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Updated: Dec 24, 2025
A Murine Model of Dengue Virus-induced Acute Viral Encephalitis-like Disease
Published on: April 28, 2019
Route of inoculation and mosquito vector exposure modulate dengue virus replication kinetics and immune responses in
Michael K McCracken1, Gregory D Gromowski1, Lindsey S Garver2
1Viral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
Abstract:
Dengue virus (DENV) is transmitted by infectious mosquitoes during blood-feeding via saliva containing biologically-active proteins. Here, we examined the effect of varying DENV infection modality in rhesus macaques in order to improve the DENV nonhuman primate (NHP) challenge model. NHPs were exposed to DENV-1 via subcutaneous or intradermal inoculation of virus only, intradermal inoculation of virus and salivary gland extract, or infectious mosquito feeding. The infectious mosquito feeding group exhibited delayed onset of viremia, greater viral loads, and altered clinical and immune responses compared to other groups. After 15 months, NHPs in the subcutaneous and infectious mosquito feeding groups were re-exposed to either DENV-1 or DENV-2. Viral replication and neutralizing antibody following homologous challenge were suggestive of sterilizing immunity, whereas heterologous challenge resulted in productive, yet reduced, DENV-2 replication and boosted neutralizing antibody. These results show that a more transmission-relevant exposure modality resulted in viral replication closer to that observed in humans.
Insights
Infectious mosquito feeding in rhesus macaques better mimics human dengue virus (DENV) infection. This improved challenge model shows distinct viral loads and immune responses, crucial for developing effective DENV vaccines.
Area of Science:
- Virology
- Immunology
- Infectious Diseases
Background:
- Dengue virus (DENV) transmission occurs via mosquito saliva containing bioactive proteins.
- Existing nonhuman primate (NHP) models for DENV challenge may not fully replicate natural transmission dynamics.
Purpose of the Study:
- To optimize the DENV NHP challenge model by evaluating different infection modalities.
- To compare the effects of subcutaneous, intradermal inoculation, and infectious mosquito feeding on DENV infection in rhesus macaques.
Main Methods:
- Rhesus macaques were exposed to DENV-1 through various routes: subcutaneous inoculation, intradermal inoculation (virus only or with salivary gland extract), and infectious mosquito feeding.
- Animals were subsequently re-exposed to DENV-1 or DENV-2 after 15 months to assess homologous and heterologous immunity.
- Viral loads, clinical signs, immune responses, and neutralizing antibody titers were monitored.
Main Results:
- Infectious mosquito feeding resulted in delayed viremia, higher viral loads, and altered clinical/immune responses compared to inoculation methods.
- Homologous re-challenge (DENV-1) suggested sterilizing immunity with minimal viral replication and high neutralizing antibodies.
- Heterologous re-challenge (DENV-2) showed reduced DENV-2 replication and boosted neutralizing antibody responses.
Conclusions:
- Infectious mosquito feeding represents a more transmission-relevant exposure modality for DENV in NHPs.
- This optimized model yields viral replication patterns more closely resembling human dengue infections.
- The findings support the use of this enhanced NHP model for preclinical evaluation of DENV vaccines and therapeutics.
