TY - JOUR
T1 - A murine model of post-acute neurological sequelae following SARS-CoV-2 variant infection
AU - Singh, Ankita
AU - Adam, Awadalkareem
AU - Aditi,
AU - Peng, Bihung
AU - Yu, Xiaoying
AU - Zou, Jing
AU - Kulkarni, Vikram V.
AU - Kan, Peter
AU - Jiang, Wei
AU - Shi, Pei-Yong
AU - Samir, Parimal
AU - Cisneros, Irma
AU - Wang, Tian
N1 - Publisher Copyright:
Copyright © 2024 Singh, Adam, Aditi, Peng, Yu, Zou, Kulkarni, Kan, Jiang, Shi, Samir, Cisneros and Wang.
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
KW - CNS inflammation
KW - inflammatory responses
KW - long COVID
KW - post-acute sequelae
KW - SARS-CoV-2 variant
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U2 - 10.3389/fimmu.2024.1384516
DO - 10.3389/fimmu.2024.1384516
M3 - Article
C2 - 38765009
AN - SCOPUS:85193468879
SN - 1664-3224
VL - 15
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 1384516
ER -