腸病毒71型（EV71）是一種感染幼兒後主要會引起手足口症的病毒，在較嚴重的病例中，甚至會引發神經病變(例如腦膜炎)進而導致高死亡率的發生。及至今日，EV71疫情爆發主要分布在東南亞及南亞地區，包括了台灣、馬來西亞、新加坡、日本和中國大陸等。然而，以公共衛生宣導來控制腸病毒傳播的成效仍顯不足。因此，研究EV71感染細胞的途徑以及其誘發的病理症狀，包括手足口症和神經病變症狀，藉以發展出有效的治療型藥物或是預防型的疫苗，來控制腸病毒疫情至關重要。最近有兩篇關於腸病毒受器的論文發表，其一是人類scavenger receptor class B, member 2 (human SCARB2, hSCARB2)，它在全身多數的體細胞都有表現；其二是P-selectin glycoprotein ligand-1 (PSGL-1)，主要表現在白血球上。因此，我們選擇了hSCARB2做為研究的主軸。為了要找出EV71感染細胞的機轉，我們建構了有表現hSCARB2 蛋白的老鼠纖維母細胞株NIH3T3-SCARB2細胞，結果發現腸病毒藉由hSCARB2感染宿主細胞主要是由clathrin和dynamin調控的胞吞作用，且caveolae並未參與。接下來為了要找出hSCARB2在EV71感染宿主中扮演的角色，我們建構了表現hSCARB2的基因轉殖鼠（hSCARB2-Tg mice）進行EV71感染試驗。結果發現此種基因轉殖鼠的確能夠被EV71感染。以B4或B5基因型的EV71感染基因轉殖鼠發生的症狀類似於人類手足口症，且部分帶有輕微的神經病變症狀；而嚴重的神經病變導致跛足、甚至死亡可以在C2、C4和克沙奇16型感染此基因轉殖鼠後觀察到。病毒量和發炎相關細胞激素與EV71誘發的症狀嚴重度有高度相關。同時，我們也將此動物模式應用在測試EV71中和性抗體N3和潛在抗EV71藥物17-AAG對EV71感染後的保護效力。結果顯示兩者均能有效降低EV71感染後引發之病理症狀及提高存活率。根據以上結果可知hSCARB2-Tg mice是一種可被EV71感染及誘發相關病症，並能應用於觀察及研究的可信賴的動物模式。瞭解了EV71的感染機制和感染動物模式的建立後，除了可根據EV71感染機制研發治療藥物，且動物模式可成為評估EV71疫苗效力和治療藥物效果的測試平台，期望能夠加速對抗腸病毒的醫療發展腳步，使更多孩童受惠

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.

1. Schmidt NJ, Lennette EH, Ho HH. An apparently new enterovirus isolated from patients with disease of the central nervous system. The Journal of infectious diseases. 1974;129:304-309
2. Miller MJ. Viral taxonomy. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 1997;25:18-20
3. Brown BA, Pallansch MA. Complete nucleotide sequence of enterovirus 71 is distinct from poliovirus. Virus research. 1995;39:195-205
4. Brown BA, Oberste MS, Alexander JP, Jr., Kennett ML, Pallansch MA. Molecular epidemiology and evolution of enterovirus 71 strains isolated from 1970 to 1998. Journal of virology. 1999;73:9969-9975
5. Shih SR, Stollar V, Li ML. Host factors in enterovirus 71 replication. Journal of virology. 2011;85:9658-9666
6. Buenz EJ, Howe CL. Picornaviruses and cell death. Trends in microbiology. 2006;14:28-36
7. Ke YY, Chen YC, Lin TH. Structure of the virus capsid protein vp1 of enterovirus 71 predicted by some homology modeling and molecular docking studies. Journal of computational chemistry. 2006;27:1556-1570
8. Chan YF, Sam IC, AbuBakar S. Phylogenetic designation of enterovirus 71 genotypes and subgenotypes using complete genome sequences. Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases. 2010;10:404-412
9. Chen X, Zhang Q, Li J, Cao W, Zhang JX, Zhang L, Zhang W, Shao ZJ, Yan Y. Analysis of recombination and natural selection in human enterovirus 71. Virology. 2010;398:251-261
10. Li ML, Hsu TA, Chen TC, Chang SC, Lee JC, Chen CC, Stollar V, Shih SR. The 3c protease activity of enterovirus 71 induces human neural cell apoptosis. Virology. 2002;293:386-395
11. Solomon T, Lewthwaite P, Perera D, Cardosa MJ, McMinn P, Ooi MH. Virology, epidemiology, pathogenesis, and control of enterovirus 71. The Lancet infectious diseases. 2010;10:778-790
12. Ishimaru Y, Nakano S, Yamaoka K, Takami S. Outbreaks of hand, foot, and mouth disease by enterovirus 71. High incidence of complication disorders of central nervous system. Archives of disease in childhood. 1980;55:583-588
13. Gilbert GL, Dickson KE, Waters MJ, Kennett ML, Land SA, Sneddon M. Outbreak of enterovirus 71 infection in victoria, australia, with a high incidence of neurologic involvement. The Pediatric infectious disease journal. 1988;7:484-488
14. Kennett ML, Birch CJ, Lewis FA, Yung AP, Locarnini SA, Gust ID. Enterovirus type 71 infection in melbourne. Bulletin of the World Health Organization. 1974;51:609-615
15. Blomberg J, Lycke E, Ahlfors K, Johnsson T, Wolontis S, von Zeipel G. Letter: New enterovirus type associated with epidemic of aseptic meningitis and-or hand, foot, and mouth disease. Lancet. 1974;2:112
16. Chumakov M, Voroshilova M, Shindarov L, Lavrova I, Gracheva L, Koroleva G, Vasilenko S, Brodvarova I, Nikolova M, Gyurova S, Gacheva M, Mitov G, Ninov N, Tsylka E, Robinson I, Frolova M, Bashkirtsev V, Martiyanova L, Rodin V. Enterovirus 71 isolated from cases of epidemic poliomyelitis-like disease in bulgaria. Archives of virology. 1979;60:329-340
