title: Enterovirus 71 infection increases expression of interferon-gamma-inducible protein 10 which protects mice by reducing viral burden in multiple tissues.
abstract: Enterovirus 71 (EV71) infection has induced fatal encephalitis in thousands of young children in the Asia-Pacific region over the last decade. EV71 infection continues to cause serious problems in areas with outbreaks, because vaccines and antiviral therapies are not available. Lymphocytes are present in the brains of infected patients and mice, and they protect mice from infection by decreasing the viral burden. The chemokines responsible for recruiting lymphocytes to infected organs are yet to be identified. Among the lymphocyte chemokines detected, high levels of interferon-gamma-inducible protein-10 (IP-10) are found in the plasma and cerebral spinal fluid of patients with brainstem encephalitis as compared with the levels of a monokine induced by gamma interferon (Mig). Using a murine model to investigate the induction of IP-10 by EV71 infection, we observed that EV71 infection significantly enhanced IP-10 protein expression in the serum and brain, with kinetics similar to viral titres in the blood and brain. Brain neurons of infected mice expressed IP-10. Using wild-type mice and IP-10 gene knockout mice to investigate the role of IP-10 in EV71 infection, we found that IP-10 deficiency significantly reduced levels of Mig in serum, and levels of gamma interferon and the number of CD8 T cells in the mouse brain. Absence of IP-10 significantly increased the mortality of infected mice by 45%, with slow virus clearance in several vital tissues. Our observations are consistent with a model where EV71 infection boosts IP-10 expression to increase gamma interferon and Mig levels, infiltration of CD8 T cells, virus clearance in tissues and the survival of mice.
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan, ROC.
authors.forename: Fang-Hsiu
authors.initials: FH
authors.lastname: Shen
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan, ROC.
authors.forename: Chia-Chun
authors.initials: CC
authors.lastname: Tsai
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan, ROC.
authors.forename: Li-Chiu
authors.initials: LC
authors.lastname: Wang
authors.affiliation: Department of Pathology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan, ROC.
authors.forename: Kung-Chao
authors.initials: KC
authors.lastname: Chang
authors.affiliation: Statistical Analysis Laboratory, Institute of Education, College of Social Sciences, National Cheng Kung University, Tainan 701, Taiwan, ROC.
authors.forename: Yuk-Ying
authors.initials: YY
authors.lastname: Tung
authors.affiliation: National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan 701, Taiwan, ROC.
authors.forename: Ih-Jen
authors.initials: IJ
authors.lastname: Su
authors.affiliation: Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan 701, Taiwan, ROC.|Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan, ROC.|Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan, ROC.
authors.forename: Shun-Hua
authors.initials: SH
authors.lastname: Chen
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D054357:Chemokine CXCL10 / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D018792:Encephalitis, Viral / Q000821:virology*; D004770:Enterovirus / Q000276:immunology / Q000502:physiology*; D004769:Enterovirus Infections / Q000276:immunology / Q000821:virology*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013154:Spleen / Q000276:immunology / Q000473:pathology / Q000821:virology; D013601:T-Lymphocytes / Q000276:immunology; D019562:Viral Load
chemical_list: D054357:Chemokine CXCL10; D007371:Interferon-gamma