Polarized Cell Migration during Cell-to-Cell Transmission of Herpes Simplex Virus in Human Skin Keratinocytes

Abstract

In addition to transmission involving extracellular free particles, a generally accepted model of virus propagation is one wherein virus replicates in one cell, producing infectious particles that transmit to the next cell via cell junctions or induced polarized contacts. This mechanism of spread is especially important in the presence of neutralizing antibody, and the concept underpins analysis of virus spread, plaque size, viral and host functions, and general mechanisms of virus propagation. Here, we demonstrate a novel process involved in cell-to-cell transmission of herpes simplex virus (HSV) in human skin cells that has not previously been appreciated. Using time-lapse microscopy of fluorescent viruses, we show that HSV infection induces the polarized migration of skin cells into the site of infection. In the presence of neutralizing antibody, uninfected skin cells migrate to the initial site of infection and spread over infected cells to become infected in a spatially confined cluster containing hundreds of cells. The cells in this cluster do not undergo cytocidal cell lysis but harbor abundant enveloped particles within cells and cell-free virus within interstitial regions below the cluster surface. Cells at the base and outside the cluster were generally negative for virus immediate-early expression. We further show, using spatially separated monolayer assays, that at least one component of this induced migration is the paracrine stimulation of a cytotactic response from infected cells to uninfected cells. The existence of this process changes our concept of virus transmission and the potential functions, virus, and host factors involved.

A novel divergent group of Ostreid herpesvirus 1 μVar variants associated with a mortality event in Pacific oyster spat in Normandy (France) in 2016

“…() did not detect wrapped virus during TEM observations. They suspected, as reported in other herpesviruses (Abaitua, Zia, Hollinshead, & O'Hare, ; Sattentau, ), the involvement of extracellular unenveloped particles in virus infection propagation within the host and a direct cell‐to‐cell spread. Cardiomyocytes and fibroblasts have been previously described as target cells for viral replication (Renault, Flaujac, & Le Deuff, ; Renault, Le Deuff et al., ), but OsHV‐1 pathogenesis is far to be fully understood.…”

Global Mapping of O-Glycosylation of Varicella Zoster Virus, Human Cytomegalovirus, and Epstein-Barr Virus

“…Given that O-glycosylation often protects from cleavage, the different extent of glycosylation could potentially be a co-regulatory mechanism for cell tropism, because gp42 is not required for infection of epithelial cells (75,106). The same site might also play a role in interaction with gH-gL, because it mapped to one of the regions required for high affinity binding (107). The immunoevasin UL16 in HCMV represents another example where a glycosylation site is mapped to an interaction surface, which down-regulates NKG2D ligand MICB expression at the cell surface and subsequent detection by NK cells (72).…”

Upsetting the Balance: When Viruses Manipulate Cell Polarity Control

“…Herpes simplex viruses (HSV1 and HSV2), cytomegalovirus, and the varicella zoster virus (VZV) infect epithelial cells where the lytic, or productive, virus life cycle occurs and it is not clear whether the polarity of these cells is involved in the virus replication cycle. However, in plaque assays, HSV infection has been shown to induce polarized cell migration (MCP) in uninfected keratinocytes, which migrate toward the site of infection, and become infected in their turn, [126], while VZV glycoprotein E expression colocalizes with the ZO1 TJ protein and can increase cell-cell contacts and enhance TJ formation in low calcium, presumably to allow cell-tocell spread of the virus particles [127]. The cytomegalovirus gpUS9 protein has similarly been reported to colocalize with cell junction components such as ZO1 and E-cadherin in polarized epithelial cells [128], although this finding has been disputed [129].…”