表达树突状细胞激活因子重组狂犬病病毒的构建及其免疫学研究
摘要
最近研究发现，先天性免疫反应的激活是狂犬病病毒（Rabies Virus,RV）减弱的机制之一。诱导先天性免疫的因素包括炎性趋化因子（RANTES, MIP-1α, IP-10等）和细胞因子（IL-6, IL-1β,和TNF-α），干扰素和干扰素相关基因（IFN-α, STAT1, Mx-1），Toll样受体(TLRs1-3)。这些先天性免疫分子具有诱导树突状细胞活化的能力而且能够引发很强的获得性免疫和对机体提供很好的保护能力。因此，我们把免疫刺激分子整合到病毒中用来增强免疫效率。树突状细胞的活化是非常重要的，特别是在加强针对狂犬病病毒的保护性免疫反应方面。我们利用树突状细胞活化分子作为狂犬病病毒疫苗的遗传佐剂，试图影响先天性免疫反应，诱导出更高的特异性的中和抗体，包括从淋巴结中成熟的和迁移的树突状细胞聚集到炎症部位。本研究中，证明树突状细胞活化分子能够诱导出针对RV的保护性免疫。粒细胞-巨噬细胞集落刺激因子（granulocyte-macrophagecolony-stimulating factor GM-CSF）,巨噬细胞来源的趋化因子CCL22和巨噬细胞炎性蛋白1α（Macrophage Inflammatory Protein-1alpha MIP-1α）分别被克隆到RV基因组全长CDNA中，并且每一个重组的RV分子的抗原性和安全性都在小鼠模型上得到了确认。所有的重组的RV分子对成年鼠无致病性，即使用最高剂量攻击成年鼠也不产生临床症状。对重组狂犬病病毒感染小鼠3天和6天的时候利用RT-PCR技术，检测病毒的总RNA和小鼠腿部肌肉中所含的插入基因，在感染开始之后，RV和重组狂犬病病毒基因组几乎相同，然而插入激活因子的病毒，相应的在免疫后激活因子含量明显升高。通过流式细胞术对进入淋巴结和血液双阳性的B细胞和树突状细胞（Dendritic Cell DC）细胞的数量和活化状态进行量化比较。重组GM-CSF的RV rLBNSE-GM-CSF,重组MDC的RV rLBNSE-MDC和重组MIP-1α的RV rLBNSE-MIP-1α实验组与无外源基因插入的重组RV rLBNSE组感染比较，在淋巴结和血液中产生了更多的B细胞和DC细胞。说明我们插入的趋化因子和细胞因子可以吸引更多的B细胞到神经末梢免疫系统，可以对成熟的DC起到激发和活化的作用。用RV的强毒CVS-24攻击免疫的小鼠，针对重组RV分子的一个单一的免疫反应能够产生GM-CSF或者CCL22的保护率是100%，而针对重组RV分子产生MIP-1α的保护率是80%，总结我们的结果表明，重组的RV分子表达树突状细胞活化分子能够加强免疫保护反应并且具有发展成为下一代RV疫苗的潜力。
Recently it was found that activation of the innate immune responses is one of the mechanisms by which rabies virus (RV) is attenuated. Induced innate response genes include inflammatory chemokines (RANTES, MIP-1 , IP-10, etc) and cytokines (IL-6, IL-1 , and TNF- ), IFN and IFN-related genes (IFN- , STAT1, Mx-1), and Toll-like receptors (TLRs1-3). These innate immune molecules are capable of inducing activation of dendritic cells triggered the strongest adaptive immune responses and provided the best protection, so we incorporate the immunostimulatory molecules into chimeric RVs to increase their efficacy. We use of dendritic cell-activation molecules as genetic adjuvants for rabies virus vaccines try to affect the very early events of an immune response and induce much higher specific neutralizing antibody responses, which includes maturation and migration of DCs from the site of inflammation to the draining lymph nodes.The recombinant rabies virus (rRV) carrying chemokines and cytokines were constructed from the SAD L16 strain which mutated the position 194 and 333 amino acids on the G protein. To determine the function of rRVs with expressing dendritic cell-activation molecules in innate and adaptive immunity, we generated rRVs that expressed murine granulocyte-macrophage colony-stimulating factor (mGM-CSF), murine CCL22 (mCCL22) and Macrophage Inflammatory Protein 1 alpha(mMIP-1 ). The rRVs carrying dendritic cell-activation molecules induced much higher increases of RV-specific antibody titers, compared to those responses elicited by just backbone rRV. The rRVs expressing each of these molecules are avirulent since infection with the highest possible dose did not induce any diseases in adult mice but have limited pathogenicity in the baby mice. Peripheral immunization with each of the virus the viral total RNA and insert gene in the mouse muscle were examined by an RT-PCR analysis for rRVs infected mice at 3 and 6dpi. There was almost the same RV genome in rRVs infected mice at the onset of infection, of course, the insert gene products were increased after immunization with recombinant virus respectliy. Double positive numbers of B cells and DC cells were assessed by flow cytometry in the lymph nodes and blood. When cells were stimulated specifically by rLBNSE-GM-CSF, rLBNSE-MDC, and rLBNSE-MIP-1 double positive B cells and DC cells showed a higher signal than rLBNSE B cells in the lymph nodes and blood. These results s ggested that the B and DC cells were more activated by different rRVs with inserts than backbone virus.One single immunization can induce 100% protection in mice against the challenge infection with virulent rabies virus. Together our results indicate that these recombinant rabies viruses expressing dendritic cell-activation molecules enhance humoral and cellular immune responses and have the potential to be developed as the next generation of rabies virus vaccines.
