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Updated: Jul 4, 2026
A Murine Model of Dengue Virus-induced Acute Viral Encephalitis-like Disease
Published on: April 28, 2019
A mouse-passaged dengue virus strain with reduced affinity for heparan sulfate causes severe disease in mice by
Tyler R Prestwood1, Daniil M Prigozhin, Kristin L Sharar
1Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, California 92037, USA.
Abstract:
The four serotypes of dengue virus (DENV1 to DENV4) cause extensive morbidity and mortality. A major obstacle to studying disease pathogenesis and developing therapies has been the lack of a small-animal model. We previously reported isolation of a DENV2 strain, obtained by passaging a clinical isolate between mosquito cells and mice, that caused severe DENV disease in mice and contained multiple mutations, including many in domain II of the envelope (E) protein. Here, we describe a recombinant virus, differing from the non-mouse-passaged virus by two mutations in the E protein, that induces vascular leakage and tumor necrosis factor alpha (TNF-alpha)-mediated lethality, while the non-mouse-passaged virus causes paralysis. This recombinant virus has a weaker affinity for heparan sulfate, resulting in an increased serum half-life, higher systemic viral loads, and high levels of TNF-alpha in the serum of infected mice. These results exemplify the role of the E protein in modulating virion clearance and connect the effect of clearance on the systemic viral loads responsible for severe disease manifestations.
Insights
Researchers developed a new dengue virus (DENV) mouse model. This model shows how mutations in the DENV envelope protein cause severe disease, including vascular leakage and lethality, by affecting viral clearance.
Area of Science:
- Virology
- Immunology
- Pathogenesis
Background:
- Dengue virus (DENV) causes significant global morbidity and mortality.
- A lack of suitable small-animal models has hindered research into DENV pathogenesis and therapeutic development.
- Previous work established a mouse-adapted DENV2 strain with mutations in the envelope (E) protein.
Purpose of the Study:
- To characterize a recombinant DENV2 virus with specific E protein mutations.
- To investigate the mechanisms underlying severe DENV disease manifestations in a mouse model.
- To elucidate the role of viral clearance in DENV pathogenesis.
Main Methods:
- Generation of a recombinant DENV2 virus with two specific E protein mutations.
- Infection of mice with the recombinant and non-mouse-passaged DENV2 viruses.
- Assessment of clinical signs, viral loads, serum cytokine levels, and viral clearance mechanisms.
Main Results:
- The recombinant DENV2 induced vascular leakage and tumor necrosis factor alpha (TNF-alpha)-mediated lethality, unlike the non-mouse-passaged virus which caused paralysis.
- The recombinant virus exhibited reduced affinity for heparan sulfate, leading to increased serum half-life and higher systemic viral loads.
- Elevated serum TNF-alpha levels were observed in mice infected with the recombinant virus.
Conclusions:
- The E protein plays a critical role in modulating DENV virion clearance.
- Altered viral clearance influences systemic viral loads, contributing to severe DENV disease.
- This recombinant DENV2 mouse model provides valuable insights into DENV pathogenesis and potential therapeutic targets.