17. Nagy G, Takatsy S, Kukan E, Mihaly I, Domok I. Virological diagnosis of enterovirus type 71 infections: Experiences gained during an epidemic of acute cns diseases in hungary in 1978. Archives of virology. 1982;71:217-227
18. Samuda GM, Chang WK, Yeung CY, Tang PS. Monoplegia caused by enterovirus 71: An outbreak in hong kong. The Pediatric infectious disease journal. 1987;6:206-208
19. Tagaya I, Moritsugu Y. Epidemic of hand, foot and mouth disease in japan. Japanese journal of medical science & biology. 1973;26:143-147
20. Alexander JP, Jr., Baden L, Pallansch MA, Anderson LJ. Enterovirus 71 infections and neurologic disease--united states, 1977-1991. The Journal of infectious diseases. 1994;169:905-908
21. Chonmaitree T, Menegus MA, Schervish-Swierkosz EM, Schwalenstocker E. Enterovirus 71 infection: Report of an outbreak with two cases of paralysis and a review of the literature. Pediatrics. 1981;67:489-493
22. Deibel R, Gross LL, Collins DN. Isolation of a new enterovirus (38506). Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine. 1975;148:203-207
23. Hayward JC, Gillespie SM, Kaplan KM, Packer R, Pallansch M, Plotkin S, Schonberger LB. Outbreak of poliomyelitis-like paralysis associated with enterovirus 71. The Pediatric infectious disease journal. 1989;8:611-616
24. Wang SM, Liu CC, Tseng HW, Wang JR, Huang CC, Chen YJ, Yang YJ, Lin SJ, Yeh TF. Clinical spectrum of enterovirus 71 infection in children in southern taiwan, with an emphasis on neurological complications. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 1999;29:184-190
25. Liu CC, Tseng HW, Wang SM, Wang JR, Su IJ. An outbreak of enterovirus 71 infection in taiwan, 1998: Epidemiologic and clinical manifestations. Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology. 2000;17:23-30
26. Chang LY, Lin TY, Hsu KH, Huang YC, Lin KL, Hsueh C, Shih SR, Ning HC, Hwang MS, Wang HS, Lee CY. Clinical features and risk factors of pulmonary oedema after enterovirus-71-related hand, foot, and mouth disease. Lancet. 1999;354:1682-1686
27. Huang SW, Hsu YW, Smith DJ, Kiang D, Tsai HP, Lin KH, Wang SM, Liu CC, Su IJ, Wang JR. Reemergence of enterovirus 71 in 2008 in taiwan: Dynamics of genetic and antigenic evolution from 1998 to 2008. Journal of clinical microbiology. 2009;47:3653-3662
28. Chang LY, Hsia SH, Wu CT, Huang YC, Lin KL, Fang TY, Lin TY. Outcome of enterovirus 71 infections with or without stage-based management: 1998 to 2002. The Pediatric infectious disease journal. 2004;23:327-332
29. Singh S, Poh CL, Chow VT. Complete sequence analyses of enterovirus 71 strains from fatal and non-fatal cases of the hand, foot and mouth disease outbreak in singapore (2000). Microbiology and immunology. 2002;46:801-808
30. Shih SR, Ho MS, Lin KH, Wu SL, Chen YT, Wu CN, Lin TY, Chang LY, Tsao KC, Ning HC, Chang PY, Jung SM, Hsueh C, Chang KS. Genetic analysis of enterovirus 71 isolated from fatal and non-fatal cases of hand, foot and mouth disease during an epidemic in taiwan, 1998. Virus research. 2000;68:127-136
31. Huang SW, Wang YF, Yu CK, Su IJ, Wang JR. Mutations in vp2 and vp1 capsid proteins increase infectivity and mouse lethality of enterovirus 71 by virus binding and rna accumulation enhancement. Virology. 2012;422:132-143
32. Yeh MT, Wang SW, Yu CK, Lin KH, Lei HY, Su IJ, Wang JR. A single nucleotide in stem loop ii of 5'-untranslated region contributes to virulence of enterovirus 71 in mice. PloS one. 2011;6:e27082
33. Kung YH, Huang SW, Kuo PH, Kiang D, Ho MS, Liu CC, Yu CK, Su IJ, Wang JR. Introduction of a strong temperature-sensitive phenotype into enterovirus 71 by altering an amino acid of virus 3d polymerase. Virology. 2010;396:1-9
34. Lin YW, Wang SW, Tung YY, Chen SH. Enterovirus 71 infection of human dendritic cells. Experimental biology and medicine. 2009;234:1166-1173
35. Geller R, Taguwa S, Frydman J. Broad action of hsp90 as a host chaperone required for viral replication. Biochimica et biophysica acta. 2012;1823:698-706
36. Wang RY, Kuo RL, Ma WC, Huang HI, Yu JS, Yen SM, Huang CR, Shih SR. Heat shock protein-90-beta facilitates enterovirus 71 viral particles assembly. Virology. 2013
