Herpes simplex virus infection of murine sensory ganglia induces proliferation of neuronal satellite cells

Abstract

Herpes simplex virus (HSV) is a virtually ubiquitous human pathogen that, following cutaneous infection, latently infects neurons of sensory ganglia. Satellite cells (SCs) ensheath and provide metabolic support for these neurons, and could potentially participate in controlling HSV disease. Although SCs are restrictive for HSV replication, hypercellularity of non-neuronal cells in ganglia is prominent during HSV infection in animal models. SCs proliferate in response to trauma, e.g. nerve cut or crush, but it is not known if proliferation occurs in response to viral infection. To address this issue, cell proliferation, measured by bromodeoxyuridine (BrdU) uptake, and immune infiltrate, measured by CD45 labelling, were examined during acute infection in a mouse model. Because SCs do not express CD45, the BrdU + CD45 2 cell subset represents the proliferating SC population. We report that during acute ganglionic HSV infection there is a substantial increase in SC numbers. We suggest that SC proliferation in response to HSV infection may occur in order to facilitate neuronal survival.Satellite cells (SCs) in the peripheral nervous system (PNS) physically and metabolically support neurons. Unlike neurons, SCs maintain the ability to divide in adult life, although these cells do not typically display evidence of rapid turnover. Consistent with this are findings of rare mitotic SCs and a small proportion of SCs labelled with tritiated thymidine present in ganglia of adult rodents and cats (Lieberman, 1976;Pannese, 1960;Wen et al., 1994). SCs proliferate in response to severe trauma, e.g. axotomy and nerve crush (Nathaniel & Nathaniel, 1973;Shinder et al., 1999), and proliferate in explant culture, in which ganglia are excised and cultured in vitro, eliminating invading blood cells while preserving structure (Wen et al., 1994). SCs proliferate in response to malnutrition, e.g. in vitamin E-deficient rats (Cecchini et al., 1999). It is proposed that proliferation of SCs in response to trauma facilitates neuronal recovery (Wen et al., 1994).The role of SCs in response to PNS infection by viruses, such as herpes simplex virus (HSV), is poorly characterized. During cutaneous infection HSV enters nerves and travels to sensory ganglia, where, after a brief bout of productive infection, it establishes latency in neurons. Neurons and SCs appear privileged in their response to HSV. In neurons this is reflected in an unusual ability to survive infection despite viral gene expression (Simmons & Tscharke, 1992), which in other cell types is typically associated with cell destruction (Roizman & Knipe, 2001). SCs undergo abortive infection with HSV, as shown by electron microscopy which finds only unenveloped virions in SCs (Hill et al., 1972) or no virions at all (Dillard et al., 1972). Viral antigens are rarely, if ever, found in SCs during acute ganglionic infection (Speck & Simmons, 1998). These studies suggest that efficient infection of SCs by HSV does not occur. Consistent with this are results of studies on infection of Sat....

Productive Varicella-Zoster Virus Infection of Cultured Intact Human Ganglia

“…1D and E). In both mock-and VZV-infected ganglia, the number of S100-expressing cells increased over time following explant, consistent with studies of mouse and rat sensory ganglia reporting that the process of explanting ganglia can induce satellite cell proliferation (6,28).…”

Satellite Glial Cells Surrounding Primary Afferent Neurons Are Activated and Proliferate during Monoarthritis in Rats: Is There a Role for ATF3?

“…In this case, proliferation started decreasing after this time-point [34]. Later, other BrdU incorporation studies showed that SGCs proliferate during Herpes Simplex virus infection, with increases up to 5 days of disease, the latest time point evaluated [35]. This was proposed to be part of a mechanism of neuronal survival during the disease [35].…”

“…Later, other BrdU incorporation studies showed that SGCs proliferate during Herpes Simplex virus infection, with increases up to 5 days of disease, the latest time point evaluated [35]. This was proposed to be part of a mechanism of neuronal survival during the disease [35]. The same group also found proliferation of SGC in an animal model of scarification of the skin, considered to be a model of minor tissue trauma [7].…”

Satellite glial cells in sensory ganglia: from form to function

“…It can be proposed that a breakdown of this barrier can lead to widespread infection of the ganglia. In DRG of HSV-infected mice there was a 3-fold increase in SGC compared with controls [44]. This proliferation could protect neurons against the virus or promote repair of damage in them.…”