Cell Fusion and Syncytium Formation in Betaherpesvirus Infection

Abstract

Cell–cell fusion is a fundamental and complex process that occurs during reproduction, organ and tissue growth, cancer metastasis, immune response, and infection. All enveloped viruses express one or more proteins that drive the fusion of the viral envelope with cellular membranes. The same proteins can mediate the fusion of the plasma membranes of adjacent cells, leading to the formation of multinucleated syncytia. While cell–cell fusion triggered by alpha- and gammaherpesviruses is well-studied, much less is known about the fusogenic potential of betaherpesviruses such as human cytomegalovirus (HCMV) and human herpesviruses 6 and 7 (HHV-6 and HHV-7). These are slow-growing viruses that are highly prevalent in the human population and associated with several diseases, particularly in individuals with an immature or impaired immune system such as fetuses and transplant recipients. While HHV-6 and HHV-7 are strictly lymphotropic, HCMV infects a very broad range of cell types including epithelial, endothelial, mesenchymal, and myeloid cells. Syncytia have been observed occasionally for all three betaherpesviruses, both during in vitro and in vivo infection. Since cell–cell fusion may allow efficient spread to neighboring cells without exposure to neutralizing antibodies and other host immune factors, viral-induced syncytia may be important for viral dissemination, long-term persistence, and pathogenicity. In this review, we provide an overview of the viral and cellular factors and mechanisms identified so far in the process of cell–cell fusion induced by betaherpesviruses and discuss the possible consequences for cellular dysfunction and pathogenesis.

A Virus Genetic System To Analyze the Fusogenicity of Human Cytomegalovirus Glycoprotein B Variants

“…HCMV gB, encoded by open reading frame UL55, is the most abundant glycoprotein present on the HCMV envelope [12]. gB is essential for virus entry into target cells and for cell-cell fusion [13,14]. Full-length gB consists of more than 900 amino acids and comprises an N-terminal signal peptide (aa 1-22), an ectodomain with five distinct antigenic domains (domain I to V; aa 23-705), a membrane-proximal region (MPR; aa 706-751), a transmembrane domain (TM; aa 752-796), and a cytoplasmic tail (Cyto; aa 797-906) [14,15].…”

Envelope-Fusion-Syncytium Formation in Microplitis bicoloratus bracovirus Maturation

“…In addition, the number of nucleocapsids in the fused viruses was not constant ( Figure 2 (C1–C3)), red arrow and number). Our TEM images provide the first evidence of fused viral envelopes, indicating that envelope fusion in the nuclei of calyx cells is similar to membrane fusion during beta herpesvirus-mediated syncytium formation [ 6 ].…”

“…Envelope fusion is a dynamic process; further, envelope fusion and cell syncytium formation possess many similarities, and both are mediated by viral proteins, forming a state of multiple nuclei or multiple nucleocapsids. Although some studies suggest that envelope proteins affecting cell syncytium formation also affect virus maturation [ 6 , 17 , 18 , 19 ], the relationship of these proteins with envelope fusion is unclear. Since envelope fusion depends on envelope proteins, diversity exists in the fusion structure.…”

“…Virus-mediated syncytium formation is induced by viral envelope proteins, which cause membrane fusion of the infected cells [ 6 , 7 , 8 , 9 , 10 ]. However, viral envelope fusion has not been reported previously.…”

Monocyte–Macrophage Lineage Cell Fusion

“…Cell fusion (fusogenesis, syncytiogenesis) is widespread in natural and pathological conditions in prokaryotes and eukaryotes. It occurs, for example, during fertilization (fusion of gametes), embryogenesis (placenta/trophoblast fusion), morphogenesis, tissue development (muscle cell and osteoclast formation), tissue and organ repair, immune response, tumor development, and pathogen infection and spreading [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. Depending on applied criteria, cell fusion can be divided into homotypic (fusion of the same cell types) versus heterotypic (different cell type fusion), and synkaryotic (homotypic or heterotypic nuclei merge creating mononuclear syncytium) versus heterokaryotic (homotypic or heterotypic multinucleated syncytium) ( Figure 2 A; [ 30 , 31 , 32 , 33 ]).…”