37. De Jesus NH. Epidemics to eradication: The modern history of poliomyelitis. Virology journal. 2007;4:70
38. Nasri D, Bouslama L, Pillet S, Bourlet T, Aouni M, Pozzetto B. Basic rationale, current methods and future directions for molecular typing of human enterovirus. Expert review of molecular diagnostics. 2007;7:419-434
39. Yamayoshi S, Yamashita Y, Li J, Hanagata N, Minowa T, Takemura T, Koike S. Scavenger receptor b2 is a cellular receptor for enterovirus 71. Nature medicine. 2009;15:798-801
40. Eskelinen EL, Tanaka Y, Saftig P. At the acidic edge: Emerging functions for lysosomal membrane proteins. Trends in cell biology. 2003;13:137-145
41. Kuronita T, Eskelinen EL, Fujita H, Saftig P, Himeno M, Tanaka Y. A role for the lysosomal membrane protein lgp85 in the biogenesis and maintenance of endosomal and lysosomal morphology. Journal of cell science. 2002;115:4117-4131
42. Nishimura Y, Shimojima M, Tano Y, Miyamura T, Wakita T, Shimizu H. Human p-selectin glycoprotein ligand-1 is a functional receptor for enterovirus 71. Nature medicine. 2009;15:794-797
43. Laszik Z, Jansen PJ, Cummings RD, Tedder TF, McEver RP, Moore KL. P-selectin glycoprotein ligand-1 is broadly expressed in cells of myeloid, lymphoid, and dendritic lineage and in some nonhematopoietic cells. Blood. 1996;88:3010-3021
44. Ley K. The role of selectins in inflammation and disease. Trends in molecular medicine. 2003;9:263-268
45. Ley K, Kansas GS. Selectins in t-cell recruitment to non-lymphoid tissues and sites of inflammation. Nature reviews. Immunology. 2004;4:325-335
46. Yang B, Chuang H, Yang KD. Sialylated glycans as receptor and inhibitor of enterovirus 71 infection to dld-1 intestinal cells. Virology journal. 2009;6:141
47. Varki NM, Varki A. Diversity in cell surface sialic acid presentations: Implications for biology and disease. Laboratory investigation; a journal of technical methods and pathology. 2007;87:851-857
48. Sadeharju K, Knip M, Virtanen SM, Savilahti E, Tauriainen S, Koskela P, Akerblom HK, Hyoty H, Finnish TSG. Maternal antibodies in breast milk protect the child from enterovirus infections. Pediatrics. 2007;119:941-946
49. Yang SL, Chou YT, Wu CN, Ho MS. Annexin ii binds to capsid protein vp1 of enterovirus 71 and enhances viral infectivity. Journal of virology. 2011;85:11809-11820
50. Kim J, Hajjar KA. Annexin ii: A plasminogen-plasminogen activator co-receptor. Frontiers in bioscience : a journal and virtual library. 2002;7:d341-348
51. Donato R, Russo-Marie F. The annexins: Structure and functions. Cell calcium. 1999;26:85-89
52. Gerke V, Moss SE. Annexins: From structure to function. Physiological reviews. 2002;82:331-371
53. Mayor S, Pagano RE. Pathways of clathrin-independent endocytosis. Nature reviews. Molecular cell biology. 2007;8:603-612
54. Sieczkarski SB, Whittaker GR. Differential requirements of rab5 and rab7 for endocytosis of influenza and other enveloped viruses. Traffic. 2003;4:333-343
55. Blanchard E, Belouzard S, Goueslain L, Wakita T, Dubuisson J, Wychowski C, Rouille Y. Hepatitis c virus entry depends on clathrin-mediated endocytosis. Journal of virology. 2006;80:6964-6972
56. Kolokoltsov AA, Deniger D, Fleming EH, Roberts NJ, Jr., Karpilow JM, Davey RA. Small interfering rna profiling reveals key role of clathrin-mediated endocytosis and early endosome formation for infection by respiratory syncytial virus. Journal of virology. 2007;81:7786-7800
57. Brodsky FM, Chen CY, Knuehl C, Towler MC, Wakeham DE. Biological basket weaving: Formation and function of clathrin-coated vesicles. Annual review of cell and developmental biology. 2001;17:517-568
58. Nabi IR, Le PU. Caveolae/raft-dependent endocytosis. The Journal of cell biology. 2003;161:673-677
59. Pelkmans L, Kartenbeck J, Helenius A. Caveolar endocytosis of simian virus 40 reveals a new two-step vesicular-transport pathway to the er. Nature cell biology. 2001;3:473-483
60. Marjomaki V, Pietiainen V, Matilainen H, Upla P, Ivaska J, Nissinen L, Reunanen H, Huttunen P, Hyypia T, Heino J. Internalization of echovirus 1 in caveolae. Journal of virology. 2002;76:1856-1865