Recently it was found that activation of the innate immune responses is one of the mechanisms by which rabies virus (RV) is attenuated. Induced innate response genes include inflammatory chemokines (RANTES, MIP-1 , IP-10, etc) and cytokines (IL-6, IL-1 , and TNF- ), IFN and IFN-related genes (IFN- , STAT1, Mx-1), and Toll-like receptors (TLRs1-3). These innate immune molecules are capable of inducing activation of dendritic cells triggered the strongest adaptive immune responses and provided the best protection, so we incorporate the immunostimulatory molecules into chimeric RVs to increase their efficacy. We use of dendritic cell-activation molecules as genetic adjuvants for rabies virus vaccines try to affect the very early events of an immune response and induce much higher specific neutralizing antibody responses, which includes maturation and migration of DCs from the site of inflammation to the draining lymph nodes.The recombinant rabies virus (rRV) carrying chemokines and cytokines were constructed from the SAD L16 strain which mutated the position 194 and 333 amino acids on the G protein. To determine the function of rRVs with expressing dendritic cell-activation molecules in innate and adaptive immunity, we generated rRVs that expressed murine granulocyte-macrophage colony-stimulating factor (mGM-CSF), murine CCL22 (mCCL22) and Macrophage Inflammatory Protein 1 alpha(mMIP-1 ). The rRVs carrying dendritic cell-activation molecules induced much higher increases of RV-specific antibody titers, compared to those responses elicited by just backbone rRV. The rRVs expressing each of these molecules are avirulent since infection with the highest possible dose did not induce any diseases in adult mice but have limited pathogenicity in the baby mice. Peripheral immunization with each of the virus the viral total RNA and insert gene in the mouse muscle were examined by an RT-PCR analysis for rRVs infected mice at 3 and 6dpi. There was almost the same RV genome in rRVs infected mice at the onset of infection, of course, the insert gene products were increased after immunization with recombinant virus respectliy. Double positive numbers of B cells and DC cells were assessed by flow cytometry in the lymph nodes and blood. When cells were stimulated specifically by rLBNSE-GM-CSF, rLBNSE-MDC, and rLBNSE-MIP-1 double positive B cells and DC cells showed a higher signal than rLBNSE B cells in the lymph nodes and blood. These results s ggested that the B and DC cells were more activated by different rRVs with inserts than backbone virus.One single immunization can induce 100% protection in mice against the challenge infection with virulent rabies virus. Together our results indicate that these recombinant rabies viruses expressing dendritic cell-activation molecules enhance humoral and cellular immune responses and have the potential to be developed as the next generation of rabies virus vaccines.
引文
1. Allan, R.S., Waithman, J., Bedoui, S., et al. Migratory dendritic cells transfer antigen to a lymph node-resident dendritic cell population for efficient CTL priming. Immunity, 2006, 25 : 153-162.
2. Anderson, L.J., Nicholson, K.G., Tauxe, R.V., et al. Human rabies in the United States, 1960 to 1979: epidemiology, diagnosis, and prevention. Ann Intern Med, 1984, 100 : 728-735.
3. Anonymous. Compendium of Animal Rabies Prevention and Control. MMWR CDC Surveill Summ, 2000, 49:19-30.
4. Baer, G.M., Antiviral action of interferon in animal systems: effect of interferon on rabies infections of animals. Tex Rep Biol Med 1977, 35 : 461-471.
5. Bahloul, C., Jacob, Y., Tordo, N., et al. DNA-based immunization for exploring the enlargement of immunological cross-reactivity against the lyssaviruses. Vaccine, 1998,16 : 417-425.
6. Banchereau, J., Briere, F., Caux, C., et al. Immunobiology of dendritic cells. Annu Rev Immunol 2000, 18 : 767-811.
7. Banchereau, J., Steinman, R.M., et al. Dendritic cells and the control of immunity. Nature 1998, 392 : 245-252.
8. Becker, Y., Immunological and regulatory functions of uninfected and virus infected immature and mature subtypes of dendritic cells--a review. Virus Genes, 2003, 26 : 119-130.
9. Belz, G.T., Smith, C.M., Eichner, D., et al. Cutting edge: conventional CD8 alpha+ dendritic cells are generally involved in priming CTL immunity to viruses. J Immunol, 2004a, 172: 1996-2000.
10. Belz, G.T., Smith, C.M., Kleinert, L., et al. Distinct migrating and nonmigrating dendritic cell populations are involved in MHC class I-restricted antigen presentation after lung infection with virus. Proc Natl Acad Sci U S A, 2004b,101 : 8670-8675.
11. Brochier, B., Blancou, J., Thomas, I., et al. Use of recombinant vaccinia-rabies glycoprotein virus for oral vaccination of wildlife against rabies: innocuity to several non-target bait consuming species. J Wildl Dis, 1989, 25 : 540-547.
12. Bro ghan, J.H., Wunner, W.H., Characterization of protein involvement in rabies virus binding to BHK-21 cells. Arch Virol, 1995, 140 : 75-93.
