登革热动物模型研究进展
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摘要
在过去的几十年间,随着社会发展和气候变暖等原因,登革热在全球的流行范围不断扩大、发病率急剧上升,已成为一个全球性公共卫生问题。建立理想的登革热动物模型对研究登革病毒感染及发病机制至关重要。鉴于登革病毒的种属特异性及特殊的致病机制,登革病毒感染动物模型的建立面临诸多挑战。登革病毒感染免疫缺陷小鼠,可产生高水平的病毒复制和严重的临床表现,如血管通透性增加及血小板下降等;但部分症状与人类不同,如出现神经症状。登革病毒感染人源化小鼠模型,可研究人体对登革病毒的部分免疫反应,但并不全面和准确。登革病毒可感染非人灵长类动物,但通常不产生明显的临床症状。因此,仍需进一步研究各种登革病毒感染模型,建立更理想的动物模型,支撑登革病毒发病机制研究及抗病毒药物、疫苗的临床前评价。本文汇集了近年来建立登革病毒感染动物模型的研究进展以及动物模型在病毒发病机制、疫苗评估、药物测试等方面的应用情况,为登革病毒感染模型的研究和应用提供参考信息。
An increase in the global population and climate warming over the past few decades has increased the global epidemic and incidence of Dengue fever, which is now a global public health problem. It is essential to establish ideal animal models of Dengue fever to study the infection mechanism and pathogenesis of Dengue virus. In view of the species specificity and specific pathogenesis of Dengue virus, research on animal models of Dengue virus infection faces many challenges. Specifically, immunodeficient mice infected with Dengue virus produce high levels of viral replication and severe disease manifestations, such as increased vascular permeability and thrombocytopenia; however, some symptoms such as neurological symptoms differ from those of humans. The humanized mouse model of Dengue virus infection can study the human immune response to Dengue virus, but it is not comprehensive or accurate. Dengue virus also effectively infects non-human primates, although they do not usually develop significant clinical symptoms. Therefore, it is necessary to improve and establish Dengue virus infection models to support research on the pathogenesis of Dengue virus and the preclinical evaluation of antiviral drugs and vaccines. This paper brings together the research progress of animal models of Dengue virus infection in recent years, and provides reference information for the research and application of the Dengue virus infection model.
An increase in the global population and climate warming over the past few decades has increased the global epidemic and incidence of Dengue fever, which is now a global public health problem. It is essential to establish ideal animal models of Dengue fever to study the infection mechanism and pathogenesis of Dengue virus. In view of the species specificity and specific pathogenesis of Dengue virus, research on animal models of Dengue virus infection faces many challenges. Specifically, immunodeficient mice infected with Dengue virus produce high levels of viral replication and severe disease manifestations, such as increased vascular permeability and thrombocytopenia; however, some symptoms such as neurological symptoms differ from those of humans. The humanized mouse model of Dengue virus infection can study the human immune response to Dengue virus, but it is not comprehensive or accurate. Dengue virus also effectively infects non-human primates, although they do not usually develop significant clinical symptoms. Therefore, it is necessary to improve and establish Dengue virus infection models to support research on the pathogenesis of Dengue virus and the preclinical evaluation of antiviral drugs and vaccines. This paper brings together the research progress of animal models of Dengue virus infection in recent years, and provides reference information for the research and application of the Dengue virus infection model.
引文
[1] Sarathy VV,Infante E,Li L,et al.Characterization of lethal Dengue virus type 4 (DENV-4) TVP-376 infection in mice lacking both IFN-alpha/beta and IFN-gamma receptors (AG129) and comparison with the DENV-2 AG129 mouse model [J].J Gen Virol,2015,96(10):3035-3048.
[2] Zompi S,Harris E.Animal models of Dengue virus infection [J].Viruses,2012,4(1):62-82.
[3] Valdes I,Gil L,Castro J,et al.Olive baboons:a non-human primate model for testing Dengue virus type 2 replication [J].Int J Infect Dis,2013,17(12):e1176-1181.
[4] Huang KJ,Li SY,Chen SC,et al.Manifestation of thrombocytopenia in Dengue-2-virus-infected mice [J].J Gen Virol,2000,81(Pt 9):2177-2182.
[5] Paes MV,Pinhao AT,Barreto DF,et al.Liver injury and viremia in mice infected with Dengue-2 virus [J].Virology,2005,338(2):236-246.
[6] Runtuwene LR,Konishi E,Yamanaka A,et al.Dengue transmission model by means of viremic adult immuno-competent mouse [J].Parasit Vectors,2014,7:143.
