Murine model for dengue virus-induced lethal disease with increased vascular permeability

Area of Science:

• Virology
• Immunology
• Pathogenesis

Background:

• Dengue virus (DEN) causes dengue fever and severe DHF/DSS.
• Lack of suitable animal models hinders understanding of DEN pathogenesis.
• Increased vascular permeability is a hallmark of DHF/DSS.

Purpose of the Study:

• To develop a more relevant murine model for DHF/DSS.
• To investigate the mechanisms of severe DEN disease in vivo.

Main Methods:

• Generated a novel DEN strain (D2S10) through alternate mosquito cell and mouse passaging.
• Infected interferon receptor-deficient mice with D2S10 and parental DEN strains.
• Analyzed viral load, tissue distribution, vascular permeability, and serum cytokine levels (TNF-alpha).
• Sequenced the D2S10 envelope protein to identify genetic determinants.

Main Results:

• D2S10-infected mice exhibited increased vascular permeability and early mortality, unlike parental DEN-infected mice.
• Infectious D2S10 virus was found in both neuronal and non-neuronal tissues.
• Elevated serum TNF-alpha levels were observed in D2S10-infected mice.
• Neutralizing TNF-alpha protected against D2S10-induced early death.
• Envelope protein sequence analysis suggested a specific region responsible for the D2S10 phenotype.

Conclusions:

• The D2S10 strain provides a more relevant animal model for severe DEN disease.
• TNF-alpha is implicated as a key mediator in severe DEN-induced disease in this murine model.
• This study offers mechanistic insights into DEN pathogenesis in vivo.