61. Lakadamyali M, Rust MJ, Zhuang X. Endocytosis of influenza viruses. Microbes and infection / Institut Pasteur. 2004;6:929-936
62. Brandenburg B, Lee LY, Lakadamyali M, Rust MJ, Zhuang X, Hogle JM. Imaging poliovirus entry in live cells. PLoS biology. 2007;5:e183
63. Mercer J, Helenius A. Vaccinia virus uses macropinocytosis and apoptotic mimicry to enter host cells. Science. 2008;320:531-535
64. Meier O, Boucke K, Hammer SV, Keller S, Stidwill RP, Hemmi S, Greber UF. Adenovirus triggers macropinocytosis and endosomal leakage together with its clathrin-mediated uptake. The Journal of cell biology. 2002;158:1119-1131
65. Altschuler Y, Barbas SM, Terlecky LJ, Tang K, Hardy S, Mostov KE, Schmid SL. Redundant and distinct functions for dynamin-1 and dynamin-2 isoforms. The Journal of cell biology. 1998;143:1871-1881
66. Marks B, Stowell MH, Vallis Y, Mills IG, Gibson A, Hopkins CR, McMahon HT. Gtpase activity of dynamin and resulting conformation change are essential for endocytosis. Nature. 2001;410:231-235
67. Soulet F, Yarar D, Leonard M, Schmid SL. Snx9 regulates dynamin assembly and is required for efficient clathrin-mediated endocytosis. Molecular biology of the cell. 2005;16:2058-2067
68. Merrifield CJ, Feldman ME, Wan L, Almers W. Imaging actin and dynamin recruitment during invagination of single clathrin-coated pits. Nature cell biology. 2002;4:691-698
69. Lee DW, Wu X, Eisenberg E, Greene LE. Recruitment dynamics of gak and auxilin to clathrin-coated pits during endocytosis. Journal of cell science. 2006;119:3502-3512
70. Praefcke GJ, McMahon HT. The dynamin superfamily: Universal membrane tubulation and fission molecules? Nature reviews. Molecular cell biology. 2004;5:133-147
71. Hussain KM, Leong KL, Ng MM, Chu JJ. The essential role of clathrin-mediated endocytosis in the infectious entry of human enterovirus 71. The Journal of biological chemistry. 2011;286:309-321
72. Ortner B, Huang CW, Schmid D, Mutz I, Wewalka G, Allerberger F, Yang JY, Huemer HP. Epidemiology of enterovirus types causing neurological disease in austria 1999-2007: Detection of clusters of echovirus 30 and enterovirus 71 and analysis of prevalent genotypes. Journal of medical virology. 2009;81:317-324
73. Lin YW, Chang KC, Kao CM, Chang SP, Tung YY, Chen SH. Lymphocyte and antibody responses reduce enterovirus 71 lethality in mice by decreasing tissue viral loads. Journal of virology. 2009;83:6477-6483
74. Wang YF, Chou CT, Lei HY, Liu CC, Wang SM, Yan JJ, Su IJ, Wang JR, Yeh TM, Chen SH, Yu CK. A mouse-adapted enterovirus 71 strain causes neurological disease in mice after oral infection. Journal of virology. 2004;78:7916-7924
75. Chen CS, Yao YC, Lin SC, Lee YP, Wang YF, Wang JR, Liu CC, Lei HY, Yu CK. Retrograde axonal transport: A major transmission route of enterovirus 71 in mice. Journal of virology. 2007;81:8996-9003
76. Chen YC, Yu CK, Wang YF, Liu CC, Su IJ, Lei HY. A murine oral enterovirus 71 infection model with central nervous system involvement. The Journal of general virology. 2004;85:69-77
77. Nagata N, Iwasaki T, Ami Y, Tano Y, Harashima A, Suzaki Y, Sato Y, Hasegawa H, Sata T, Miyamura T, Shimizu H. Differential localization of neurons susceptible to enterovirus 71 and poliovirus type 1 in the central nervous system of cynomolgus monkeys after intravenous inoculation. The Journal of general virology. 2004;85:2981-2989
78. Nagata N, Shimizu H, Ami Y, Tano Y, Harashima A, Suzaki Y, Sato Y, Miyamura T, Sata T, Iwasaki T. Pyramidal and extrapyramidal involvement in experimental infection of cynomolgus monkeys with enterovirus 71. Journal of medical virology. 2002;67:207-216
79. Wang W, Duo J, Liu J, Ma C, Zhang L, Wei Q, Qin C. A mouse muscle-adapted enterovirus 71 strain with increased virulence in mice. Microbes and infection / Institut Pasteur. 2011;13:862-870
80. Lin TY, Hsia SH, Huang YC, Wu CT, Chang LY. Proinflammatory cytokine reactions in enterovirus 71 infections of the central nervous system. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2003;36:269-274
