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

Karen Elson1, Peter Speck1 and Anthony Simmons2

1 Herpes Research Laboratory, Institute of Medical and Veterinary Science, Frome Road, Adelaide, SA 5000, Australia
2 Department of Pediatrics and Sealy Center for Vaccine Development, 2.330 Children's Hospital, 301 University Boulevard, Galveston, TX 77555-0373, USA

Correspondence
Peter Speck
peter.speck{at}imvs.sa.gov.au


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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- 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.


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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.1 cells, which is a clonally derived adult satellite cell line (Wilkinson et al., 1999). Sat.1 cells were shown to produce a thousandfold less infectious virus than Vero cells, a permissive line, and the total virus yield never exceeded inoculum. Overall these data suggest that SCs are restrictive for HSV replication. Consequently, it has been suggested that SCs assist in restricting intraneural virus spread in the PNS (Wilkinson et al., 1999). Finally, the potential immunologic functions of SCs are largely unexplored, although microglia, a central nervous system counterpart, have been suggested to have immune functions (Streit, 2002). In view of the SC proliferation in response to trauma, we hypothesized that SC proliferation may occur in response to PNS infection with HSV.

To determine whether experimental HSV infection of ganglia causes SC proliferation, uptake of the thymidine analogue bromodeoxyuridine (BrdU) (Bick & Davidson, 1974), readily detected by immunofluorescence (Gratzner, 1982), was used. We administered BrdU to mice and measured its incorporation in SCs after infecting skin within the same neurodermatome with HSV. The zosteriform model was used, in which skin is scarified through a droplet of virus suspension (Simmons & Nash, 1984). Because the hypercellularity found in ganglia during acute infection may in part reflect the presence of infiltrating immune cells, we enumerated immune cells by staining for CD45, present on all immune cells, as well as counting BrdU+ cells. Because SCs lack CD45, the BrdU+ CD45- subset of cells was interpreted as proliferating SCs.

We report that during acute ganglionic HSV infection, there is marked proliferation of SCs. We suggest that SCs participate in ganglionic responses to acute HSV infection and proliferate to facilitate clearance of virus from the PNS.

Female C57BL/6J mice >6 weeks old, from Laboratory Animal Services, University of Adelaide, were housed at the specific pathogen-free facility at the Institute of Medical and Veterinary Science, Adelaide. Virus, HSV strain SC16, was prepared as described (Speck & Simmons, 1991).

Animals drank water containing 0·8 mg BrdU (Sigma) ml-1 from 48 h prior to treatment until tissue collection. At this dose, mice do not display adverse effects from BrdU and gain weight and behave indistinguishably from normal mice over a BrdU administration period of up to 45 days (data not shown). Flanks of mice were infected as described (Speck & Simmons, 1991), by scarification through a droplet containing 5x105 p.f.u. of virus. In mock-infected animals, skin was scarified through cell culture medium. Infection was confirmed by assaying for HSV antigens in ganglionic sections taken on day 5 after inoculation (data not shown). Antigen staining was performed as described (Speck & Simmons, 1991).

Mice were killed and the eighth to thirteenth thoracic (T8–T13) dorsal root ganglia (DRG) were excised as described (Speck & Simmons, 1991). Thirty pooled DRG from groups of at least five animals were fixed, for BrdU staining, in PLP (McLean & Nakane, 1974) or, for CD45 staining, in zinc fixative (Beckstead, 1994), with gut and spleen tissues used as controls. Serial sections (5 µm) were collected and the number of individual ganglionic profiles per slide ranged from 4 to 15. Cross-sections through ganglia (ganglionic profiles) considered large enough in surface area to be included in analysis typically allowed visualization of approximately 100 to 150 neurons. Experiments were carried out in duplicate; thus for each timepoint typically >100 ganglionic profiles representing tissues from 10–15 animals were examined. Assessment for BrdU+ and CD45+ cells was performed on at least 10 sections randomly selected from over 70 sections cut from each tissue block. The number of ganglionic profiles per section and the total number of positive cells within each ganglionic section were counted. For each treatment block, the number of positive cells was divided by the number of ganglionic profiles to give the number of positive cells per ganglionic profile.

