Differences in affinity of binding of lymphocytic choriomeningitis virus strains to the cellular receptor α-dystroglycan correlate with viral tropism and disease kinetics
Differences in affinity of binding of lymphocytic choriomeningitis virus strains to the cellular receptor α-dystroglycan correlate with viral tropism and disease kinetics
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DOI：
10.1128/jvi.75.1.448-457.2001
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发表时间：
2001-01-01
影响因子：
5.4
通讯作者：
Oldstone, MBA
中科院分区：
文献类型：
--
作者：
Smelt, SC;Borrow, P;Oldstone, MBA
最近发现α -糖醛酸失调蛋白（α -DG）是淋巴细胞性脉络膜脑膜炎病毒（LCMV）和其他沙粒病毒（包括拉沙热病毒）的受体（W. Cao， M. D. Henry， P. Borrow， H. Yamada， J. H. Elder， E. V. Ravkov， S. T. Nichol， R. W. Compans， K. P. Campbell和M. B. a . Oldstone, Science, 282:2079-2081, 1998）。本文的数据表明，LCMV与或DG结合的亲和力决定了病毒在小鼠体内的趋向性和感染结果。为了描述这种关系，我们评估了α -DG与几种LCMV菌株、变体和重组之间的相互作用。这些病毒根据与α -DG结合的亲和力、对该蛋白进入细胞的依赖性、病毒的趋向性和病程可分为两组。与α -DG具有高亲和力结合的病毒在进入细胞时明显依赖α -DG，并被1至4 nM可溶性α -DG阻断感染小鼠3T6成纤维细胞。此外，与α -DG的高亲和力结合与浸润脾脏白髓（t依赖）区域的能力相关，在感染后第7天引起细胞毒性t淋巴细胞（CTL）反应的消融，并建立持续感染。相比之下，与α - dg结合亲和力较低的病毒仅部分抑制α - dg（-/-）胚胎干细胞的感染，并且需要高于100 nM的可溶性α - dg浓度才能阻止小鼠3T6成纤维细胞的感染。这些低亲和力结合的病毒主要局限于脾红髓，宿主产生有效的CTL反应，迅速清除感染。以高亲和力和低亲和力结合α -DG的病毒重组体被用于将导致所述差异的基因定位到含有病毒附着蛋白糖蛋白1的S RNA。
alpha -Dystroglycan (alpha -DG) was recently identified as a receptor for lymphocytic choriomeningitis virus (LCMV) and several other arenaviruses, including Lassa fever virus (W. Cao, M. D. Henry, P. Borrow, H. Yamada, J. H. Elder, E. V. Ravkov, S. T. Nichol, R. W. Compans, K. P. Campbell, and M. B. A. Oldstone, Science 282:2079-2081, 1998). Data presented in this paper indicate that the affinity of binding of LCMV to or DG determines viral tropism and the outcome of infection in mice. To characterize this relationship, we evaluated the interaction between alpha -DG and several LCMV strains, variants, and reassortants. These viruses could be divided into two groups with respect to affinity of binding to alpha -DG, dependence on this protein for cell entry, viral tropism, and disease course. Viruses that exhibited high-affinity binding to alpha -DG displayed a marked dependence on alpha -DG for cell entry and were blocked from infecting mouse 3T6 fibroblasts by 1 to 4 nM soluble alpha -DG. In addition, high-affinity binding to alpha -DG correlated with an ability to infiltrate the white pulp (T-dependent) area of the spleen, cause ablation of the cytotoxic T-lymphocyte (CTL) response by day 7 postinfection, and establish a persistent infection. In contrast, viruses,vith a lower affinity of binding to alpha -DG were only partially inhibited from infecting alpha -DG(-/-) embryonic stem cells and required a concentration of soluble alpha -DG higher than 100 nM to prevent infection of mouse 3T6 fibroblasts. These viruses that bound at low affinity were mainly restricted to the splenic red pulp, and the host generated an effective CTL response that rapidly cleared the infection. Reassortants of viruses that bound to alpha -DG at high and low affinities were used to map genes responsible for the differences described to the S RNA, containing the virus attachment protein glycoprotein 1.