81. Chang LY, Hsiung CA, Lu CY, Lin TY, Huang FY, Lai YH, Chiang YP, Chiang BL, Lee CY, Huang LM. Status of cellular rather than humoral immunity is correlated with clinical outcome of enterovirus 71. Pediatric research. 2006;60:466-471
82. Arita M, Nagata N, Iwata N, Ami Y, Suzaki Y, Mizuta K, Iwasaki T, Sata T, Wakita T, Shimizu H. An attenuated strain of enterovirus 71 belonging to genotype a showed a broad spectrum of antigenicity with attenuated neurovirulence in cynomolgus monkeys. Journal of virology. 2007;81:9386-9395
83. Christensen JE, de Lemos C, Moos T, Christensen JP, Thomsen AR. Cxcl10 is the key ligand for cxcr3 on cd8+ effector t cells involved in immune surveillance of the lymphocytic choriomeningitis virus-infected central nervous system. Journal of immunology. 2006;176:4235-4243
84. Muller M, Carter S, Hofer MJ, Campbell IL. Review: The chemokine receptor cxcr3 and its ligands cxcl9, cxcl10 and cxcl11 in neuroimmunity--a tale of conflict and conundrum. Neuropathology and applied neurobiology. 2010;36:368-387
85. Garcia-Lopez MA, Sanchez-Madrid F, Rodriguez-Frade JM, Mellado M, Acevedo A, Garcia MI, Albar JP, Martinez C, Marazuela M. Cxcr3 chemokine receptor distribution in normal and inflamed tissues: Expression on activated lymphocytes, endothelial cells, and dendritic cells. Laboratory investigation; a journal of technical methods and pathology. 2001;81:409-418
86. Sauty A, Dziejman M, Taha RA, Iarossi AS, Neote K, Garcia-Zepeda EA, Hamid Q, Luster AD. The t cell-specific cxc chemokines ip-10, mig, and i-tac are expressed by activated human bronchial epithelial cells. Journal of immunology. 1999;162:3549-3558
87. Wang SM, Lei HY, Yu CK, Wang JR, Su IJ, Liu CC. Acute chemokine response in the blood and cerebrospinal fluid of children with enterovirus 71-associated brainstem encephalitis. The Journal of infectious diseases. 2008;198:1002-1006
88. Li ZH, Li CM, Ling P, Shen FH, Chen SH, Liu CC, Yu CK, Chen SH. Ribavirin reduces mortality in enterovirus 71-infected mice by decreasing viral replication. The Journal of infectious diseases. 2008;197:854-857
89. Huang SW, Lee YP, Hung YT, Lin CH, Chuang JI, Lei HY, Su IJ, Yu CK. Exogenous interleukin-6, interleukin-13, and interferon-gamma provoke pulmonary abnormality with mild edema in enterovirus 71-infected mice. Respiratory research. 2011;12:147
90. Khong WX, Yan B, Yeo H, Tan EL, Lee JJ, Ng JK, Chow VT, Alonso S. A non-mouse-adapted enterovirus 71 (ev71) strain exhibits neurotropism, causing neurological manifestations in a novel mouse model of ev71 infection. Journal of virology. 2012;86:2121-2131
91. Liu L, Zhao H, Zhang Y, Wang J, Che Y, Dong C, Zhang X, Na R, Shi H, Jiang L, Wang L, Xie Z, Cui P, Xiong X, Liao Y, Zhao S, Gao J, Tang D, Li Q. Neonatal rhesus monkey is a potential animal model for studying pathogenesis of ev71 infection. Virology. 2011;412:91-100
92. Zhang Y, Cui W, Liu L, Wang J, Zhao H, Liao Y, Na R, Dong C, Wang L, Xie Z, Gao J, Cui P, Zhang X, Li Q. Pathogenesis study of enterovirus 71 infection in rhesus monkeys. Laboratory investigation; a journal of technical methods and pathology. 2011;91:1337-1350
93. Khong WX, Foo DG, Trasti SL, Tan EL, Alonso S. Sustained high levels of interleukin-6 contribute to the pathogenesis of enterovirus 71 in a neonate mouse model. Journal of virology. 2011;85:3067-3076
94. Liu J, Dong W, Quan X, Ma C, Qin C, Zhang L. Transgenic expression of human p-selectin glycoprotein ligand-1 is not sufficient for enterovirus 71 infection in mice. Archives of virology. 2012;157:539-543
95. Wu SC, Liu CC, Lian WC. Optimization of microcarrier cell culture process for the inactivated enterovirus type 71 vaccine development. Vaccine. 2004;22:3858-3864
96. Liu CC, Lian WC, Butler M, Wu SC. High immunogenic enterovirus 71 strain and its production using serum-free microcarrier vero cell culture. Vaccine. 2007;25:19-24
97. Chang JY, Chang CP, Tsai HH, Lee CD, Lian WC, Ih Jen S, Sai IH, Liu CC, Chou AH, Lu YJ, Chen CY, Lee PH, Chiang JR, Chong PC. Selection and characterization of vaccine strain for enterovirus 71 vaccine development. Vaccine. 2012;30:703-711