[7] Shresta S,Sharar KL,Prigozhin DM,et al.Murine model for Dengue virus-induced lethal disease with increased vascular permeability [J].J Virol,2006,80(20):10208-10217.
[8] Zellweger RM,Prestwood TR,Shresta S.Enhanced infection of liver sinusoidal endothelial cells in a mouse model of antibody-induced severe Dengue disease [J].Cell Host Microbe,2010,7(2):128-139.
[9] Tan GK,Ng JK,Trasti SL,et al.A non mouse-adapted Dengue virus strain as a new model of severe Dengue infection in AG129 mice [J].PLoS Negl Trop Dis,2010,4(4):e672.
[10] Sarathy VV,White M,Li L,et al.A lethal murine infection model for Dengue virus 3 in AG129 mice deficient in type I and II interferon receptors leads to systemic disease [J].J Virol,2015,89(2):1254-1266.
[11] Milligan GN,Sarathy VV,Infante E,et al.A Dengue virus type 4 model of disseminated lethal infection in AG129 mice [J].PLoS One,2015,10(5):e0125476.
[12] Sukupolvi-Petty S,Brien JD,Austin SK,et al.Functional analysis of antibodies against Dengue virus type 4 reveals strain-dependent epitope exposure that impacts neutralization and protection [J].J Virol,2013,87(16):8826-8842.
[13] Orozco S,Schmid MA,Parameswaran P,et al.Characterization of a model of lethal Dengue virus 2 infection in C57BL/6 mice deficient in the alpha/beta interferon receptor [J].J Gen Virol,2012,93(Pt 10):2152-2157.
[14] Milligan GN,Sarathy VV,White MM,et al.A lethal model of disseminated Dengue virus type 1 infection in AG129 mice [J].J Gen Virol,2017,98(10):2507-2519.
[15] Zust R,Toh YX,Valdes I,et al.Type I interferon signals in macrophages and dendritic cells control Dengue virus infection:implications for a new mouse model to test Dengue vaccines [J].J Virol,2014,88(13):7276-7285.
[16] Tang WW,Grewal R,Shresta S.Influence of antibodies and T cells on Dengue disease outcome:insights from interferon receptor-deficient mouse models [J].Curr Opin Virol,2015,13:61-66.
[17] Bente DA,Melkus MW,Garcia JV,et al.Dengue fever in humanized NOD/SCID mice [J].J Virol,2005,79(21):13797-13799.
[18] Jaiswal S,Pearson T,Friberg H,et al.Dengue virus infection and virus-specific HLA-A2 restricted immune responses in humanized NOD-scidIL2rγnull mice [J].PLoS One,2009,4(10):e7251.
[19] Mota J,Rico-Hesse R.Humanized mice show clinical signs of Dengue fever according to infecting virus genotype [J].J Virol,2009,83(17):8638-8645.
[20] Mota J,Rico-Hesse R.Dengue virus tropism in humanized mice recapitulates human Dengue fever [J].PLoS One,2011,6(6):e20762.
[21] Guirakhoo F,Pugachev K,Zhang Z,et al.Safety and efficacy of chimeric yellow fever-Dengue virus tetravalent vaccine formulations in nonhuman primates [J].J Virol,2004,78(9):4761-4775.
[22] Robert Putnak J,Coller BA,Voss G,et al.An evaluation of Dengue type-2 inactivated,recombinant subunit,and live-attenuated vaccine candidates in the rhesus macaque model [J].Vaccine,2005,23(35):4442-4452.
[23] Bischof GF,Magnani DM,Ricciardi M,et al.Use of a recombinant γ-2 herpesvirus vaccine vector against Dengue virus in rhesus monkeys [J].J Virol,2017,91(16).
[24] Fernandez S,Thomas SJ,De La Barrera R,et al.An adjuvanted,tetravalent Dengue virus purified inactivated vaccine candidate induces long-lasting and protective antibody responses against Dengue challenge in rhesus macaques [J].Am J Trop Med Hyg,2015,92(4):698-708.
[25] Ferreira MS,de Castro PH,Silva GA,et al.Callithrix penicillata:a feasible experimental model for Dengue virus infection [J].Immunol Lett,2014,158(1-2):126-133.
[26] Moi ML,Takasaki T,Omatsu T,et al.Demonstration of marmosets (Callithrix jacchus) as a non-human primate model for secondary Dengue virus infection:high levels of viraemia and serotype cross-reactive antibody responses consistent with secondary infection of humans [J].J Gen Virol,2014,95(Pt 3):591-600.
