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A Murine Model of Dengue Virus-induced Acute Viral Encephalitis-like Disease
Published on: April 28, 2019
Mice with different susceptibility to Japanese encephalitis virus infection show selective neutralizing antibody
1Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institute for Biological Sciences, Shanghai, China.
Background:
Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus that causes public health problems in Asian countries. Only a limited number of JEV-infected individuals show symptoms and develop severe encephalitis, indicating host-dependent susceptibilities.
Methodology/Principal Findings:
C3H/HeN and DBA/2 mice, which exhibit different mortalities when infected by intraperitoneal inoculation with JEV, were used as experimental models to compare viral pathogenesis and host responses. One hundred infectious virus particles killed 95% of C3H/HeN mice whereas only 40% of DBA/2 mice died. JEV RNA was detected with similar low levels in peripheral lymphoid organs and in the sera of both mouse strains. High levels of viral and cytokine RNA were observed simultaneously in the brains of C3H/HeN and DBA/2 mice starting on days 6 and 9 post-infection, respectively. The kinetics of the cytokines in sera correlated with the viral replication in the brain. Significantly earlier and higher titers of neutralizing antibodies were detected in the DBA/2 strain. Primary embryonic fibroblasts, bone marrow-derived dendritic cells and macrophages from the two mouse strains were cultured. Fibroblasts displayed similar JEV replication abilities, whereas DBA/2-derived myeloid antigen-presenting cells had lower viral infectivity and production compared to the C3H/HeN-derived cells.
Conclusions/Significance:
Mice with different susceptibilities to JEV neuroinvasion did not show changes in viral tropism and host innate immune responses prior to viral entry into the central nervous system. However, early and high neutralizing antibody responses may be crucial for preventing viral neuroinvasion and host fatality. In addition, low permissiveness of myeloid dendritic cells and macrophages to JEV infection in vitro may be elements associated with late and decreased mouse neuroinvasion.
Insights
Host immune responses influence Japanese encephalitis virus (JEV) severity. Early neutralizing antibodies and less permissive myeloid cells in DBA/2 mice may prevent JEV neuroinvasion and reduce fatality.
Area of Science:
- Virology
- Immunology
- Neuroscience
Background:
- Japanese encephalitis virus (JEV) poses a significant public health threat in Asia.
- Host susceptibility determines JEV-induced encephalitis severity, with limited individuals developing severe symptoms.
Purpose of the Study:
- To compare JEV pathogenesis and host responses in mouse strains with differing susceptibilities.
- To investigate the role of immune responses and cellular permissiveness in JEV neuroinvasion.
Main Methods:
- Infection of C3H/HeN and DBA/2 mice with JEV.
- Quantification of viral RNA in lymphoid organs, sera, and brains.
- Analysis of cytokine and neutralizing antibody kinetics.
- In vitro culture and infection of fibroblasts, dendritic cells, and macrophages.
Main Results:
- DBA/2 mice exhibited lower mortality than C3H/HeN mice despite similar viral loads in peripheral organs.
- High viral and cytokine RNA levels were detected in the brains of both strains post-infection.
- DBA/2 mice developed significantly earlier and higher titers of neutralizing antibodies.
- DBA/2-derived myeloid cells showed lower JEV infectivity and production in vitro compared to C3H/HeN cells.
Conclusions:
- Host innate immune responses prior to CNS entry do not explain differential JEV susceptibility.
- Early and robust neutralizing antibody responses are critical for preventing JEV neuroinvasion and fatality.
- Reduced permissiveness of myeloid dendritic cells and macrophages to JEV in vitro may contribute to decreased neuroinvasion.
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