98. Danthi P, Chow M. Cholesterol removal by methyl-beta-cyclodextrin inhibits poliovirus entry. Journal of virology. 2004;78:33-41
99. Brinster RL, Chen HY, Trumbauer ME, Yagle MK, Palmiter RD. Factors affecting the efficiency of introducing foreign DNA into mice by microinjecting eggs. Proceedings of the National Academy of Sciences of the United States of America. 1985;82:4438-4442
100. Liu CC, Chou AH, Lien SP, Lin HY, Liu SJ, Chang JY, Guo MS, Chow YH, Yang WS, Chang KH, Sia C, Chong P. Identification and characterization of a cross-neutralization epitope of enterovirus 71. Vaccine. 2011;29:4362-4372
101. Grove J, Huby T, Stamataki Z, Vanwolleghem T, Meuleman P, Farquhar M, Schwarz A, Moreau M, Owen JS, Leroux-Roels G, Balfe P, McKeating JA. Scavenger receptor bi and bii expression levels modulate hepatitis c virus infectivity. Journal of virology. 2007;81:3162-3169
102. Eckhardt ER, Cai L, Shetty S, Zhao Z, Szanto A, Webb NR, Van der Westhuyzen DR. High density lipoprotein endocytosis by scavenger receptor sr-bii is clathrin-dependent and requires a carboxyl-terminal dileucine motif. The Journal of biological chemistry. 2006;281:4348-4353
103. Nawa M, Takasaki T, Yamada K, Kurane I, Akatsuka T. Interference in japanese encephalitis virus infection of vero cells by a cationic amphiphilic drug, chlorpromazine. The Journal of general virology. 2003;84:1737-1741
104. Wang LH, Rothberg KG, Anderson RG. Mis-assembly of clathrin lattices on endosomes reveals a regulatory switch for coated pit formation. The Journal of cell biology. 1993;123:1107-1117
105. Inoue Y, Tanaka N, Tanaka Y, Inoue S, Morita K, Zhuang M, Hattori T, Sugamura K. Clathrin-dependent entry of severe acute respiratory syndrome coronavirus into target cells expressing ace2 with the cytoplasmic tail deleted. Journal of virology. 2007;81:8722-8729
106. Sun X, Yau VK, Briggs BJ, Whittaker GR. Role of clathrin-mediated endocytosis during vesicular stomatitis virus entry into host cells. Virology. 2005;338:53-60
107. Bayer N, Schober D, Huttinger M, Blaas D, Fuchs R. Inhibition of clathrin-dependent endocytosis has multiple effects on human rhinovirus serotype 2 cell entry. The Journal of biological chemistry. 2001;276:3952-3962
108. Baba T, Damke H, Hinshaw JE, Ikeda K, Schmid SL, Warnock DE. Role of dynamin in clathrin-coated vesicle formation. Cold Spring Harbor symposia on quantitative biology. 1995;60:235-242
109. Richterova Z, Liebl D, Horak M, Palkova Z, Stokrova J, Hozak P, Korb J, Forstova J. Caveolae are involved in the trafficking of mouse polyomavirus virions and artificial vp1 pseudocapsids toward cell nuclei. Journal of virology. 2001;75:10880-10891
110. Aoki T, Nomura R, Fujimoto T. Tyrosine phosphorylation of caveolin-1 in the endothelium. Experimental cell research. 1999;253:629-636
111. Liu P, Anderson RG. Spatial organization of egf receptor transmodulation by pdgf. Biochemical and biophysical research communications. 1999;261:695-700
112. Eash S, Querbes W, Atwood WJ. Infection of vero cells by bk virus is dependent on caveolae. Journal of virology. 2004;78:11583-11590
113. Schnitzer JE, Oh P, Pinney E, Allard J. Filipin-sensitive caveolae-mediated transport in endothelium: Reduced transcytosis, scavenger endocytosis, and capillary permeability of select macromolecules. The Journal of cell biology. 1994;127:1217-1232
114. Orlandi PA, Fishman PH. Filipin-dependent inhibition of cholera toxin: Evidence for toxin internalization and activation through caveolae-like domains. The Journal of cell biology. 1998;141:905-915
115. Rothberg KG, Ying YS, Kamen BA, Anderson RG. Cholesterol controls the clustering of the glycophospholipid-anchored membrane receptor for 5-methyltetrahydrofolate. The Journal of cell biology. 1990;111:2931-2938
116. Pelkmans L, Helenius A. Insider information: What viruses tell us about endocytosis. Current opinion in cell biology. 2003;15:414-422
117. Tjelle TE, Brech A, Juvet LK, Griffiths G, Berg T. Isolation and characterization of early endosomes, late endosomes and terminal lysosomes: Their role in protein degradation. Journal of cell science. 1996;109 ( Pt 12):2905-2914
