title: Immunodeficient mouse models with different disease profiles by in vivo infection with the same clinical isolate of enterovirus 71.
abstract: Like poliovirus infection, severe infection with enterovirus 71 (EV71) can cause neuropathology. Unlike poliovirus, EV71 is often associated with hand-foot-and-mouth disease (HFMD). Here we established three mouse models for experimental infection with the same clinical isolate of EV71. The NOD/SCID mouse model is unique for the development of skin rash, an HFMD-like symptom. While the NOD/SCID mice developed limb paralysis and death at near-100% efficiency, the gamma interferon receptor knockout (ifngr KO) and stat-1 knockout mice exhibited paralysis and death rates near 78% and 30%, respectively. Productive infection with EV71 depends on the viral dose, host age, and inoculation route. Levels of infectious EV71, and levels of VP1-specific RNA and protein in muscle, brain, and spinal cord, were compared side by side between the NOD/SCID and stat-1 knockout models before, during, and after disease onset. Spleen fibrosis and muscle degeneration are common in the NOD/SCID and stat-1 knockout models. The main differences between these two models include their disease manifestations and cytokine/chemokine profiles. The pathology of the NOD/SCID model includes (i) inflammation and expression of viral VP1 antigen in muscle, (ii) increased neutrophil levels and decreased eosinophil and lymphocyte levels, and (iii) hair loss and skin rash. The characteristic pathology of the stat-1 knockout model includes (i) a strong tropism of EV71 for the central nervous system, (ii) detection of VP1 protein in the Purkinje layer of cerebellar cortex, pons, brain stem, and spinal cord, (iii) amplification of microglial cells, and (iv) dystrophy of intestinal villi. Our comparative studies on these new models with oral or intraperitoneal (i.p.) infection underscored the contribution of host immunity, including the gamma interferon receptor, to EV71 pathogenesis.
  
  
  OBJECTIVE
  In the past decade, enterovirus 71 (EV71) has emerged as a major threat to public health in the Asia-Pacific region. Disease manifestations include subclinical infection, common-cold-like syndromes, hand-foot-and-mouth disease (HFMD), uncomplicated brain stem encephalitis, severe dysregulation of the autonomic nerve system, fatal pulmonary edema, and cardiopulmonary collapse. To date, no effective vaccine or treatment is available. A user-friendly and widely accessible animal model for researching EV71 infection and pathogenesis is urgently needed by the global community, both in academia and in industry.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Chun-Che
authors.initials: CC
authors.lastname: Liao
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan Taiwan International Graduate Program (TIGP) in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: An-Ting
authors.initials: AT
authors.lastname: Liou
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Ya-Shu
authors.initials: YS
authors.lastname: Chang
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Szu-Yao
authors.initials: SY
authors.lastname: Wu
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chih-Shin
authors.initials: CS
authors.lastname: Chang
authors.affiliation: Institute of Immunology, National Taiwan University, Taipei, Taiwan.
authors.forename: Chien-Kuo
authors.initials: CK
authors.lastname: Lee
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
authors.forename: John T
authors.initials: JT
authors.lastname: Kung
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Pang-Hsien
authors.initials: PH
authors.lastname: Tu
authors.affiliation: Section of Clinical Virology and Molecular Diagnosis, Department of Laboratory Medicine, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Ya-Yen
authors.initials: YY
authors.lastname: Yu
authors.affiliation: Section of Clinical Virology and Molecular Diagnosis, Department of Laboratory Medicine, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Chi-Yung
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Section of Clinical Virology and Molecular Diagnosis, Department of Laboratory Medicine, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Jen-Shiou
authors.initials: JS
authors.lastname: Lin
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan Taiwan International Graduate Program (TIGP) in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan cshih@ibms.sinica.edu.tw.
authors.forename: Chiaho
authors.initials: C
authors.lastname: Shih
mesh_terms: D000818:Animals; D001921:Brain / Q000821:virology; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D029821:Enterovirus A, Human / Q000254:growth & development*; D005355:Fibrosis / Q000473:pathology; D006232:Hand, Foot and Mouth Disease / Q000473:pathology* / Q000821:virology*; D007962:Leukocytes / Q000276:immunology; D018345:Mice, Knockout; D016513:Mice, SCID; D009132:Muscles / Q000473:pathology / Q000821:virology; D013116:Spinal Cord / Q000821:virology; D013154:Spleen / Q000473:pathology; D016019:Survival Analysis; D019562:Viral Load
chemical_list: D016207:Cytokines