Essential roles for soluble virion-associated heparan sulfonated proteoglycans and growth factors in human papillomavirus infections.
Essential roles for soluble virion-associated heparan sulfonated proteoglycans and growth factors in human papillomavirus infections.
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DOI：
10.1371/journal.ppat.1002519
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发表时间：
2012-02
期刊：
影响因子：
6.7
通讯作者：
Ozbun MA
中科院分区：
文献类型：
--
作者：
Surviladze Z;Dziduszko A;Ozbun MA
人乳头瘤病毒（HPV）的一部分感染与人类上皮肿瘤和癌症的发生有因果关系。像许多病原体一样，HPV进入靶细胞首先是通过与硫酸乙酰肝素蛋白聚糖（HSPG）细胞表面附着因子结合而启动的。然后病毒必须转移到不同的次级受体，这些受体负责病毒粒子的内化。尽管进行了深入研究，但HPV转移到次级受体的机制以及次级受体的性质一直不清楚。我们报道HPV16病毒粒子不是通过解离从结合的HSPG附着因子中释放出来，而是通过一种以前在病原体 - 宿主细胞相互作用中未报道过的过程释放出来。病毒粒子与HSPG（包括多配体聚糖 - 1）以及生物活性化合物（如生长因子）存在于有感染性的可溶性高分子量复合物中。基质金属蛋白酶抑制剂可阻止HSPG和病毒从细胞中释放，从而干扰病毒感染。通过共培养实验，我们证明与可溶性HSPG - 生长因子复合物相关的HPV能够感染缺乏HSPG的细胞。HPV - HSPG - 生长因子复合物与生长因子受体的相互作用会迅速激活对感染很重要的信号通路，而多种生长因子受体抑制剂会阻碍病毒诱导的信号传导和感染。多配体聚糖 - 1或表皮生长因子的缺失以及血清因子的去除会减少感染，而补充生长因子则会恢复感染。我们的研究结果支持一种感染模型，即HPV通过可溶性HSPG复合物篡夺正常宿主向细胞呈递生长因子的机制，作为一种与进入受体相互作用的新方法，而不依赖于病毒 - 细胞受体的直接相互作用。
120多种不同类型的人乳头瘤病毒（HPV）中的一部分是性传播感染最常见的原因。某些HPV还与全球约5%的癌症有关。像许多病原体一样，HPV在转移到更特异的摄取受体之前，首先与细胞上的硫酸乙酰肝素蛋白聚糖（HSPGs）结合。然而，对于触发HPV从HSPGs转移到促进进入的受体的机制知之甚少。作为专性寄生虫，病毒已经进化出许多劫持宿主细胞功能以引起感染的方法。我们报道了病原体 - 宿主相互作用的两种新机制。首先，结合的HPV粒子是在与HSPG和生长因子的活性复合物中从细胞中释放出来，而不是从糖类解离以结合次级受体。其次，HPV利用相关生长因子的特异性与它们的同源受体连接，而不是直接结合到细胞内化受体。在这些相互作用过程中传递的信号对HPV感染很重要。我们的研究为一种重要的病毒病原体的传播提供了新的见解，并揭示了微生物在感染宿主过程中可能重新利用正常细胞功能的新方法。同样，这项工作为HPV预防揭示了新的靶点。
A subset of human papillomavirus (HPV) infections is causally related to the development of human epithelial tumors and cancers. Like a number of pathogens, HPV entry into target cells is initiated by first binding to heparan sulfonated proteoglycan (HSPG) cell surface attachment factors. The virus must then move to distinct secondary receptors, which are responsible for particle internalization. Despite intensive investigation, the mechanism of HPV movement to and the nature of the secondary receptors have been unclear. We report that HPV16 particles are not liberated from bound HSPG attachment factors by dissociation, but rather are released by a process previously unreported for pathogen-host cell interactions. Virus particles reside in infectious soluble high molecular weight complexes with HSPG, including syndecan-1 and bioactive compounds, like growth factors. Matrix mellatoproteinase inhibitors that block HSPG and virus release from cells interfere with virus infection. Employing a co-culture assay, we demonstrate HPV associated with soluble HSPG-growth factor complexes can infect cells lacking HSPG. Interaction of HPV-HSPG-growth factor complexes with growth factor receptors leads to rapid activation of signaling pathways important for infection, whereas a variety of growth factor receptor inhibitors impede virus-induced signaling and infection. Depletion of syndecan-1 or epidermal growth factor and removal of serum factors reduce infection, while replenishment of growth factors restores infection. Our findings support an infection model whereby HPV usurps normal host mechanisms for presenting growth factors to cells via soluble HSPG complexes as a novel method for interacting with entry receptors independent of direct virus-cell receptor interactions. A subset of the >120 different types of human papillomaviruses (HPVs) are the most common cause of sexually transmitted infections. Certain HPVs are also associated with approximately 5% of all cancers worldwide. Like many pathogens, HPVs bind first to heparan sulfate proteoglycans (HSPGs) on cells before moving to more specific uptake receptors. However, relatively little is known about the mechanism(s) that triggers the translocation of HPV from HSPGs to the receptors that facilitate entry. As obligate parasites, viruses have evolved numerous means to hijack host cell functions to cause infection. We report two novel mechanisms of pathogen-host interactions. First, bound HPV particles are liberated from cells in an active complex with HSPGs and growth factors rather than dissociating from the sugars to engage secondary receptors. Second, HPV uses the specificity of the associated growth factors to bridge to their cognate receptors as opposed to direct binding to a cell internalization receptor. Signals transduced during these interactions are important for HPV infection. Our study provides new insights into the transmission of a significant viral pathogen and reveals novel means whereby microbes may repurpose normal cell functions during infection of their hosts. Likewise, this work uncovers new targets for HPV prophylaxis.
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