118. Marsh M, Helenius A. Virus entry: Open sesame. Cell. 2006;124:729-740
119. Brown MS, Goldstein JL. Multivalent feedback regulation of hmg coa reductase, a control mechanism coordinating isoprenoid synthesis and cell growth. Journal of lipid research. 1980;21:505-517
120. Subtil A, Gaidarov I, Kobylarz K, Lampson MA, Keen JH, McGraw TE. Acute cholesterol depletion inhibits clathrin-coated pit budding. Proceedings of the National Academy of Sciences of the United States of America. 1999;96:6775-6780
121. Rodal SK, Skretting G, Garred O, Vilhardt F, van Deurs B, Sandvig K. Extraction of cholesterol with methyl-beta-cyclodextrin perturbs formation of clathrin-coated endocytic vesicles. Molecular biology of the cell. 1999;10:961-974
122. Region WHOWP. A guide to clinical management and public health response for hand, foot and mouth disease (hfmd). Geneva: World Health Organization. 2011
123. Wang SM, Lei HY, Huang KJ, Wu JM, Wang JR, Yu CK, Su IJ, Liu CC. Pathogenesis of enterovirus 71 brainstem encephalitis in pediatric patients: Roles of cytokines and cellular immune activation in patients with pulmonary edema. The Journal of infectious diseases. 2003;188:564-570
124. Lin TY, Chang LY, Huang YC, Hsu KH, Chiu CH, Yang KD. Different proinflammatory reactions in fatal and non-fatal enterovirus 71 infections: Implications for early recognition and therapy. Acta paediatrica. 2002;91:632-635
125. Lin KH, Hwang KP, Ke GM, Wang CF, Ke LY, Hsu YT, Tung YC, Chu PY, Chen BH, Chen HL, Kao CL, Wang JR, Eng HL, Wang SY, Hsu LC, Chen HY. Evolution of ev71 genogroup in taiwan from 1998 to 2005: An emerging of subgenogroup c4 of ev71. Journal of medical virology. 2006;78:254-262
126. Chang HW, Liu CC, Lin MH, Ho HM, Yang YT, Chow YH, Chong P, Sia C. Generation of murine monoclonal antibodies which cross-neutralize human enterovirus genogroup b isolates. Journal of virological methods. 2011;173:189-195
127. Neckers L, Schulte TW, Mimnaugh E. Geldanamycin as a potential anti-cancer agent: Its molecular target and biochemical activity. Investigational new drugs. 1999;17:361-373
128. Supko JG, Hickman RL, Grever MR, Malspeis L. Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent. Cancer chemotherapy and pharmacology. 1995;36:305-315
129. Schulte TW, Neckers LM. The benzoquinone ansamycin 17-allylamino-17-demethoxygeldanamycin binds to hsp90 and shares important biologic activities with geldanamycin. Cancer chemotherapy and pharmacology. 1998;42:273-279
130. Glaze ER, Lambert AL, Smith AC, Page JG, Johnson WD, McCormick DL, Brown AP, Levine BS, Covey JM, Egorin MJ, Eiseman JL, Holleran JL, Sausville EA, Tomaszewski JE. Preclinical toxicity of a geldanamycin analog, 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-dmag), in rats and dogs: Potential clinical relevance. Cancer chemotherapy and pharmacology. 2005;56:637-647
131. Lin HY, Yang YT, Yu SL, Hsiao KN, Liu CC, Sia C, Chow YH. Caveolar endocytosis is required for human psgl-1-mediated enterovirus 71 infection. Journal of virology. 2013
132. Yamayoshi S, Ohka S, Fujii K, Koike S. Functional comparison of scarb2 and psgl1 as receptors for enterovirus 71. Journal of virology. 2013;87:3335-3347
133. Lin YC, Wu CN, Shih SR, Ho MS. Characterization of a vero cell-adapted virulent strain of enterovirus 71 suitable for use as a vaccine candidate. Vaccine. 2002;20:2485-2493
134. Yamayoshi S, Koike S. Identification of a human scarb2 region that is important for enterovirus 71 binding and infection. Journal of virology. 2011;85:4937-4946
135. Chen H, Zhang Y, Yang E, Liu L, Che Y, Wang J, Zhao H, Tang D, Dong C, Yang L, Shen D, Wang X, Liao Y, Wang L, Na R, Liang Y, Li Q. The effect of enterovirus 71 immunization on neuropathogenesis and protein expression profiles in the thalamus of infected rhesus neonates. Virology. 2012;432:417-426
136. Douche-Aourik F, Berlier W, Feasson L, Bourlet T, Harrath R, Omar S, Grattard F, Denis C, Pozzetto B. Detection of enterovirus in human skeletal muscle from patients with chronic inflammatory muscle disease or fibromyalgia and healthy subjects. Journal of medical virology. 2003;71:540-547