13. Chantry, D., Romagnani, P., Raport, C.J., et al. Macrophage-derived chemokine is localized tothymic medullary epithelial cells and is a chemoattractant for CD3(+), CD4(+), CD8(low) thymocytes. Blood, 1999, 94 : 1890-1898.
14. Chen, B.P., Kuziel, W.A., Lane, T.E., Lack of CCR2 results in increased mortality and impaired leukocyte activation and trafficking following infection of the central nervous system with a neurotropic coronavirus. J Immunol, 2001,167 : 4585-4592.
15. Chenik, M., Chebli, K., Gaudin, Y., et al. In vivo interaction of rabies virus phosphoprotein (P) and nucleoprotein (N): existence of two N-binding sites on P protein. J Gen Virol, 1994, 75 ( Pt 11), 2889-2896.
16. Clark, E.A., Regulation of B lymphocytes by dendritic cells. J Exp Med, 1997,185 : 801-803.
17. Crampton, S.P., Voynova, E., Bolland, S., Innate pathways to B-cell activation and tolerance. Ann N Y Acad Sci, 2010,1183 : 58-68.
18. Dietzschold, B., Kao, M., Zheng, Y.M., et al. Delineation of putative mechanisms involved in antibody-mediated clearance of rabies virus from the central nervous system. Proceedings of the National Academy of Sciences of the United States of America, 1992, 89 : 7252-7256.
19. Dietzschold, B., Wunner, W.H., Wiktor, T.J., et al. Characterization of an antigenic determinant of the glycoprotein that correlates with pathogenicity of rabies virus. Proc Natl Acad Sci U S A, 1983, 80 : 70-74.
20. Disis, M.L., Bernhard, H., Shiota, F.M., et al. Granulocyte-macrophage colony-stimulating factor: an effective adjuvant for protein and peptide-based vaccines. Blood, 1996, 88 : 202-210.
21. Dorner, B.G., Scheffold, A., Rolph, M.S., et al. MIP-1alpha, MIP-1beta, RANTES, and ATAC/lymphotactin function together with IFN-gamma as type 1 cytokines. Proc Natl Acad Sci U S A, 2002, 99 : 6181-6186.
22. Dubois, B., Bridon, J.M., Fayette, J., et al. Dendritic cells directly modulate B cell growth and differentiation. J Leukoc Biol, 1999, 66 : 224-230.
23. Esh, J.B., Cunningham, J.G., Wiktor, T.J., Vaccine-induced rabies in four cats. J Am Vet Med Assoc,1982, 180 : 1336-1339.
24. Faber, M., Pulmanausahakul, R., Hodawadekar, S.S., et al. Overexpression of the rabies virus glycoprotein results in enhancement of apoptosis and antiviral immune response. J Virol, 2002, 76 : 3374-3381.
25. Finke, S., Mueller-Waldeck, R., Conzelmann, K.K., Rabies virus matrix protein regulates thebalance of virus transcription and replication. J Gen Virol, 2003, 84 :1613-1621.
26. Foley, H.D., McGettigan, J.P., Siler, C.A., et al. A recombinant rabies virus expressing vesicular stomatitis virus glycoprotein fails to protect against rabies virus infection. Proceedings of the National Academy of Sciences of the United States of America, 2000, 97 : 14680-14685.
27. Frazatti-Gallina, N.M., Mourao-Fuches, R.M., Paoli, R.L., et al. Vero-cell rabies vaccine produced using serum-free medium. Vaccine, 2004, 23, 511-517.
28. Fu, Z.F., Rabies and rabies research: past, present and future. Vaccine, 1997, 15 : S20-24.
29. Godiska, R., Chantry, D., Raport, C.J., et al. Human macrophage-derived chemokine (MDC), a novel chemoattractant for monocytes, monocyte-derived dendritic cells, and natural killer cells. J Exp Med, 1997, 185 : 1595-1604.
30. Haddad, D., Ramprakash, J., Sedegah, M., et al. Plasmid vaccine expressing granulocyte-macrophage colony-stimulating factor attracts infiltrates including immature dendritic cells into injected muscles. J Immunol, 2000, 165 : 3772-3781.
31. Hamilton, J.A., Anderson, G.P., GM-CSF Biology. Growth Factors, 2004, 22 : 225-231.
32. Hemachudha, T., Human rabies: clinical aspects, pathogenesis, and potential therapy. Curr Top Microbiol Immunol, 1994,187 : 121-143.
33. Hercus, T.R., Thomas, D., Guthridge, M.A., et al. The granulocyte-macrophage colony-stimulating factor receptor: linking its structure to cell signaling and its role in disease. Blood, 2009, 114: 1289-1298.
34. Hooper, D.C., Morimoto, K., Bette, M., et a. Collaboration of antibody and inflammation in clearance of rabies virus from the central nervous system. J Virol, 1998, 72 : 3711-3719.
35. Iellem, A., Mariani, M., Lang, R.,et al. Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 by CD4(+)CD25(+) regulatory T cells. J Exp Med, 2001, 194 : 847-853.
36. Imai, T., Nagira, M., Takagi, S., et al. Selective recruitment of CCR4-bearing Th2 cells toward antigen-presenting cells by the CC chemokines thymus and activation-regulated chemokine and macrophage-derived chemokine. Int Immunol, 1999, 11 : 81-88.
