Cellular entry of hantaviruses which cause hemorrhagic fever with renal syndrome is mediated by β3 integrins
Cellular entry of hantaviruses which cause hemorrhagic fever with renal syndrome is mediated by β3 integrins
复制标题
DOI：
10.1128/jvi.73.5.3951-3959.1999
复制
发表时间：
1999-05-01
影响因子：
5.4
通讯作者：
Mackow, ER
中科院分区：
文献类型：
--
作者：
Gavrilovskaya, IN;Brown, EJ;Mackow, ER
汉坦病毒主要在血管内皮中复制，并引起两种人类疾病：肾综合征出血热（HFRS）和汉坦病毒肺综合征（HPS）。在本报告中，我们证明了在血小板、内皮细胞和巨噬细胞上表达的特异性整合素促进了hfrs相关汉坦病毒的细胞进入。hfrs引起的汉坦病毒Hantaan （HTN）、Seoul （SEO）和Puumala （PUU）感染人脐静脉内皮细胞和Vero E6细胞可被α (v) β(3)整合素抗体和整合素配体vitronectin抑制。通过将重组α (IIb) β(3)或α (v) β(3)整合素引入β(3)-整合素缺失的CHO细胞，HTN、SEO和PUU病毒进入细胞，但非致病性Prospect Hill （PH）汉坦病毒（即一种没有相关人类疾病的病毒）不进入细胞。此外，PH传染性不受α (v) β(3)特异性血清或玻璃体连接蛋白的抑制，但被α (5) β(1)特异性血清和整合素配体纤维连接蛋白阻断。所有汉坦病毒G1和G2表面糖蛋白中都不存在整合素配体相互作用所需的RGD三肽，并且GRGDSP肽对汉坦病毒的传染性没有抑制作用。此外，小鼠-人杂化β(3)整合素特异性Fab片段c7E3 （ReoPro）也能抑制HTN、SEO和PUU以及hps相关汉坦病毒Sin Nombre （SN）和New York-1 （NY-1）的感染性。这些发现表明致病性HPS和hfrs引起的汉坦病毒通过β(3)整合素进入细胞，β(3)整合素存在于血小板、内皮细胞和巨噬细胞表面。由于β(3)整合素调节血管通透性和血小板功能，这些发现也将β(3)整合素的使用与汉坦病毒发病机制的共同因素联系起来。
Hantaviruses replicate primarily in the vascular endothelium and cause two human diseases, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). In this report, we demonstrate that the cellular entry of HFRS-associated hantaviruses is facilitated by specific integrins expressed on platelets, endothelial cells, and macrophages. Infection of human umbilical vein endothelial cells and Vero E6 cells by the HFRS-causing hantaviruses Hantaan (HTN), Seoul (SEO), and Puumala (PUU) is inhibited by antibodies to alpha(v)beta(3) integrins and by the integrin ligand vitronectin. The cellular entry of HTN, SEO, and PUU viruses, but not the nonpathogenic Prospect Hill (PH) hantavirus (i.e., a virus with no associated human disease), was also mediated by introducing recombinant alpha(IIb)beta(3) or alpha(v)beta(3) integrins into beta(3)-integrin-deficient CHO cells. In addition, PH infectivity was not inhibited by alpha(v)beta(3)-specific sera or vitronectin but was blocked by alpha(5)beta(1)-specific sera and the integrin ligand fibronectin. RGD tripeptides, which are required for many integrin-ligand interactions, are absent from all hantavirus G1 and G2 surface glycoproteins, and GRGDSP peptides did not inhibit hantavirus infectivity. Further, a mouse-human hybrid beta(3) integrin-specific Fab fragment, c7E3 (ReoPro), also inhibited the infectivity of HTN, SEO, and PUU as well as HPS-associated hantaviruses, Sin Nombre (SN) and New York-1 (NY-1). These findings indicate that pathogenic HPS- and HFRS-causing hantaviruses enter cells via beta(3) integrins, which are present on the surfaces of platelets, endothelial cells, and macrophages. Since beta(3) integrins regulate vascular permeability and platelet function, these findings also correlate beta(3) integrin usage with common elements of hantavirus pathogenesis.