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Updated: Jun 26, 2025
A Murine Model of Dengue Virus-induced Acute Viral Encephalitis-like Disease
Published on: April 28, 2019
A murine model of post-acute neurological sequelae following SARS-CoV-2 variant infection
Ankita Singh1, Awadalkareem Adam1, Aditi1
1Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United States.
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.
Insights
Viral variants like Delta can cause long COVID symptoms in mice, leading to lasting brain and motor issues. This study reveals persistent immune responses, not active virus, may drive these post-acute sequelae of COVID-19 (PASC) symptoms.
Area of Science:
- Virology
- Immunology
- Neuroscience
Background:
- Viral variants are a risk factor for post-acute sequelae of COVID-19 (PASC), but the underlying mechanisms remain unclear.
- Understanding PASC pathogenesis is crucial for developing effective treatments for long COVID.
Purpose of the Study:
- To investigate the pathogenesis of PASC induced by the SARS-CoV-2 Delta variant in a mouse model.
- To identify persistent physiological and immunological changes following acute infection.
Main Methods:
- K18-hACE2 mice were infected with the SARS-CoV-2 Delta variant.
- Longitudinal behavioral studies were conducted on surviving mice up to 4 months post-infection.
- Brain tissue analysis, transcriptome analysis, and immunological assays (T cell responses, antibody neutralization) were performed.
Main Results:
- Acute infection led to significant inflammation, weight loss, and mortality.
- Surviving mice exhibited persistent neuropsychiatric and motor deficits, with recovery of reflex and sensory functions.
- No detectable viral RNA was found in the brain, with minimal immune cell activation.
- Transcriptome analysis indicated persistent activation of immune pathways and gene expression linked to neurological dysfunction.
- Mice maintained robust systemic T helper 1 immune responses and neutralizing antibodies against SARS-CoV-2 variants.
Conclusions:
- The K18-hACE2 mouse model effectively recapitulates persistent clinical symptoms of long COVID.
- Persistent immune activation, rather than active viral presence, may be a key driver of PASC.
- Findings highlight the role of systemic and brain-resident immune factors in PASC pathogenesis.