37. Inaba, K., Inaba, M., Romani, N., et al. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J Exp Med, 1992, 176 : 1693-1702.
38. Iwasaki, Y., Sako, K., Tsunoda, I., et al. Phenotypes of mononuclear cell infiltrates in human central nervous system. Acta Neuropathol, 1993, 85 : 653-657.
39. Jackson, A.C., Rabies pathogenesis. Journal of neurovirology, 2002, 8 : 267-269.
40. Janeway, C.A., Jr., Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol, 1989, 54 (1 ): 1-13.
41. Jelley-Gibbs, D.M., Strutt, T.M., McKinstry, K.K., et al. Influencing the fates of CD4 T cells on the path to memory: lessons from influenza. Immunol Cell Biol, 2008,86 : 343-352.
42. Johnson, N., C. S. McKimmie, K. L. Mansfield, P. R. et al. Lyssavirus infection activates interferon gene expression in the brain. J Gen Virol, 2006, 87: 2663-2667.
43. Katou, F., Ohtani, H., Nakayama, T., et al. Macrophage-derived chemokine (MDC/CCL22) and CCR4 are involved in the formation of T lymphocyte-dendritic cell clusters in human inflamed skin and secondary lymphoid tissue. Am J Pathol, 2001, 158 : 1263-1270.
44. Kawai, T., Akira, S., Toll-like receptor and RIG-I-like receptor signaling. Ann N Y Acad Sci, 2008, 1143 : 1-20.
45. Kuang, Y., Lackay, S.N., Zhao, L., et al. Role of chemokines in the enhancement of BBB permeability and inflammatory infiltration after rabies virus infection. Virus Res, 2009, 144 : 18-26.
46. Langevin, C., Tuffereau, C., Mutations conferring resistance to neutralization by a soluble form of the neurotrophin receptor (p75NTR) map outside of the known antigenic sites of the rabies virus glycoprotein. J Virol, 2002, 76 : 10756-10765.
47. Leroy, M., Pire, G., Baise, E., et al. Expression of the interferon-alpha/beta-inducible bovine Mx1 dynamin interferes with replication of rabies virus. Neurobiol Dis, 2006, 21 : 515-521.
48. Lodmell, D.L., Arai, Y.T., Ewalt, L.C., Influence of cell type and virus upon lysis of rabies virus-infected cells by antibody and complement. Arch Virol, 1981, 70 : 147-155.
49. Martinez, L., Global infectious disease surveillance. Int J Infect Dis, 2000, 4 : 222-228.
50. McGettigan, J.P., Foley, H.D., Belyakov, I.M., et al. Rabies virus-based vectors expressing human immunodeficiency virus type 1 (HIV-1) envelope protein induce a strong, cross-reactive cytotoxic T-lymphocyte response against envelope proteins from different HIV-1 isolates. J Virol, 2001, 75: 4430-4434.
51. McKay, P.F., Barouch, D.H., Santra, S., et al. Recruitment of different subsets of antigen-presentingcells selectively modulates DNA vaccine-elicited CD4+ and CD8+ T lymphocyte responses. Eur J Immunol, 2004, 34 : 1011-1020.
52. Mebatsion, T., Weiland, F., Conzelmann, K.K., Matrix protein of rabies virus is responsible for the assembly and budding of bullet-shaped particles and interacts with the transmembrane spike glycoprotein G. J Virol, 1999, 73 : 242-250.
53. Mellman, I., Steinman, R.M., Dendritic cells: specialized and regulated antigen processing machines. Cell, 2001, 106 : 255-258.
54. Metcalf, D., Hematopoietic cytokines. Blood, 2008, 111 : 485-491.
55. Morrissey, P.J., Bressler, L., Park, L.S., et al. Granulocyte-macrophage colony-stimulating factor a gments the primary antibody response by enhancing the function of antigen-presenting cells. J Immunol, 1987, 139 : 1113-1119.
56. Nakamichi, K., Inoue, S., Takasaki, T., Morimoto, K., Kurane, I., 2004, Rabies virus stimulates nitric oxide production and CXC chemokine ligand 10 expression in macrophages thro gh activation of extracellular signal-regulated kinases 1 and 2. J Virol 78, 9376-9388.
57. Prehaud, C., Megret, F., Lafage, M., et al. Virus infection switches TLR-3-positive human neurons to become strong producers of beta interferon. J Virol, 2005, 79 : 12893-12904.
58. Rupprecht, C.E., Glickman, L.T., Spencer, P.A., et al. Epidemiology of rabies virus variants. Differentiation using monoclonal antibodies and discriminant analysis. Am J Epidemiol, 1987, 126 : 298-309.
59. Rupprecht, C.E., Smith, J.S., Fekadu, M., et al. The ascension of wildlife rabies: a cause for public health concern or intervention? Emerg Infect Dis, 1995, 1 : 107-114.
60. Rupprecht, C.E., Smith, J.S., Krebs, J.W., et al. Molecular epidemiology of rabies in the United States: reemergence of a classical neurotropic agent. J Neurovirol, 1997, 3 Suppl 1, S52-53.
61. Schaniel, C., Pardali, E., Sallusto, F., et al. Activated murine B lymphocytes and dendritic cells produce a novel CC chemokine which acts selectively on activated T cells. J Exp Med, 1998, 188 : 451-463.
