Welstead G Grant, Iorio Caterina, Draker Ryan, Bayani Jane, Squire Jeremy, Vongpunsawad Sompong, Cattaneo Roberto, Richardson Christopher D
Department of Medical Biophysics, University of Toronto, 610 University Avenue, Toronto, ON, Canada M5C 2C8.
Proc Natl Acad Sci U S A. 2005 Nov 8;102(45):16415-20. doi: 10.1073/pnas.0505945102. Epub 2005 Oct 31.
A transgenic mouse containing the complete human SLAM (hSLAM/CD150) gene, including its endogenous promoter for transcription, was generated by using human genomic DNA cloned into a bacterial artificial chromosome. hSLAM, the primary receptor for measles viruses (MV), was expressed on activated B, T, and dendritic cells with an expression profile equivalent to that of humans. We demonstrated that hSLAM(+) cells obtained from the transgenic mouse, including activated B, T, and dendritic cells, were susceptible to MV infection in a receptor-dependent manner. Evidence was provided for transient infection in the nasal lymph nodes of hSLAM(+) mice after intranasal inoculation. Virus was rapidly cleared without signs of secondary replication. To improve the efficiency of MV production, the hSLAM(+) mice were bred with mice having a Stat1-deficient background. These mice were more susceptible to MV infection and produced more virus particles. After intranasal and intraperitoneal inoculation of these mice with MV, infections of the thymus, spleen, nasal, mesenteric, and leg lymph nodes were detected. Upon necropsy, enlarged lymph nodes and spleen were apparent. Flow cytometric analysis showed that abnormally large numbers of mature neutrophils and natural killer cells caused the splenomegaly. The hSLAM transgenic mouse constitutes an improved rodent model for studying the interaction of MV with immune cells that more accurately reflects the infection pattern found in humans.
通过使用克隆到细菌人工染色体中的人类基因组DNA，构建了一种转基因小鼠，其包含完整的人类信号淋巴细胞激活分子（hSLAM/CD150）基因，包括其用于转录的内源性启动子。hSLAM是麻疹病毒（MV）的主要受体，在活化的B细胞、T细胞和树突状细胞上表达，其表达谱与人类相当。我们证明，从转基因小鼠获得的hSLAM(+)细胞，包括活化的B细胞、T细胞和树突状细胞，以受体依赖的方式易受MV感染。有证据表明，经鼻接种后，hSLAM(+)小鼠的鼻淋巴结出现短暂感染。病毒迅速清除，无二次复制迹象。为提高MV的生产效率，将hSLAM(+)小鼠与具有Stat1缺陷背景的小鼠进行杂交。这些小鼠对MV感染更敏感，产生更多病毒颗粒。经鼻和腹腔接种MV后，在这些小鼠的胸腺、脾脏、鼻、肠系膜和腿部淋巴结中检测到感染。尸检时，可见淋巴结和脾脏肿大。流式细胞术分析表明，异常大量的成熟中性粒细胞和自然杀伤细胞导致脾肿大。hSLAM转基因小鼠构成了一种改进的啮齿动物模型，用于研究MV与免疫细胞的相互作用，能更准确地反映人类的感染模式。
