Mechanisms and Consequences of Human Cytomegalovirus-Induced Cell Fusion

人巨细胞病毒诱导细胞融合的机制和后果

• 批准号: 503799379
• 负责人: Professor Dr. Wolfram Brune
• 金额: --
• 依托单位: Leibniz-Institut für Virologie (LIV)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/503799379?language=en
• 关键词: Mechanisms; Consequences; Human; Cytomegalovirus; Induced

Congenital HCMV infection is the most common congenital infection worldwide, affecting approximately 1% of all newborns. Up to 15% of congenitally infected children suffer from long-term neurological sequelae such as sensineural hearing loss or mental retardation. Little is known about the viral and host factors determining the likelihood of transplacentar virus transmission and pathogenicity in the offspring.HCMV infects many different cell types and tissues in its human host. Epithelial and myeloid cells play important roles in viral dissemination. Some of the HCMV-encoded protein show substantial variability, suggesting that HCMV strains with different pathogenicity exist. Viral envelope glycoproteins, which interact with entry receptors and mediate fusion of the viral envelope with cellular membranes, have been proposed as determinants of viral genotypes and genotype-associated pathogenicity because they are targets of neutralizing antibodies. However, functional differences of viral glycoproteins in viral attachment, fusion, and entry have not been evaluated as the basis of pathogenicity.We have recently shown that strain-specific variants in the HCMV envelope glycoprotein B (gB) can cause rapid viral entry into cells, cell fusion (syncytium formation), and cellular genome instability. Moreover, results of others have shown that syncytium-forming HCMV strains are present in congenital HCMV isolates. These results give rise to the question whether functional differences of viral glycoproteins might be the basis of strain-specific differences in transmission and pathogenicity.In the proposed project we want to identify variants of HCMV envelope glycoproteins that mediate cell fusion in fibroblasts, epithelial cells, and macrophages. We will use characterized HCMV strains as well as congenital HCMV isolates to determine which envelope glycoproteins contribute to a syncytial phenotype and whether syncytium-forming variants are a frequent occurrence in congenital HCMV isolates. Finally, we will infect human placental tissue samples ex vivo to determine variant-specific differences in the infection of relevant cell types. Moreover, we aim to establish a system that allows us to evaluate the pathogenicity of syncytial variants in a small animal model.

先天性HCMV感染是世界范围内最常见的先天性感染，约占所有新生儿的1%。高达15%的先天性感染儿童患有长期的神经系统后遗症，如感觉神经性听力损失或智力迟钝。目前对决定经胎盘病毒在后代中传播和致病性的病毒和宿主因素知之甚少。HCMV感染人类宿主中许多不同的细胞类型和组织。上皮细胞和骨髓细胞在病毒传播中起重要作用。一些HCMV编码的蛋白质显示出很大的变异性，表明存在具有不同致病性的HCMV毒株。病毒包膜糖蛋白与进入受体相互作用并介导病毒包膜与细胞膜的融合，已被认为是病毒基因型和基因型相关致病性的决定因素，因为它们是中和抗体的靶标。然而，在病毒的附着，融合，并进入病毒糖蛋白的功能差异还没有被评估为基础的致病性。我们最近表明，株特异性的变体在HCMV包膜糖蛋白B（g B）可以导致快速病毒进入细胞，细胞融合（合胞体形成），和细胞基因组的不稳定性。此外，其他人的结果表明，合胞体形成HCMV株存在于先天性HCMV分离株中。这些结果引起的问题是否病毒糖蛋白的功能差异可能是基础上的菌株特异性差异的传输和pathogenicity.In拟议的项目中，我们要确定的HCMV包膜糖蛋白的变体，介导细胞融合成纤维细胞，上皮细胞和巨噬细胞。我们将使用表征的HCMV毒株以及先天性HCMV分离株来确定哪些包膜糖蛋白有助于合胞体表型以及合胞体形成变体是否在先天性HCMV分离株中频繁发生。最后，我们将离体感染人类胎盘组织样本，以确定相关细胞类型感染中的变体特异性差异。此外，我们的目标是建立一个系统，使我们能够在小动物模型中评估合胞体变体的致病性。