A lethal DENV-2 wild-type mouse model for mutagenesis investigations

Area of Science:

• Virology
• Immunology
• Infectious Diseases

Background:

• Existing dengue virus (DENV) mouse models like AG129 are costly and have limitations due to absent interferon-gamma (IFN-γ) signaling.
• Wild-type mouse models typically show mild DENV symptoms, hindering research into severe disease and antiviral efficacy.
• There is a need for cost-effective, labor-efficient mouse models for DENV research.

Purpose of the Study:

• To develop a lethal, wild-type mouse model for studying DENV-2 infection.
• To create a viable model for testing antiviral medications and evaluating viral mutations.
• To overcome the limitations of existing immunodeficient models for DENV research.

Main Methods:

• Developed a lethal DENV-2 365 strain infection model in C57BL/6 wild-type mice.
• Blocked the type I interferon receptor prior to viral challenge to restore immune response later in infection.
• Utilized the model to assess an adaptable NS2A protein mutation common to Zika virus and DENV-2.

Main Results:

• The developed model exhibited severe DENV symptoms, including weight loss, high viremia, elevated cytokines, and vascular leakage.
• Pathological changes were observed in multiple organs (brain, kidney, liver, spleen), alongside severe central nervous system symptoms.
• Achieved 100% mortality in the infected wild-type mice, demonstrating a lethal outcome.

Conclusions:

• Introduced a novel, lethal wild-type mouse model for DENV research.
• This model serves as a valuable alternative to expensive immunodeficient models.
• Provides a robust platform for investigating viral mutations and testing antiviral interventions.