Valsamakis A, Auwaerter P G, Rima B K, Kaneshima H, Griffin D E
Molecular Microbiology and Immunology, Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland, USA.
J Virol. 1999 Oct;73(10):8791-7. doi: 10.1128/JVI.73.10.8791-8797.1999.
To understand the molecular determinants of measles virus (MV) virulence, we have used the SCID-hu thymus/liver xenograft model (SCID-hu thy/liv) in which in vivo MV virulence phenotypes are faithfully duplicated. Stromal epithelial and monocytic cells are infected by MV in thymus implants, and virulent strains induce massive thymocyte apoptosis, although thymocytes are not infected. To determine whether passage of an avirulent vaccine strain in human tissue increases virulence, we studied a virus isolated from thymic tissue 90 days after infection with the vaccine strain Moraten (pMor-1) and a virus isolated from an immunodeficient child with progressive vaccine-induced disease (Hu2). These viruses were compared to a minimally passaged wild-type Edmonston strain (Ed-wt) and the vaccine strain Moraten. pMor-1, Hu2, and Ed-wt displayed virulent phenotypes in thymic implants, with high levels of virus being detected by 3 days after infection (10(5.2), 10(2.8), and 10(3. 4), respectively) and maximal levels being detected between 7 and 14 days after infection. In contrast, Moraten required over 14 days to grow to detectable levels. pMor-1 produced the highest levels of virus throughout infection, suggesting thymic adaptation of this strain. Similar to other virulent strains, Ed-wt, Hu2, and pMor-1 caused a decrease in the number of viable thymocytes as assessed by trypan blue exclusion and fluorescence-activated cell sorter analysis. Thymic architecture was also disrupted by these strains. Sequence analysis of the hemagglutinin (H) and matrix (M) genes showed no common changes in Hu2 and pMor-1. M sequences were identical in pMor-1 and Mor and varied in H at amino acid 469 (threonine to alanine), a position near the base of propeller 4 in the propeller blade/stem model of H structure. Further study will provide insights into the determinants of virulence.
为了解麻疹病毒（MV）毒力的分子决定因素，我们使用了重症联合免疫缺陷小鼠-人胸腺/肝脏异种移植模型（SCID-hu thy/liv），该模型能如实地重现MV在体内的毒力表型。在胸腺植入物中，基质上皮细胞和单核细胞会被MV感染，尽管胸腺细胞未被感染，但强毒株会诱导大量胸腺细胞凋亡。为确定减毒疫苗株在人体组织中传代是否会增加毒力，我们研究了一株在感染疫苗株莫拉坦（Moraten）90天后从胸腺组织中分离出的病毒（pMor-1）以及一株从患有进行性疫苗诱导疾病的免疫缺陷儿童中分离出的病毒（Hu2）。将这些病毒与传代次数极少的野生型埃德蒙斯顿毒株（Ed-wt）和疫苗株莫拉坦进行比较。pMor-1、Hu2和Ed-wt在胸腺植入物中表现出强毒表型，感染后3天就能检测到高水平的病毒（分别为10(5.2)、10(2.8)和10(3.4)），在感染后7至14天检测到最高水平。相比之下，莫拉坦需要超过14天才能生长到可检测水平。在整个感染过程中，pMor-1产生的病毒水平最高，表明该毒株对胸腺有适应性。与其他强毒株类似，Ed-wt、Hu2和pMor-1通过台盼蓝排斥法和荧光激活细胞分选仪分析评估，导致存活胸腺细胞数量减少。这些毒株也破坏了胸腺结构。血凝素（H）和基质（M）基因的序列分析显示，Hu2和pMor-1没有共同变化。pMor-1和莫拉坦的M序列相同，H序列在氨基酸469处不同（苏氨酸变为丙氨酸），该位置在H结构的螺旋桨叶片/茎模型中螺旋桨4的基部附近。进一步的研究将深入了解毒力的决定因素。
