Establishment of human SCARB2 receptor transgenic mouse model for enterovirus 71 infection

博士 === 國立清華大學 === 分子醫學研究所 === 102 === Enterovirus 71 (EV-71) is a caustic agent for hand, foot, and mouth disease (HFMD) in young children, but in some severe cases, neurological disorders with high mortality rates had been found. To date, epidemic outbreaks of EV71 have been reported mainly in Sout...

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Bibliographic Details
Main Authors: Lin, Yi-Wen, 林怡玟
Other Authors: 張晃猷
Format: Others
Language:en_US
Published: 2013
Online Access:http://ndltd.ncl.edu.tw/handle/69853725264084001643
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Summary:博士 === 國立清華大學 === 分子醫學研究所 === 102 === Enterovirus 71 (EV-71) is a caustic agent for hand, foot, and mouth disease (HFMD) in young children, but in some severe cases, neurological disorders with high mortality rates had been found. To date, epidemic outbreaks of EV71 have been reported mainly in Southeast and East Asia including Taiwan, Malaysia, Singapore, Japan, and China. The control of EV71 infection through public health interventions remains ineffectual and the treatments are unmet. Thus, study of the mechanisms of EV71 entry and it’s pathogenesis including HFMD and central nerve system (CNS) syndromes to develop a useful effective medications or prophylactic vaccines is important. Recently two EV71 receptors, human scavenger receptor class B, member 2 (SCARB2) expressed in the most of human tissues and P-selectin glycoprotein ligand-1 (PSGL-1) which restrictively expressed in the leukocytes, had been identified. Therefore, we chose human SCARB2 as a target for my research. In order to study the mechanism of EV71 infection, we made a human-SCARB2-transgenic mice fibroblast cell line, NIH3T3-SCARB2 cells, to investigate the pathway of EV71 entry. We had demonstrated that the EV71 entry into its host cells through a clathrin and dynamin-mediated but not caveolae-mediated endocytosis pathway. This pathway is a human hSCARB2-dependence. Following to understand the role of human SCARB2 in EV71-mediated diseases, we established a transgenic animal expressing human SCARB2. We found that this transgenic animal (hSCARB2-Tg mice) was highly susceptible to natural EV71 infection. The diseases observed in B4 or B5 genotype of EV71-infected hSCARB2-Tg mice was human-like HFMD syndromes and CNS dysfunction. Severe to death of CNS-like limb paralysis was observed in C2 and C4 of EV71 and even CVA16 infected hSCARB2-Tg mice. Viral loads associated with proinflammatory chemokines secretion were correlated with EV71-mediated pathogenesis. Also, we applied this animal model to evaluate the protective efficacy of EV71 neutralizing antibody N3 and potential anti-viral drug 17-AAG. Both of them can protect mice from EV71-induced illness and survive. These results implied that hSCARB2-Tg mouse is a reliable model for studying the EV71 pathogenicity in vivo. Understanding of the mechanisms of EV71 infections as well as infectious model establishment provide evidences to accelerate anti-EV71 medications development and serve as a platform to evaluate the efficacy of the vaccine candidates and antiviral drugs.