137. Loetscher M, Gerber B, Loetscher P, Jones SA, Piali L, Clark-Lewis I, Baggiolini M, Moser B. Chemokine receptor specific for ip10 and mig: Structure, function, and expression in activated t-lymphocytes. The Journal of experimental medicine. 1996;184:963-969
138. Groom JR, Luster AD. Cxcr3 in t cell function. Experimental cell research. 2011;317:620-631
139. Dyer KD, Percopo CM, Fischer ER, Gabryszewski SJ, Rosenberg HF. Pneumoviruses infect eosinophils and elicit myd88-dependent release of chemoattractant cytokines and interleukin-6. Blood. 2009;114:2649-2656
140. Luster AD, Ravetch JV. Biochemical characterization of a gamma interferon-inducible cytokine (ip-10). The Journal of experimental medicine. 1987;166:1084-1097
141. Lo BK, Yu M, Zloty D, Cowan B, Shapiro J, McElwee KJ. Cxcr3/ligands are significantly involved in the tumorigenesis of basal cell carcinomas. The American journal of pathology. 2010;176:2435-2446
142. Hsieh YH, Chen CW, Schmitz SF, King CC, Chen WJ, Wu YC, Ho MS. Candidate genes associated with susceptibility for sars-coronavirus. Bulletin of mathematical biology. 2010;72:122-132
143. Klein RS, Lin E, Zhang B, Luster AD, Tollett J, Samuel MA, Engle M, Diamond MS. Neuronal cxcl10 directs cd8+ t-cell recruitment and control of west nile virus encephalitis. Journal of virology. 2005;79:11457-11466
144. Sin J, Kim JJ, Pachuk C, Satishchandran C, Weiner DB. DNA vaccines encoding interleukin-8 and rantes enhance antigen-specific th1-type cd4(+) t-cell-mediated protective immunity against herpes simplex virus type 2 in vivo. Journal of virology. 2000;74:11173-11180
145. Lane BR, King SR, Bock PJ, Strieter RM, Coffey MJ, Markovitz DM. The c-x-c chemokine ip-10 stimulates hiv-1 replication. Virology. 2003;307:122-134
146. Shen FH, Tsai CC, Wang LC, Chang KC, Tung YY, Su IJ, Chen SH. Enterovirus 71 infection increases expression of interferon-gamma-inducible protein 10 which protects mice by reducing viral burden in multiple tissues. The Journal of general virology. 2013;94:1019-1027
147. Yoon HA, Aleyas AG, George JA, Park SO, Han YW, Lee JH, Kang HY, Kang SH, Cho JG, Eo SK. Modulation of immune responses induced by DNA vaccine expressing glycoprotein b of pseudorabies virus via coadministration of ifn-gamma-associated cytokines. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research. 2006;26:730-738
148. Tani M, Fuentes ME, Peterson JW, Trapp BD, Durham SK, Loy JK, Bravo R, Ransohoff RM, Lira SA. Neutrophil infiltration, glial reaction, and neurological disease in transgenic mice expressing the chemokine n51/kc in oligodendrocytes. The Journal of clinical investigation. 1996;98:529-539
149. Bonecchi R, Polentarutti N, Luini W, Borsatti A, Bernasconi S, Locati M, Power C, Proudfoot A, Wells TN, Mackay C, Mantovani A, Sozzani S. Up-regulation of ccr1 and ccr3 and induction of chemotaxis to cc chemokines by ifn-gamma in human neutrophils. Journal of immunology. 1999;162:474-479
150. Chiu CH, Chu C, He CC, Lin TY. Protection of neonatal mice from lethal enterovirus 71 infection by maternal immunization with attenuated salmonella enterica serovar typhimurium expressing vp1 of enterovirus 71. Microbes and infection / Institut Pasteur. 2006;8:1671-1678
151. Wu TC, Wang YF, Lee YP, Wang JR, Liu CC, Wang SM, Lei HY, Su IJ, Yu CK. Immunity to avirulent enterovirus 71 and coxsackie a16 virus protects against enterovirus 71 infection in mice. Journal of virology. 2007;81:10310-10315
152. Wang SM, Lei HY, Huang MC, Su LY, Lin HC, Yu CK, Wang JL, Liu CC. Modulation of cytokine production by intravenous immunoglobulin in patients with enterovirus 71-associated brainstem encephalitis. Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology. 2006;37:47-52
153. Beliakoff J, Whitesell L. Hsp90: An emerging target for breast cancer therapy. Anti-cancer drugs. 2004;15:651-662
154. Georgakis GV, Younes A. Heat-shock protein 90 inhibitors in cancer therapy: 17aag and beyond. Future oncology. 2005;1:273-281