Mechanisms and Consequences of Human Cytomegalovirus-Induced Cell Fusion

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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.