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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 D, Shirai K, Aoki K, Nagata N, Simantini DS, Kitaura K, Takamatsu Y, Gould E, Suzuki R, Morita K - PLoS ONE (2013)

Bottom Line: Our findings therefore provide the first evidence that TNF-α 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-α 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-α will be an important priority to enable the development of effective treatment strategies for Japanese encephalitis.

View Article: PubMed Central - PubMed

Affiliation: Department of Virology, Institute of Tropical Medicine, GCOE program, Leading Graduate School Program, Nagasaki University, Nagasaki, Nagasaki, Japan. hayasaka@nagasaki-u.ac.jp

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-α in the brains of severe cases. However, unexpectedly, the mortality rate of TNF-α KO mice was significantly increased compared with that of WT mice, indicating that TNF-α plays a protective role against fatal infection. Interestingly, there were no significant differences of viral load in the CNS between WT and TNF-α KO mice. However, exaggerated inflammatory responses were observed in the CNS of TNF-α KO mice. Although these observations were also obtained in IL-10 KO mice, the mortality and enhanced inflammatory responses were more pronounced in TNF-α KO mice. Our findings therefore provide the first evidence that TNF-α 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-α 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-α will be an important priority to enable the development of effective treatment strategies for Japanese encephalitis.

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Viral loads and cytokine levels in the brains of severe and mild cases of JaOArS982-infected mice.(A) Viral loads in the CNS of severe (weight loss: <0.75, n=8) and mild (weight loss: >0.90, n=24) cases of JaOArS982-infected B6 mice at 13 days pi. P: Mann Whitney test. (B) mRNA levels of TNF-α, IL-10, IFNγ, IL-2, IL-4 and IL-5 quantified by real-time PCR in the brain cortex of JaOArS982-infected B6 mice at 13 days pi. Uninfected group (U group, n=8), Severe group: S (n=8), Mild group with high viral load of >106 pfu/g of brain tissue: MH (n=11), Mild group with low viral load of <106 pfu/g of brain tissue: ML (n=13). P: Kruskal-Wallis test, p: Mann Whitney test.
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pone-0071643-g003: Viral loads and cytokine levels in the brains of severe and mild cases of JaOArS982-infected mice.(A) Viral loads in the CNS of severe (weight loss: <0.75, n=8) and mild (weight loss: >0.90, n=24) cases of JaOArS982-infected B6 mice at 13 days pi. P: Mann Whitney test. (B) mRNA levels of TNF-α, IL-10, IFNγ, IL-2, IL-4 and IL-5 quantified by real-time PCR in the brain cortex of JaOArS982-infected B6 mice at 13 days pi. Uninfected group (U group, n=8), Severe group: S (n=8), Mild group with high viral load of >106 pfu/g of brain tissue: MH (n=11), Mild group with low viral load of <106 pfu/g of brain tissue: ML (n=13). P: Kruskal-Wallis test, p: Mann Whitney test.

Mentions: We next compared the viral loads in the CNS between severe and mild DSG in JaOArS982-infected mice at 13 days pi. Viral loads in brain cortex, thalamus and brainstem but not cerebellum and spinal cord were significantly higher in severe DSG mice than in mild DSG (Figure 3A). However, in the brain cortex, the variance of virus titer in the mild DSG mice ranged from the minimal detection limit to 108 pfu/g of tissue, whereas all mice exhibited more than 106 pfu/g of tissue in the severe DSG (Figure 3A). These results imply that 45.8% (11/24) of mice in the mild DSG produced high viral loads similar to those in the severe DSG. Thus, it is likely that high viral infection alone is not a critical determinant of severe disease and additional factors contribute to the fatal encephalitis.


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

Hayasaka D, Shirai K, Aoki K, Nagata N, Simantini DS, Kitaura K, Takamatsu Y, Gould E, Suzuki R, Morita K - PLoS ONE (2013)

Viral loads and cytokine levels in the brains of severe and mild cases of JaOArS982-infected mice.(A) Viral loads in the CNS of severe (weight loss: <0.75, n=8) and mild (weight loss: >0.90, n=24) cases of JaOArS982-infected B6 mice at 13 days pi. P: Mann Whitney test. (B) mRNA levels of TNF-α, IL-10, IFNγ, IL-2, IL-4 and IL-5 quantified by real-time PCR in the brain cortex of JaOArS982-infected B6 mice at 13 days pi. Uninfected group (U group, n=8), Severe group: S (n=8), Mild group with high viral load of >106 pfu/g of brain tissue: MH (n=11), Mild group with low viral load of <106 pfu/g of brain tissue: ML (n=13). P: Kruskal-Wallis test, p: Mann Whitney test.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3733918&req=5

pone-0071643-g003: Viral loads and cytokine levels in the brains of severe and mild cases of JaOArS982-infected mice.(A) Viral loads in the CNS of severe (weight loss: <0.75, n=8) and mild (weight loss: >0.90, n=24) cases of JaOArS982-infected B6 mice at 13 days pi. P: Mann Whitney test. (B) mRNA levels of TNF-α, IL-10, IFNγ, IL-2, IL-4 and IL-5 quantified by real-time PCR in the brain cortex of JaOArS982-infected B6 mice at 13 days pi. Uninfected group (U group, n=8), Severe group: S (n=8), Mild group with high viral load of >106 pfu/g of brain tissue: MH (n=11), Mild group with low viral load of <106 pfu/g of brain tissue: ML (n=13). P: Kruskal-Wallis test, p: Mann Whitney test.
Mentions: We next compared the viral loads in the CNS between severe and mild DSG in JaOArS982-infected mice at 13 days pi. Viral loads in brain cortex, thalamus and brainstem but not cerebellum and spinal cord were significantly higher in severe DSG mice than in mild DSG (Figure 3A). However, in the brain cortex, the variance of virus titer in the mild DSG mice ranged from the minimal detection limit to 108 pfu/g of tissue, whereas all mice exhibited more than 106 pfu/g of tissue in the severe DSG (Figure 3A). These results imply that 45.8% (11/24) of mice in the mild DSG produced high viral loads similar to those in the severe DSG. Thus, it is likely that high viral infection alone is not a critical determinant of severe disease and additional factors contribute to the fatal encephalitis.

Bottom Line: Our findings therefore provide the first evidence that TNF-α 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-α 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-α will be an important priority to enable the development of effective treatment strategies for Japanese encephalitis.

View Article: PubMed Central - PubMed

Affiliation: Department of Virology, Institute of Tropical Medicine, GCOE program, Leading Graduate School Program, Nagasaki University, Nagasaki, Nagasaki, Japan. hayasaka@nagasaki-u.ac.jp

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-α in the brains of severe cases. However, unexpectedly, the mortality rate of TNF-α KO mice was significantly increased compared with that of WT mice, indicating that TNF-α plays a protective role against fatal infection. Interestingly, there were no significant differences of viral load in the CNS between WT and TNF-α KO mice. However, exaggerated inflammatory responses were observed in the CNS of TNF-α KO mice. Although these observations were also obtained in IL-10 KO mice, the mortality and enhanced inflammatory responses were more pronounced in TNF-α KO mice. Our findings therefore provide the first evidence that TNF-α 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-α 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-α will be an important priority to enable the development of effective treatment strategies for Japanese encephalitis.

Show MeSH
Related in: MedlinePlus