[27] Guzman MG,Harris E.Dengue [J].Lancet,2015,385(9966):453-465.
[28] Elong Ngono A,Chen HW,Tang WW,et al.Protective role of cross-reactive CD8 T cells against Dengue virus infection [J].EBioMedicine,2016,13:284-293.
[29] Zellweger RM,Tang WW,Eddy WE,et al.CD8+ T cells can mediate short-term protection against heterotypic Dengue virus reinfection in mice [J].J Virol,2015,89(12):6494-6505.
[30] Guabiraba R,Ryffel B.Dengue virus infection:current concepts in immune mechanisms and lessons from murine models [J].Immunology,2014,141(2):143-156.
[31] Jaiswal S,Smith K,Ramirez A,et al.Dengue virus infection induces broadly cross-reactive human IgM antibodies that recognize intact virions in humanized BLT-NSG mice [J].Exp Biol Med (Maywood),2015,240(1):67-78.
[32] Talarico LB,Batalle JP,Byrne AB,et al.The role of heterotypic DENV-specific CD8+ T lymphocytes in an immunocompetent mouse model of secondary Dengue virus infection [J].EBioMedicine,2017,20:202-216.
[33] Barros VE,dos Santos-Junior NN,Amarilla AA,et al.Differential replicative ability of clinical Dengue virus isolates in an immunocompetent C57BL/6 mouse model [J].BMC Microbiol,2015,15:189.
[34] Frias-Staheli N,Dorner M,Marukian S,et al.Utility of humanized BLT mice for analysis of Dengue virus infection and antiviral drug testing [J].J Virol,2014,88(4):2205-2218.
[35] Pinto AK,Brien JD,Lam CY,et al.Defining new therapeutics using a more immunocompetent mouse model of antibody-enhanced Dengue virus infection [J].MBio,2015,6(5):e01316-01315.
[2] Zompi S,Harris E.Animal models of Dengue virus infection [J].Viruses,2012,4(1):62-82.
[3] Valdes I,Gil L,Castro J,et al.Olive baboons:a non-human primate model for testing Dengue virus type 2 replication [J].Int J Infect Dis,2013,17(12):e1176-1181.
[4] Huang KJ,Li SY,Chen SC,et al.Manifestation of thrombocytopenia in Dengue-2-virus-infected mice [J].J Gen Virol,2000,81(Pt 9):2177-2182.
[5] Paes MV,Pinhao AT,Barreto DF,et al.Liver injury and viremia in mice infected with Dengue-2 virus [J].Virology,2005,338(2):236-246.
[6] Runtuwene LR,Konishi E,Yamanaka A,et al.Dengue transmission model by means of viremic adult immuno-competent mouse [J].Parasit Vectors,2014,7:143.
[7] Shresta S,Sharar KL,Prigozhin DM,et al.Murine model for Dengue virus-induced lethal disease with increased vascular permeability [J].J Virol,2006,80(20):10208-10217.
[8] Zellweger RM,Prestwood TR,Shresta S.Enhanced infection of liver sinusoidal endothelial cells in a mouse model of antibody-induced severe Dengue disease [J].Cell Host Microbe,2010,7(2):128-139.
[9] Tan GK,Ng JK,Trasti SL,et al.A non mouse-adapted Dengue virus strain as a new model of severe Dengue infection in AG129 mice [J].PLoS Negl Trop Dis,2010,4(4):e672.
[10] Sarathy VV,White M,Li L,et al.A lethal murine infection model for Dengue virus 3 in AG129 mice deficient in type I and II interferon receptors leads to systemic disease [J].J Virol,2015,89(2):1254-1266.
[11] Milligan GN,Sarathy VV,Infante E,et al.A Dengue virus type 4 model of disseminated lethal infection in AG129 mice [J].PLoS One,2015,10(5):e0125476.
[12] Sukupolvi-Petty S,Brien JD,Austin SK,et al.Functional analysis of antibodies against Dengue virus type 4 reveals strain-dependent epitope exposure that impacts neutralization and protection [J].J Virol,2013,87(16):8826-8842.
[13] Orozco S,Schmid MA,Parameswaran P,et al.Characterization of a model of lethal Dengue virus 2 infection in C57BL/6 mice deficient in the alpha/beta interferon receptor [J].J Gen Virol,2012,93(Pt 10):2152-2157.
[14] Milligan GN,Sarathy VV,White MM,et al.A lethal model of disseminated Dengue virus type 1 infection in AG129 mice [J].J Gen Virol,2017,98(10):2507-2519.