62. Shi, Y., Liu, C.H., Roberts, A.I., Das, J., Xu, G., Ren, G., Zhang, Y., Zhang, L., Yuan, Z.R., Tan, H.S., Das, G., Devadas, S., 2006, Granulocyte-macrophage colony-stimulating factor (GM-CSF) and T-cell responses: what we do and don't know. Cell Res 16, 126-133.
63. Shim, E., Hampson, K., Cleaveland, S., et al. Evaluating the cost-effectiveness of rabiespost-exposure prophylaxis: a case study in Tanzania. Vaccine, 2009, 27 : 7167-7172.
64. Steece, R.S., Calisher, C.H., Evidence for prenatal transfer of rabies virus in the Mexican free-tailed bat (Tadarida brasiliensis Mexicana). J Wildl Dis, 1989, 25 : 329-334.
65. Tarr, P.E., Granulocyte-macrophage colony-stimulating factor and the immune system. Med Oncol, 1996, 13 : 133-140.
66. Teoh, D., Johnson, L.A., Hanke, T., et al. Blocking development of a CD8+ T cell response by targeting lymphatic recruitment of APC. J Immunol, 2009, 182 : 2425-2431.
67. Tirawatnpong, S., Hemachudha, T., Manutsathit, S., et al. Regional distribution of rabies viral antigen in central nervous system of human encephalitic and paralytic rabies. J Neurol Sci, 1989, 92 : 91-99.
68. Tolson, N.D., Charlton, K.M., Stewart, R.B., et al. Immune response in skunks to a vaccinia virus recombinant expressing the rabies virus glycoprotein. Can J Vet Res,1987, 51: 363-366.
69. Trabelsi, K., Rourou, S., Loukil, H., et al. Optimization of virus yield as a strategy to improve rabies vaccine production by Vero cells in a bioreactor. J Biotechnol, 2006, 121 : 261-271.
70. Trumpfheller, C., Tenner-Racz, K., Racz, P., et al. Expression of macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and RANTES genes in lymph nodes from HIV+ individuals: correlation with a Th1-type cytokine response. Clin Exp Immunol, 1998, 112 : 92-99.
71. Tuffereau, C., Desmezieres, E., Benejean, J., et al. Interaction of lyssaviruses with the low-affinity nerve-growth factor receptor p75NTR. J Gen Virol, 2001, 82 : 2861-2867.
72. Wandeler, A.I., Wildlife rabies in perspective. Onderstepoort J Vet Res, 1993, 60 : 347-350.
73. Wang, Z.W., Sarmento, L., Wang, Y., et al. Attenuated rabies virus activates, while pathogenic rabies virus evades, the host innate immune responses in the central nervous system. J Virol, 2005, 79 : 12554-12565.
74. Whetstone, C.A., Bunn, T.O., Emmons, R.W., et al. Use of monoclonal antibodies to confirm vaccine-induced rabies in ten dogs, two cats, and one fox. J Am Vet Med Assoc, 1984,185 : 285-288.
75. Wilson, N.S., El-Sukkari, D., Belz, G.T., et al. Most lymphoid organ dendritic cell types are phenotypically and functionally immature. Blood, 2003, 102 : 2187-2194.
76. Wu, M., Fang, H., Hwang, S.T., Cutting edge: CCR4 mediates antigen-primed T cell binding toactivated dendritic cells. J Immunol, 2001, 167 : 4791-4795.
77. Wu, X., Gong, X., Foley, H.D., et al. Both viral transcription and replication are reduced when the rabies virus nucleoprotein is not phosphorylated. J Virol, 2002, 76 : 4153-4161.
78. Yamashita, U., Kuroda, E., Regulation of macrophage-derived chemokine (MDC, CCL22) production. Crit Rev Immunol, 2002, 22 : 105-114.
79. Yoshie, O., Imai, T., Nomiyama, H., 2001, Chemokines in immunity. Adv Immunol 78, 57-110.
80. Zhao, L., Toriumi, H., Kuang, Y., et al. The roles of chemokines in rabies virus infection: overexpression may not always be beneficial. J Virol, 2009, 83 : 11808-11818.
81. Zlotnik, A., Morales, J., Hedrick, J.A., Recent advances in chemokines and chemokine receptors. Crit Rev Immunol, 1999, 19, 1-47.
2. Anderson, L.J., Nicholson, K.G., Tauxe, R.V., et al. Human rabies in the United States, 1960 to 1979: epidemiology, diagnosis, and prevention. Ann Intern Med, 1984, 100 : 728-735.
3. Anonymous. Compendium of Animal Rabies Prevention and Control. MMWR CDC Surveill Summ, 2000, 49:19-30.
4. Baer, G.M., Antiviral action of interferon in animal systems: effect of interferon on rabies infections of animals. Tex Rep Biol Med 1977, 35 : 461-471.
5. Bahloul, C., Jacob, Y., Tordo, N., et al. DNA-based immunization for exploring the enlargement of immunological cross-reactivity against the lyssaviruses. Vaccine, 1998,16 : 417-425.
6. Banchereau, J., Briere, F., Caux, C., et al. Immunobiology of dendritic cells. Annu Rev Immunol 2000, 18 : 767-811.
7. Banchereau, J., Steinman, R.M., et al. Dendritic cells and the control of immunity. Nature 1998, 392 : 245-252.
8. Becker, Y., Immunological and regulatory functions of uninfected and virus infected immature and mature subtypes of dendritic cells--a review. Virus Genes, 2003, 26 : 119-130.
