Different Potential of C-Type Lectin-Mediated Entry between Marburg Virus Strains
Different Potential of C-Type Lectin-Mediated Entry between Marburg Virus Strains
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DOI：
10.1128/jvi.02021-09
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发表时间：
2010-05-01
影响因子：
5.4
通讯作者：
Takada, Ayato
中科院分区：
文献类型：
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作者：
Matsuno, Keita;Kishida, Noriko;Takada, Ayato
丝状病毒的糖蛋白(GP)负责病毒进入细胞。已知GP与细胞内的C型凝集素相互作用，使病毒附着在细胞上。由于丝状病毒的主要靶细胞表达C型凝集素，C型凝集素介导的进入被认为可能是病毒嗜性和致病的决定因素。我们利用水疱性口炎病毒(VSV)假型系统比较了Marburg病毒安哥拉株和Musoke株C型凝集素介导的导入效率。表达C型凝集素、人巨噬细胞半乳糖C型凝集素(HMGL)或树突状细胞特异性ICAM-3结合非整合素(DC-SIGN)的VSV(VSV-安哥拉)感染K562细胞比感染Musoke GP假型(VSV-Musoke)的K562细胞更有效。出乎意料的是，C型凝集素与GP上碳水化合物的结合亲和力与C型凝集素介导的进入的不同效率无关。定点突变确定了547位氨基酸，这改变了C型凝集素介导的进入效率。在GP的三维模型中，这种氨基酸非常接近组织蛋白酶加工的假定位置。有趣的是，在表达C型凝集素的K562细胞中，组织蛋白酶抑制剂降低VSV-安哥拉的感染性的效率低于VSV-Musoke，而在对照细胞中仅发现有限的差异。547位氨基酸对抑制物对病毒感染性的不同影响起关键作用。这些结果表明，C型凝集素介导的丝状病毒进入的效率不仅受控于C型凝集素与GP之间的结合亲和力，还受控于内体进入的机制，如组织蛋白酶的蛋白水解性处理。
The glycoproteins (GPs) of filoviruses are responsible for virus entry into cells. It is known that GP interacts with cellular C-type lectins for virus attachment to cells. Since primary target cells of filoviruses express C-type lectins, C-type lectin-mediated entry is thought to be a possible determinant of virus tropism and pathogenesis. We compared the efficiency of C-type lectin-mediated entry between Marburg virus strains Angola and Musoke by using a vesicular stomatitis virus (VSV) pseudotype system. VSV pseudotyped with Angola GP (VSV-Angola) infected K562 cells expressing the C-type lectin, human macrophage galactose-type C-type lectin (hMGL), or dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN) more efficiently than VSV pseudotyped with Musoke GP (VSV-Musoke). Unexpectedly, the binding affinity of the C-type lectins to the carbohydrates on GPs did not correlate with the different efficiency of C-type lectin-mediated entry. Site-directed mutagenesis identified the amino acid at position 547, which switched the efficiency of C-type lectin-mediated entry. In a three-dimensional model of GP, this amino acid was in close proximity to the putative site of cathepsin processing. Interestingly, the cathepsin inhibitors reduced the infectivity of VSV-Angola less efficiently than that of VSV-Musoke in C-type lectin-expressing K562 cells, whereas only a limited difference was found in control cells. The amino acid at position 547 was critical for the different effects of the inhibitors on the virus infectivities. These results suggest that the efficiency of C-type lectin-mediated entry of filoviruses is controlled not only by binding affinity between C-type lectins and GP but also by mechanisms underlying endosomal entry, such as proteolytic processing by the cathepsins.