[15] Zust R,Toh YX,Valdes I,et al.Type I interferon signals in macrophages and dendritic cells control Dengue virus infection:implications for a new mouse model to test Dengue vaccines [J].J Virol,2014,88(13):7276-7285.
[16] Tang WW,Grewal R,Shresta S.Influence of antibodies and T cells on Dengue disease outcome:insights from interferon receptor-deficient mouse models [J].Curr Opin Virol,2015,13:61-66.
[17] Bente DA,Melkus MW,Garcia JV,et al.Dengue fever in humanized NOD/SCID mice [J].J Virol,2005,79(21):13797-13799.
[18] Jaiswal S,Pearson T,Friberg H,et al.Dengue virus infection and virus-specific HLA-A2 restricted immune responses in humanized NOD-scidIL2rγnull mice [J].PLoS One,2009,4(10):e7251.
[19] Mota J,Rico-Hesse R.Humanized mice show clinical signs of Dengue fever according to infecting virus genotype [J].J Virol,2009,83(17):8638-8645.
[20] Mota J,Rico-Hesse R.Dengue virus tropism in humanized mice recapitulates human Dengue fever [J].PLoS One,2011,6(6):e20762.
[21] Guirakhoo F,Pugachev K,Zhang Z,et al.Safety and efficacy of chimeric yellow fever-Dengue virus tetravalent vaccine formulations in nonhuman primates [J].J Virol,2004,78(9):4761-4775.
[22] Robert Putnak J,Coller BA,Voss G,et al.An evaluation of Dengue type-2 inactivated,recombinant subunit,and live-attenuated vaccine candidates in the rhesus macaque model [J].Vaccine,2005,23(35):4442-4452.
[23] Bischof GF,Magnani DM,Ricciardi M,et al.Use of a recombinant γ-2 herpesvirus vaccine vector against Dengue virus in rhesus monkeys [J].J Virol,2017,91(16).
[24] Fernandez S,Thomas SJ,De La Barrera R,et al.An adjuvanted,tetravalent Dengue virus purified inactivated vaccine candidate induces long-lasting and protective antibody responses against Dengue challenge in rhesus macaques [J].Am J Trop Med Hyg,2015,92(4):698-708.
[25] Ferreira MS,de Castro PH,Silva GA,et al.Callithrix penicillata:a feasible experimental model for Dengue virus infection [J].Immunol Lett,2014,158(1-2):126-133.
[26] Moi ML,Takasaki T,Omatsu T,et al.Demonstration of marmosets (Callithrix jacchus) as a non-human primate model for secondary Dengue virus infection:high levels of viraemia and serotype cross-reactive antibody responses consistent with secondary infection of humans [J].J Gen Virol,2014,95(Pt 3):591-600.
[27] Guzman MG,Harris E.Dengue [J].Lancet,2015,385(9966):453-465.
[28] Elong Ngono A,Chen HW,Tang WW,et al.Protective role of cross-reactive CD8 T cells against Dengue virus infection [J].EBioMedicine,2016,13:284-293.
[29] Zellweger RM,Tang WW,Eddy WE,et al.CD8+ T cells can mediate short-term protection against heterotypic Dengue virus reinfection in mice [J].J Virol,2015,89(12):6494-6505.
[30] Guabiraba R,Ryffel B.Dengue virus infection:current concepts in immune mechanisms and lessons from murine models [J].Immunology,2014,141(2):143-156.
[31] Jaiswal S,Smith K,Ramirez A,et al.Dengue virus infection induces broadly cross-reactive human IgM antibodies that recognize intact virions in humanized BLT-NSG mice [J].Exp Biol Med (Maywood),2015,240(1):67-78.
[32] Talarico LB,Batalle JP,Byrne AB,et al.The role of heterotypic DENV-specific CD8+ T lymphocytes in an immunocompetent mouse model of secondary Dengue virus infection [J].EBioMedicine,2017,20:202-216.
[33] Barros VE,dos Santos-Junior NN,Amarilla AA,et al.Differential replicative ability of clinical Dengue virus isolates in an immunocompetent C57BL/6 mouse model [J].BMC Microbiol,2015,15:189.
[34] Frias-Staheli N,Dorner M,Marukian S,et al.Utility of humanized BLT mice for analysis of Dengue virus infection and antiviral drug testing [J].J Virol,2014,88(4):2205-2218.
[35] Pinto AK,Brien JD,Lam CY,et al.Defining new therapeutics using a more immunocompetent mouse model of antibody-enhanced Dengue virus infection [J].MBio,2015,6(5):e01316-01315.