Immunodeficient mouse models with different disease profiles by in vivo infection with the same clinical isolate of enterovirus 71
Journal
Journal of Virology
Journal Volume
88
Journal Issue
21
Pages
12485-12499
Date Issued
2014
Author(s)
Chiu, HM
Liao, Chun-Che
Chang, CY
Liou, An-Ting
Chang, Ya-Shu
Chen, CC
Wu, Szu-Yao
Lee, YC
Wu, MS
Chang, Chih-Shin
Lin, JT
Shun, CT
Kung, John T.
Wang, HP.
Tu, Pang-Hsien
Yu, Ya-Yen
Lin, Chi-Yung
Lin, Jen-Shiou
Shih, Chiaho
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. ? 2014, American Society for Microbiology.
SDGs
Other Subjects
gamma interferon receptor; protein VP1; cytokine; animal cell; animal experiment; animal model; animal tissue; Article; brain stem; central nervous system; cerebellum cortex; controlled study; death; Enterovirus 71; Enterovirus infection; eosinophil count; experimental infection; hair loss; human; human cell; immune response; in vivo study; inoculation; leg disease; limb paralysis; lymphocyte count; microglia; microvillus; mouse; mouth infection; muscle; muscle atrophy; myositis; neutrophil count; nonhuman; paralysis; pons; protein expression; Purkinje cell; rash; spinal cord; spleen disease; spleen fibrosis; viral tropism; virus replication; animal; blood; brain; disease model; Enterovirus A; fibrosis; growth, development and aging; hand foot and mouth disease; immunology; knockout mouse; leukocyte; pathology; SCID mouse; spleen; survival; virology; virus load; Animals; Brain; Cytokines; Disease Models, Animal; Enterovirus A, Human; Fibrosis; Hand, Foot and Mouth Disease; Leukocytes; Mice, Knockout; Mice, SCID; Muscles; Spinal Cord; Spleen; Survival Analysis; Viral Load
Type
journal article