron variants months post-acute infection. Overall, our findings suggest that infection in K18-hACE2 mice recapitulates the persistent clinical symptoms reported in long-COVID patients and provides new insights into the role of systemic and brain residential immune factors in PASC pathogenesis., Competing Interests: The authors declare the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Singh, Adam, Aditi, Peng, Yu, Zou, Kulkarni, Kan, Jiang, Shi, Samir, Cisneros and Wang.)
- Published
- 2024
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