Herpes simplex virus glycoproteins E and I facilitate cell-to-cell spread in vivo and across junctions of cultured cells

Abstract

Herpes simplex virus (HSV) glycoproteins E and I (gE and gI) can act as a receptor for the Fc domain of immunoglobulin G (IgG). To examine the role of HSV IgG Fc receptor in viral pathogenesis, rabbits and mice were infected by the corneal route with HSV gEor gImutants. Wild-type HSV-1 produced large dendritic lesions in the corneal epithelium and subsequent stromal disease leading to viral encephalitis, whereas gEand gImutant viruses produced microscopic punctate or small dendritic lesions in the epithelium and no corneal disease or encephalitis. These differences were not related to the ability of the gE-gI oligomer to bind IgG because the differences were observed before the appearance of anti-HSV IgG and in mice, in which IgG binds to the Fc receptor poorly or not at all. Mutant viruses produced small plaques on monolayers of normal human fibroblasts and epithelial cells. Replication of gE-and gImutant viruses in human fibroblasts were normal, and the rates of entry of mutant and wild-type viruses into fibroblasts were similar; however, spread of gEand gImutant viruses from cell to cell was significantly slower than that of wild-type HSV-1. In experiments in which fibroblast monolayers were infected with low multiplicities of virus and multiple rounds of infection occurred, the presence of neutralizing antibodies in the culture medium caused the yields of mutant viruses to drop dramatically, whereas there was a lesser effect on the production of wild-type HSV. It appears that cell-to-cell transmission of wild-type HSV-1 occurs by at least two mechanisms: (i) release of virus from cells and entry of extracellular virus into a neighboring cell and (ii) transfer of virus across cell junctions in a manner resistant to neutralizing antibodies. Our results suggest that gEand gImutants are defective in the latter mechanism of spread, suggesting the possibility that the gE-gI complex facilitates virus transfer across cell junctions, a mode of spread which may predominate in some tissues. It is ironic that the gE-gI complex, usually considered an IgG Fc receptor, may, through its ability to mediate cell-to-cell spread, actually protect HSV from IgG in a manner different than previously thought.

Insulin Degrading Enzyme Is a Cellular Receptor Mediating Varicella-Zoster Virus Infection and Cell-to-Cell Spread

“…A naturally occurring VZV mutant with a point mutation in gE shows accelerated cell-to-cell spread in cell culture and in human cells in SCID-hu mice (Santos et al, 2000). HSV gE, which is homologous to the VZV glycoprotein, is necessary for directing egress of virus to the basolateral surface of polarized cells (Collins and Johnson, 2003;Dingwell et al, 1994).…”

Herpesviral Fcγ receptors: culprits attenuating antiviral IgG?

“…The minimal mutation introduced into the gE mutants affected the IgG-related functions of gE:gI, but did not interfere with the other important gE function, i.e. to mediate direct cell-to-cell spread of nascent virions [95].…”

Host Src controls gallid alpha herpesvirus 1 intercellular spread in a cellular fatty acid metabolism-dependent manner

“…4). In addition, herpesviruses can travel from infected cells to neighbouring cells via budding at the basolateral intercellular junction or by crossing the tight junctions between cells (Cocchi et al, 2000;Dingwell et al, 1994;York and Johnson, 1993). Whether these mechanisms are responsible for the accelerated spread of ILTV that we observed remains unclear.…”

“…Numerous efforts have been made to elucidate the mechanisms involved in the intercellular spread of viruses. The simplest and most widely used model of cell-to-cell spread is plaque formation in cell cultures with or without the addition of a neutralizing antibody, which reflects the cumulative processes of the host-virus interaction, including viral binding, penetration and replication, reorganization of cell-to-cell junctions, viral intercellular transport, and restriction mechanisms used by the host to resist infection, such as antiviral immune responses and factors (Dingwell et al, 1994;Johnson et al, 2001;Mettenleiter et al, 2009). Such models have been frequently used to investigate the processes of cell-to-cell spread and the essential viral and host factors for these processes (Farnsworth and Johnson, 2006;Krummenacher et al, 2003;Sourvinos and Everett, 2002).…”