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Updated: Jul 4, 2025
A Murine Model of Dengue Virus-induced Acute Viral Encephalitis-like Disease
Published on: April 28, 2019
Aged AG129 mice support the generation of highly virulent novel mouse-adapted DENV (1-4) viruses exhibiting
Gazala Siddqui1, Preeti Vishwakarma1, Shikha Saxena1
1Influenza and Respiratory Virus Laboratory, Centre for Virus Research, Therapeutics and Vaccines, Translational Health Science and Technology Institute, NCR-Biotech Science Cluster, 3rd Milestossne, Faridabad-Gurgaon Expressway, Faridabad, Haryana 121001, India.
Abstract:
Dengue virus infection in humans ranges from asymptomatic infection to severe infection, with ∼2.5 % overall disease fatality rate. Evidence of neurological manifestations is seen in the severe form of the disease, which might be due to the direct invasion of the viruses into the CNS system but is poorly understood. In this study, we demonstrated that the aged AG129 mice are highly susceptible to dengue serotypes 1-4, and following the adaptation, this resulted in the generation of neurovirulent strains that showed enhanced replication, aggravated disease severity, increased neuropathogenesis, and high lethality in both adult and aged AG129 mice. The infected mice had endothelial dysfunction, elicited pro-inflammatory cytokine responses, and exhibited 100 % mortality. Further analysis revealed that aged-adapted DENV strains induced measurable alterations in TLR expression in the aged mice as compared to the adult mice. In addition, metabolomics analysis of the serum samples from the infected adult mice revealed dysregulation of 18 metabolites and upregulation of 6-keto-prostaglandin F1 alpha, phosphocreatine, and taurocholic acid. These metabolites may serve as key biomarkers to decipher and comprehend the severity of dengue-associated severe neuro-pathogenesis.
Insights
Aged mice infected with adapted Dengue virus (DENV) strains developed severe neuro-pathogenesis and high mortality. Specific metabolites were identified as potential biomarkers for dengue-associated neurological severity.
Area of Science:
- Virology
- Immunology
- Neuroscience
Background:
- Dengue virus infection causes a wide spectrum of illness, from asymptomatic to severe disease with a fatality rate of ~2.5%.
- Neurological manifestations occur in severe dengue, potentially due to direct central nervous system (CNS) invasion, but the mechanisms remain unclear.
Purpose of the Study:
- To investigate the neurovirulence of adapted Dengue virus (DENV) strains in aged AG129 mice.
- To identify potential biomarkers for severe dengue-associated neuropathogenesis.
Main Methods:
- Aged AG129 mice were infected with adapted DENV serotypes 1-4.
- Neuropathogenesis, disease severity, mortality, endothelial dysfunction, and pro-inflammatory cytokine responses were assessed.
- Toll-like receptor (TLR) expression and serum metabolomics were analyzed.
Main Results:
- Aged AG129 mice showed high susceptibility to adapted DENV, resulting in neurovirulent strains with enhanced replication, aggravated disease, and 100% mortality.
- Infected mice exhibited endothelial dysfunction and pro-inflammatory cytokine responses.
- Metabolomics analysis revealed dysregulation of 18 metabolites, including upregulation of 6-keto-prostaglandin F1 alpha, phosphocreatine, and taurocholic acid.
Conclusions:
- Aged-adapted DENV strains induce severe neuropathogenesis and high lethality in mice.
- Specific metabolites identified may serve as biomarkers for understanding dengue-associated severe neuro-pathogenesis.