9. Belz, G.T., Smith, C.M., Eichner, D., et al. Cutting edge: conventional CD8 alpha+ dendritic cells are generally involved in priming CTL immunity to viruses. J Immunol, 2004a, 172: 1996-2000.
10. Belz, G.T., Smith, C.M., Kleinert, L., et al. Distinct migrating and nonmigrating dendritic cell populations are involved in MHC class I-restricted antigen presentation after lung infection with virus. Proc Natl Acad Sci U S A, 2004b,101 : 8670-8675.
11. Brochier, B., Blancou, J., Thomas, I., et al. Use of recombinant vaccinia-rabies glycoprotein virus for oral vaccination of wildlife against rabies: innocuity to several non-target bait consuming species. J Wildl Dis, 1989, 25 : 540-547.
12. Bro ghan, J.H., Wunner, W.H., Characterization of protein involvement in rabies virus binding to BHK-21 cells. Arch Virol, 1995, 140 : 75-93.
13. Chantry, D., Romagnani, P., Raport, C.J., et al. Macrophage-derived chemokine is localized tothymic medullary epithelial cells and is a chemoattractant for CD3(+), CD4(+), CD8(low) thymocytes. Blood, 1999, 94 : 1890-1898.
14. Chen, B.P., Kuziel, W.A., Lane, T.E., Lack of CCR2 results in increased mortality and impaired leukocyte activation and trafficking following infection of the central nervous system with a neurotropic coronavirus. J Immunol, 2001,167 : 4585-4592.
15. Chenik, M., Chebli, K., Gaudin, Y., et al. In vivo interaction of rabies virus phosphoprotein (P) and nucleoprotein (N): existence of two N-binding sites on P protein. J Gen Virol, 1994, 75 ( Pt 11), 2889-2896.
16. Clark, E.A., Regulation of B lymphocytes by dendritic cells. J Exp Med, 1997,185 : 801-803.
17. Crampton, S.P., Voynova, E., Bolland, S., Innate pathways to B-cell activation and tolerance. Ann N Y Acad Sci, 2010,1183 : 58-68.
18. Dietzschold, B., Kao, M., Zheng, Y.M., et al. Delineation of putative mechanisms involved in antibody-mediated clearance of rabies virus from the central nervous system. Proceedings of the National Academy of Sciences of the United States of America, 1992, 89 : 7252-7256.
19. Dietzschold, B., Wunner, W.H., Wiktor, T.J., et al. Characterization of an antigenic determinant of the glycoprotein that correlates with pathogenicity of rabies virus. Proc Natl Acad Sci U S A, 1983, 80 : 70-74.
20. Disis, M.L., Bernhard, H., Shiota, F.M., et al. Granulocyte-macrophage colony-stimulating factor: an effective adjuvant for protein and peptide-based vaccines. Blood, 1996, 88 : 202-210.
21. Dorner, B.G., Scheffold, A., Rolph, M.S., et al. MIP-1alpha, MIP-1beta, RANTES, and ATAC/lymphotactin function together with IFN-gamma as type 1 cytokines. Proc Natl Acad Sci U S A, 2002, 99 : 6181-6186.
22. Dubois, B., Bridon, J.M., Fayette, J., et al. Dendritic cells directly modulate B cell growth and differentiation. J Leukoc Biol, 1999, 66 : 224-230.
23. Esh, J.B., Cunningham, J.G., Wiktor, T.J., Vaccine-induced rabies in four cats. J Am Vet Med Assoc,1982, 180 : 1336-1339.
24. Faber, M., Pulmanausahakul, R., Hodawadekar, S.S., et al. Overexpression of the rabies virus glycoprotein results in enhancement of apoptosis and antiviral immune response. J Virol, 2002, 76 : 3374-3381.
25. Finke, S., Mueller-Waldeck, R., Conzelmann, K.K., Rabies virus matrix protein regulates thebalance of virus transcription and replication. J Gen Virol, 2003, 84 :1613-1621.
26. Foley, H.D., McGettigan, J.P., Siler, C.A., et al. A recombinant rabies virus expressing vesicular stomatitis virus glycoprotein fails to protect against rabies virus infection. Proceedings of the National Academy of Sciences of the United States of America, 2000, 97 : 14680-14685.
27. Frazatti-Gallina, N.M., Mourao-Fuches, R.M., Paoli, R.L., et al. Vero-cell rabies vaccine produced using serum-free medium. Vaccine, 2004, 23, 511-517.
28. Fu, Z.F., Rabies and rabies research: past, present and future. Vaccine, 1997, 15 : S20-24.
29. Godiska, R., Chantry, D., Raport, C.J., et al. Human macrophage-derived chemokine (MDC), a novel chemoattractant for monocytes, monocyte-derived dendritic cells, and natural killer cells. J Exp Med, 1997, 185 : 1595-1604.
30. Haddad, D., Ramprakash, J., Sedegah, M., et al. Plasmid vaccine expressing granulocyte-macrophage colony-stimulating factor attracts infiltrates including immature dendritic cells into injected muscles. J Immunol, 2000, 165 : 3772-3781.
