Function of bovine CD46 as a cellular receptor for bovine viral diarrhea virus is determined by complement control protein 1
Function of bovine CD46 as a cellular receptor for bovine viral diarrhea virus is determined by complement control protein 1
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DOI：
10.1128/jvi.80.8.3912-3922.2006
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发表时间：
2006-04-01
影响因子：
5.4
通讯作者：
Rümenapf, T
中科院分区：
文献类型：
--
作者：
Krey, T;Himmelreich, A;Rümenapf, T
疫病病毒牛病毒性腹泻病毒(BVDV)被证明与牛CD46分子结合，从而促进病毒进入。为了解BVDV 1型(BVDV-1)和BVDV-2(BVDV-2)的受体利用情况，对30株BVDV临床分离株进行了抗CD46抗体敏感性检测。除单个例外，所有受试BVDV-1和BVDV-2毒株的感染性均被抗CD46抗体抑制，这表明CD46作为BVDV受体的普遍用途。通过定位CD46分子上的病毒结合部位，对CD46与BVD病毒粒子的相互作用进行了分子分析。牛CD46中的单个补体控制蛋白模块(CCP)被删除或被猪CD46的类似CCP取代，猪CD46不与BVDV结合。虽然抗CD46单抗识别的阻断BVDV感染的表位属于CCP1和CCP2，但在功能分析中，只有CCP1是BVDV结合和感染所必需的。在CCP1中，位于反平行的β链上的两个短肽被鉴定为对BVDV的结合至关重要。这两个肽序列的交换足以导致牛CD46功能的丧失和猪CD46功能的获得。对CD46大小限制的测定表明，最小长度为4个CCP是受体功能所必需的。通过插入1~6个牛C4结合蛋白CCP来增加病毒结合域与质膜之间的距离，对BVDV的敏感性影响很小。
The pestivirus bovine viral diarrhea virus (BVDV) was shown to bind to the bovine CD46 molecule, which subsequently promotes entry of the virus. To assess the receptor usage of BVDV type 1 (BVDV-1) and BVDV-2, 30 BVDV isolates including clinical samples were assayed for their sensitivity to anti-CD46 antibodies. With a single exception the infectivity of all tested strains of BVDV-1 and BVDV-2 was inhibited by anti-CD46 antibodies, which indicates the general usage of CD46 as a BVDV receptor. Molecular analysis of the interaction between CD46 and the BVD virion was performed by mapping the virus binding site on the CD46 molecule. Single complement control protein modules (CCPs) within the bovine CD46 were either deleted or replaced by analogous CCPs of porcine CD46, which does not bind BVDV. While the epitopes recognized by anti-CD46 monoclonal antibodies which block BVDV infection were attributed to CCP1 and CCP2, in functional assays only CCP1 turned out to be essential for BVDV binding and infection. Within CCP1 two short peptides on antiparallel beta strands were identified as crucial for the binding of BVDV. Exchanges of these two peptide sequences were sufficient for a loss of function in bovine CD46 as well as a gain of function in porcine CD46. Determination of the size constraints of CD46 revealed that a minimum length of four CCPs is essential for receptor function. An increase of the distance between the virus binding domain and the plasma membrane by insertion of one to six CCPs of bovine C4 binding protein exhibited only a minor influence on susceptibility to BVDV.