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Type-I interferon response affects an inoculation dose-independent mortality in mice following Japanese encephalitis
Kotaro Aoki, Satoshi Shimada, Dash Sima Simantini
1Department of Virology, Institute of Tropical Medicine, GCOE program, Leading Graduate School Program, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan. hayasaka@nagasaki-u.ac.jp.
Background:
The laboratory mouse model is commonly employed to study the pathogenesis of encephalitic flaviviruses such as Japanese encephalitis virus (JEV). However, it is known that some strains of these viruses do not elicit a typical mortality dose response curve from this organism after peripheral infection and the reason for it has not yet been fully understood. It is suggested that induction of more vigorous Type-I IFN (IFN-I) response might control early virus dissemination following increasing infectious challenge doses of the virus. Thus, the objective of this study was to examine this suggested role of IFN-I in the mortality of mice infected with various doses of JEV.
Methods:
Inbred 129 mice and their IFNAR KO (A129) mice were subcutaneously inoculated with 100, 102, 104 or 106 pfu of JaOArS982 strain of JEV. Mice were weighed daily and observed for clinical signs. Virus titers in the brains and spleens of JEV-infected mice were determined by plaque forming assays. The upregulated mRNA levels of genes related to IFN-I response of mice were examined by real-time PCR.
Results:
The mortality rates of 129 mice infected with JaOArS982 did not significantly increase despite the increase in inoculation dose and no significant difference of viral loads was observed between their brains. However, there was clear elevation of the mRNA levels of interferon regulatory factor (IRF)3, IRF7, IRF9, MDA5 and RIG-I at 24 hours post-infection depending on the inoculation dose. In A129 mice, length of survival days and the viral loads of spleen and brain were observed to be inoculation dose-dependent.
Conclusions:
From these results, it is suggested that early IFN-I response elicited by high inoculation doses of JEV provides an anti-viral effect during the early phase of infection. Accordingly, virus replication is counteracted by IFN-I response at each increasing inoculation dose resulting in the interference of impending severe disease course or fatal outcome; hence, this might explain the inoculation dose-independent mortality in mice caused by Japanese encephalitis virus.
Insights
Japanese encephalitis virus (JEV) infection in mice shows dose-independent mortality due to a strong early Type-I Interferon (IFN-I) response. This IFN-I response effectively controls virus replication, preventing severe outcomes even with higher JEV challenge doses.
Area of Science:
- Virology
- Immunology
- Infectious Diseases
Background:
- Laboratory mice are crucial for studying Japanese encephalitis virus (JEV) pathogenesis.
- However, JEV strains sometimes lack a clear mortality dose-response in mice, with the underlying mechanisms unclear.
- A robust Type-I Interferon (IFN-I) response may limit early viral spread, influencing mortality.
Purpose of the Study:
- To investigate the role of IFN-I in JEV-induced mortality in mice challenged with varying virus doses.
- To understand why some JEV infections do not show a dose-dependent mortality curve.
Main Methods:
- Inbred 129 mice and IFNAR knockout (A129) mice were infected with 100, 102, 104, or 106 pfu of JEV.
- Mice were monitored for clinical signs and weight changes.
- Viral loads in brains and spleens were quantified using plaque assays, and IFN-I-related gene expression was analyzed via real-time PCR.
Main Results:
- 129 mice exhibited dose-independent mortality and similar brain viral loads regardless of JEV inoculation dose.
- Elevated mRNA levels of interferon regulatory factors (IRF3, IRF7, IRF9), MDA5, and RIG-I were observed in 129 mice post-infection, correlating with inoculation dose.
- A129 mice showed survival days and viral loads in spleen and brain that were dependent on the JEV inoculation dose.
Conclusions:
- Early IFN-I responses triggered by high JEV doses confer antiviral protection during initial infection.
- IFN-I counteracts JEV replication at increasing doses, mitigating severe disease and mortality.
- This IFN-I-mediated control mechanism likely explains the observed JEV dose-independent mortality in mice.
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