31. Hamilton, J.A., Anderson, G.P., GM-CSF Biology. Growth Factors, 2004, 22 : 225-231.
32. Hemachudha, T., Human rabies: clinical aspects, pathogenesis, and potential therapy. Curr Top Microbiol Immunol, 1994,187 : 121-143.
33. Hercus, T.R., Thomas, D., Guthridge, M.A., et al. The granulocyte-macrophage colony-stimulating factor receptor: linking its structure to cell signaling and its role in disease. Blood, 2009, 114: 1289-1298.
34. Hooper, D.C., Morimoto, K., Bette, M., et a. Collaboration of antibody and inflammation in clearance of rabies virus from the central nervous system. J Virol, 1998, 72 : 3711-3719.
35. Iellem, A., Mariani, M., Lang, R.,et al. Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 by CD4(+)CD25(+) regulatory T cells. J Exp Med, 2001, 194 : 847-853.
36. Imai, T., Nagira, M., Takagi, S., et al. Selective recruitment of CCR4-bearing Th2 cells toward antigen-presenting cells by the CC chemokines thymus and activation-regulated chemokine and macrophage-derived chemokine. Int Immunol, 1999, 11 : 81-88.
37. Inaba, K., Inaba, M., Romani, N., et al. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J Exp Med, 1992, 176 : 1693-1702.
38. Iwasaki, Y., Sako, K., Tsunoda, I., et al. Phenotypes of mononuclear cell infiltrates in human central nervous system. Acta Neuropathol, 1993, 85 : 653-657.
39. Jackson, A.C., Rabies pathogenesis. Journal of neurovirology, 2002, 8 : 267-269.
40. Janeway, C.A., Jr., Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol, 1989, 54 (1 ): 1-13.
41. Jelley-Gibbs, D.M., Strutt, T.M., McKinstry, K.K., et al. Influencing the fates of CD4 T cells on the path to memory: lessons from influenza. Immunol Cell Biol, 2008,86 : 343-352.
42. Johnson, N., C. S. McKimmie, K. L. Mansfield, P. R. et al. Lyssavirus infection activates interferon gene expression in the brain. J Gen Virol, 2006, 87: 2663-2667.
43. Katou, F., Ohtani, H., Nakayama, T., et al. Macrophage-derived chemokine (MDC/CCL22) and CCR4 are involved in the formation of T lymphocyte-dendritic cell clusters in human inflamed skin and secondary lymphoid tissue. Am J Pathol, 2001, 158 : 1263-1270.
44. Kawai, T., Akira, S., Toll-like receptor and RIG-I-like receptor signaling. Ann N Y Acad Sci, 2008, 1143 : 1-20.
45. Kuang, Y., Lackay, S.N., Zhao, L., et al. Role of chemokines in the enhancement of BBB permeability and inflammatory infiltration after rabies virus infection. Virus Res, 2009, 144 : 18-26.
46. Langevin, C., Tuffereau, C., Mutations conferring resistance to neutralization by a soluble form of the neurotrophin receptor (p75NTR) map outside of the known antigenic sites of the rabies virus glycoprotein. J Virol, 2002, 76 : 10756-10765.
47. Leroy, M., Pire, G., Baise, E., et al. Expression of the interferon-alpha/beta-inducible bovine Mx1 dynamin interferes with replication of rabies virus. Neurobiol Dis, 2006, 21 : 515-521.
48. Lodmell, D.L., Arai, Y.T., Ewalt, L.C., Influence of cell type and virus upon lysis of rabies virus-infected cells by antibody and complement. Arch Virol, 1981, 70 : 147-155.
49. Martinez, L., Global infectious disease surveillance. Int J Infect Dis, 2000, 4 : 222-228.
50. McGettigan, J.P., Foley, H.D., Belyakov, I.M., et al. Rabies virus-based vectors expressing human immunodeficiency virus type 1 (HIV-1) envelope protein induce a strong, cross-reactive cytotoxic T-lymphocyte response against envelope proteins from different HIV-1 isolates. J Virol, 2001, 75: 4430-4434.
51. McKay, P.F., Barouch, D.H., Santra, S., et al. Recruitment of different subsets of antigen-presentingcells selectively modulates DNA vaccine-elicited CD4+ and CD8+ T lymphocyte responses. Eur J Immunol, 2004, 34 : 1011-1020.
52. Mebatsion, T., Weiland, F., Conzelmann, K.K., Matrix protein of rabies virus is responsible for the assembly and budding of bullet-shaped particles and interacts with the transmembrane spike glycoprotein G. J Virol, 1999, 73 : 242-250.
53. Mellman, I., Steinman, R.M., Dendritic cells: specialized and regulated antigen processing machines. Cell, 2001, 106 : 255-258.
54. Metcalf, D., Hematopoietic cytokines. Blood, 2008, 111 : 485-491.
55. Morrissey, P.J., Bressler, L., Park, L.S., et al. Granulocyte-macrophage colony-stimulating factor a gments the primary antibody response by enhancing the function of antigen-presenting cells. J Immunol, 1987, 139 : 1113-1119.
56. Nakamichi, K., Inoue, S., Takasaki, T., Morimoto, K., Kurane, I., 2004, Rabies virus stimulates nitric oxide production and CXC chemokine ligand 10 expression in macrophages thro gh activation of extracellular signal-regulated kinases 1 and 2. J Virol 78, 9376-9388.
