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TNF-? acts as an immunoregulator in the mouse brain by reducing the incidence of severe disease following Japanese encephalitis virus infection.

ABSTRACT: Japanese encephalitis virus (JEV) causes acute central nervous system (CNS) disease in humans, in whom the clinical symptoms vary from febrile illness to meningitis and encephalitis. However, the mechanism of severe encephalitis has not been fully elucidated. In this study, using a mouse model, we investigated the pathogenetic mechanisms that correlate with fatal JEV infection. Following extraneural infection with the JaOArS982 strain of JEV, infected mice exhibited clinical signs ranging from mild to fatal outcome. Comparison of the pathogenetic response between severe and mild cases of JaOArS982-infected mice revealed increased levels of TNF-? in the brains of severe cases. However, unexpectedly, the mortality rate of TNF-? KO mice was significantly increased compared with that of WT mice, indicating that TNF-? plays a protective role against fatal infection. Interestingly, there were no significant differences of viral load in the CNS between WT and TNF-? KO mice. However, exaggerated inflammatory responses were observed in the CNS of TNF-? KO mice. Although these observations were also obtained in IL-10 KO mice, the mortality and enhanced inflammatory responses were more pronounced in TNF-? KO mice. Our findings therefore provide the first evidence that TNF-? has an immunoregulatory effect on pro-inflammatory cytokines in the CNS during JEV infection and consequently protects the animals from fatal disease. Thus, we propose that the increased level of TNF-? in severe cases was the result of severe disease, and secondly that immunopathological effects contribute to severe neuronal degeneration resulting in fatal disease. In future, further elucidation of the immunoregulatory mechanism of TNF-? will be an important priority to enable the development of effective treatment strategies for Japanese encephalitis.

SUBMITTER: Hayasaka D

PROVIDER: S-EPMC3733918 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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TNF-α acts as an immunoregulator in the mouse brain by reducing the incidence of severe disease following Japanese encephalitis virus infection.

Hayasaka Daisuke D Shirai Kenji K Aoki Kotaro K Nagata Noriyo N Simantini Dash Sima DS Kitaura Kazutaka K Takamatsu Yuki Y Gould Ernest E Suzuki Ryuji R Morita Kouichi K

PloS one 20130805 8

Japanese encephalitis virus (JEV) causes acute central nervous system (CNS) disease in humans, in whom the clinical symptoms vary from febrile illness to meningitis and encephalitis. However, the mechanism of severe encephalitis has not been fully elucidated. In this study, using a mouse model, we investigated the pathogenetic mechanisms that correlate with fatal JEV infection. Following extraneural infection with the JaOArS982 strain of JEV, infected mice exhibited clinical signs ranging from m ...[more]

PMID: 23940775

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Project description:BACKGROUND:Japanese encephalitis (JE) is a leading cause of childhood viral encephalitis both at global level and in China. Vaccination is recommended as a key strategy to control JE. In China most JE cases have been reported in southwest provinces, which include Yunnan. In this study, we quantify the epidemiological shift of JE in Yunnan Province from 2005 to 2017, covering before and after the introduction of JE vaccination into routine Expanded Program on Immunization (EPI) in 2007. METHODS:We used routinely collected data in the case-based JE surveillance system from 2005 through 2017 in Yunnan. Cases were reported from hospital and county-level Centers for Disease Control in line with the National JE Surveillance Guideline. Epidemiological data were extracted, analysed and presented in appropriate ways. Immunization coverage was estimated from actual JE doses administered and new births for each year. RESULTS:A total 4780 JE cases (3077 laboratory-confirmed, 1266 clinical and 437 suspected) were reported in the study period. Incidence of JE (per 100?000 population) increased from 0.95 in 2005 to 1.69 in 2007. With increase in vaccination coverage, incidence rates decreased steadily from 1.16 in 2009 to 0.17 in 2017. However, seasonality remained similar across the years, peaking in June-September. Banna (bordering Myanmar and Laos), Dehong (bordering Myanmar), and Zhaotong (an inland prefecture) had the highest incidence rates of 2.3, 1.9, and 1.6, respectively. 97% of all cases were among local residents. As vaccination coverage increased (and incidence decreased), proportion of JE cases among children <?10?years old decreased from 70% in 2005 to 32% in 2017, while that among adults ?20?years old increased from 12 to 48%. There were a large number of JE cases with unknown treatment outcomes, especially in the earlier years of the surveillance system. CONCLUSIONS:The 13-year JE surveillance data in Yunnan Province showed dramatic decrease of total incidence and a shift from children to adults. Improving vaccination coverage, including access to adults at risk, and strengthening the JE surveillance system is needed to further control or eliminate JE in the province.

Project description:BackgroundTo identify potential environmental drivers of Japanese Encephalitis virus (JE) transmission in Nepal, we conducted an ecological study to determine the spatial association between 2005 Nepal JE incidence, and climate, agricultural, and land-cover variables at district level.MethodsDistrict-level data on JE cases were examined using Local Indicators of Spatial Association (LISA) analysis to identify spatial clusters from 2004 to 2008 and 2005 data was used to fit a spatial lag regression model with climate, agriculture and land-cover variables.ResultsPrior to 2006, there was a single large cluster of JE cases located in the Far-West and Mid-West terai regions of Nepal. After 2005, the distribution of JE cases in Nepal shifted with clusters found in the central hill areas. JE incidence during the 2005 epidemic had a stronger association with May mean monthly temperature and April mean monthly total precipitation compared to mean annual temperature and precipitation. A parsimonious spatial lag regression model revealed, 1) a significant negative relationship between JE incidence and April precipitation, 2) a significant positive relationship between JE incidence and percentage of irrigated land 3) a non-significant negative relationship between JE incidence and percentage of grassland cover, and 4) a unimodal non-significant relationship between JE Incidence and pig-to-human ratio.ConclusionJE cases clustered in the terai prior to 2006 where it seemed to shift to the Kathmandu region in subsequent years. The spatial pattern of JE cases during the 2005 epidemic in Nepal was significantly associated with low precipitation and the percentage of irrigated land. Despite the availability of an effective vaccine, it is still important to understand environmental drivers of JEV transmission since the enzootic cycle of JEV transmission is not likely to be totally interrupted. Understanding the spatial dynamics of JE risk factors may be useful in providing important information to the Nepal immunization program.

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TNF-? acts as an immunoregulator in the mouse brain by reducing the incidence of severe disease following Japanese encephalitis virus infection.

Publications

TNF-α acts as an immunoregulator in the mouse brain by reducing the incidence of severe disease following Japanese encephalitis virus infection.

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