57. Prehaud, C., Megret, F., Lafage, M., et al. Virus infection switches TLR-3-positive human neurons to become strong producers of beta interferon. J Virol, 2005, 79 : 12893-12904.
58. Rupprecht, C.E., Glickman, L.T., Spencer, P.A., et al. Epidemiology of rabies virus variants. Differentiation using monoclonal antibodies and discriminant analysis. Am J Epidemiol, 1987, 126 : 298-309.
59. Rupprecht, C.E., Smith, J.S., Fekadu, M., et al. The ascension of wildlife rabies: a cause for public health concern or intervention? Emerg Infect Dis, 1995, 1 : 107-114.
60. Rupprecht, C.E., Smith, J.S., Krebs, J.W., et al. Molecular epidemiology of rabies in the United States: reemergence of a classical neurotropic agent. J Neurovirol, 1997, 3 Suppl 1, S52-53.
61. Schaniel, C., Pardali, E., Sallusto, F., et al. Activated murine B lymphocytes and dendritic cells produce a novel CC chemokine which acts selectively on activated T cells. J Exp Med, 1998, 188 : 451-463.
62. Shi, Y., Liu, C.H., Roberts, A.I., Das, J., Xu, G., Ren, G., Zhang, Y., Zhang, L., Yuan, Z.R., Tan, H.S., Das, G., Devadas, S., 2006, Granulocyte-macrophage colony-stimulating factor (GM-CSF) and T-cell responses: what we do and don't know. Cell Res 16, 126-133.
63. Shim, E., Hampson, K., Cleaveland, S., et al. Evaluating the cost-effectiveness of rabiespost-exposure prophylaxis: a case study in Tanzania. Vaccine, 2009, 27 : 7167-7172.
64. Steece, R.S., Calisher, C.H., Evidence for prenatal transfer of rabies virus in the Mexican free-tailed bat (Tadarida brasiliensis Mexicana). J Wildl Dis, 1989, 25 : 329-334.
65. Tarr, P.E., Granulocyte-macrophage colony-stimulating factor and the immune system. Med Oncol, 1996, 13 : 133-140.
66. Teoh, D., Johnson, L.A., Hanke, T., et al. Blocking development of a CD8+ T cell response by targeting lymphatic recruitment of APC. J Immunol, 2009, 182 : 2425-2431.
67. Tirawatnpong, S., Hemachudha, T., Manutsathit, S., et al. Regional distribution of rabies viral antigen in central nervous system of human encephalitic and paralytic rabies. J Neurol Sci, 1989, 92 : 91-99.
68. Tolson, N.D., Charlton, K.M., Stewart, R.B., et al. Immune response in skunks to a vaccinia virus recombinant expressing the rabies virus glycoprotein. Can J Vet Res,1987, 51: 363-366.
69. Trabelsi, K., Rourou, S., Loukil, H., et al. Optimization of virus yield as a strategy to improve rabies vaccine production by Vero cells in a bioreactor. J Biotechnol, 2006, 121 : 261-271.
70. Trumpfheller, C., Tenner-Racz, K., Racz, P., et al. Expression of macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and RANTES genes in lymph nodes from HIV+ individuals: correlation with a Th1-type cytokine response. Clin Exp Immunol, 1998, 112 : 92-99.
71. Tuffereau, C., Desmezieres, E., Benejean, J., et al. Interaction of lyssaviruses with the low-affinity nerve-growth factor receptor p75NTR. J Gen Virol, 2001, 82 : 2861-2867.
72. Wandeler, A.I., Wildlife rabies in perspective. Onderstepoort J Vet Res, 1993, 60 : 347-350.
73. Wang, Z.W., Sarmento, L., Wang, Y., et al. Attenuated rabies virus activates, while pathogenic rabies virus evades, the host innate immune responses in the central nervous system. J Virol, 2005, 79 : 12554-12565.
74. Whetstone, C.A., Bunn, T.O., Emmons, R.W., et al. Use of monoclonal antibodies to confirm vaccine-induced rabies in ten dogs, two cats, and one fox. J Am Vet Med Assoc, 1984,185 : 285-288.
75. Wilson, N.S., El-Sukkari, D., Belz, G.T., et al. Most lymphoid organ dendritic cell types are phenotypically and functionally immature. Blood, 2003, 102 : 2187-2194.
76. Wu, M., Fang, H., Hwang, S.T., Cutting edge: CCR4 mediates antigen-primed T cell binding toactivated dendritic cells. J Immunol, 2001, 167 : 4791-4795.
77. Wu, X., Gong, X., Foley, H.D., et al. Both viral transcription and replication are reduced when the rabies virus nucleoprotein is not phosphorylated. J Virol, 2002, 76 : 4153-4161.
78. Yamashita, U., Kuroda, E., Regulation of macrophage-derived chemokine (MDC, CCL22) production. Crit Rev Immunol, 2002, 22 : 105-114.
79. Yoshie, O., Imai, T., Nomiyama, H., 2001, Chemokines in immunity. Adv Immunol 78, 57-110.
80. Zhao, L., Toriumi, H., Kuang, Y., et al. The roles of chemokines in rabies virus infection: overexpression may not always be beneficial. J Virol, 2009, 83 : 11808-11818.
81. Zlotnik, A., Morales, J., Hedrick, J.A., Recent advances in chemokines and chemokine receptors. Crit Rev Immunol, 1999, 19, 1-47.