BrdU was detected by denaturing tissue with 2 M HCl and treating with 0·1 % trypsin, each for 30 min at 37 °C. The primary antibody, mouse monoclonal anti-BrdU (Sigma), was detected with FITC-conjugated goat anti-mouse IgG (Jackson). Non-specific binding was blocked by treating sections for 15 min in 8 % swine serum in PBS prior to addition of primary antibody. All antibodies were diluted in this solution. Omission of primary antibody provided negative controls. Sections were mounted in anti-fade solution (Johnson & Araujo, 1981). CD45 was detected with rat anti-mouse CD45 (PharMingen), followed with goat anti-rat whole IgG Cy3-conjugated Ab (Jackson).

SCs are the small cells surrounding sensory neurons (Fig. 1). In infected ganglia, these cells morphologically resemble infiltrating immune cells. Differing approaches have been taken to the controversial issue of identifying SCs, including morphology and perineural position (Cecchini et al., 1999; Lu & Richardson, 1991; Shimeld et al., 1995), staining for SC marker GFAP and lack of staining for macrophage marker ED2 (Zhou et al., 1999), and S100 staining (Bradley et al., 1997). Confirmation of SC identity is hampered by the reported lack of expression of the SC-specific markers GFAP and S100 during SC proliferation (Wen et al., 1994). In our hands, S100 and GFAP are down-regulated during proliferation and were deemed unsuitable for recognition of proliferating SCs. The only other plausible candidates for proliferating cells present in infected ganglia are leukocytes, which express the leukocyte-common antigen, CD45, (Johnson et al., 1997; Ledbetter & Herzenberg, 1979). Hence we elected to quantify proliferating SCs on the basis of morphology and perineural position, BrdU uptake and lack of CD45 expression. The numbers of CD45+ cells were subtracted from the numbers of proliferating (i.e. BrdU+) ganglionic cells to arrive at the number of proliferating SCs (i.e. the BrdU+ CD45- cell population). At early times after infection the BrdU+ cells could also be identified morphologically by their characteristic elongated shape and shell-like proximity to neurons.



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Fig. 1. (A) Low-power (approx. x100) view of a portion of haematoxylin and eosin-stained ganglionic profile, showing approximately 100 sensory neurons. (B) High-power (approx. x400) view of a sensory neuron, showing its associated ring of satellite cells.

 
Specificity of immunohistochemical labelling procedures was assessed as follows. BrdU+ cells are readily identified by nuclear-localized green fluorescence in cells taking up label. In BrdU-fed mice >95 % of gut epithelial cells were BrdU+ after 5 days of BrdU administration (Fig. 2A) whereas untreated animals had none (data not shown). In nervous tissue BrdU+ cells were morphologically varied and were evident throughout ganglia (Fig. 2B). Neurons, distinctively large, did not incorporate BrdU. There was no BrdU signal in tissue sections when primary antibody was omitted, or in tissue not acid denatured or trypsin digested prior to immunohistochemistry (data not shown). Spleen tissue was used as positive control for CD45 (Fig. 3A). Neurons, lacking CD45, provide a negative control within each section. CD45 signal was absent when primary antibody was omitted.



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Fig. 2. (A) Low-power view of a section of gut from a mouse fed BrdU in its drinking water. BrdU is detected using anti-BrdU antibodies followed by goat anti-mouse–FITC antibody. After 5 days of BrdU administration, >95 % of gut cells are labelled, consistent with the high turnover rate of these cells. (B) Low-power view of mouse ganglia showing BrdU uptake by satellite cells. After 5 days BrdU uptake, there are ca. five BrdU+ cells per ganglionic profile. This view encompasses two adjacent ganglionic profiles. (C) Low-power view of ganglionic profile from an HSV-infected mouse. Ganglia taken 5 days after abrasion typically show ca. 100–200 BrdU+ cells per ganglionic profile. (D) High-power (approx. x400) view of a ganglionic profile taken from a BrdU-fed mouse 5 days after infection of flank skin, showing a ring of BrdU+ cells which surround a sensory neuron (not visible in this fluorescent image).

 


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Fig. 3. (A) Positive control tissue for CD45 staining. Low-power view of section of mouse spleen, showing CD45 staining, detected using rat anti-mouse CD45 followed by goat anti-rat–Cy3 antibody. (B) CD45 signal on immune cells: this field is a high-power (approx. x400) view of a portion of a ganglionic profile of tissue, taken from a mouse 3 days after infection, showing approximately 10 CD45+ cells. In the negative control for CD45 staining, no signal was evident on mouse spleen sections when primary antibody was omitted (not shown).

 
There was a low background level of BrdU+ and CD45+ cells in sensory ganglia in uninfected animals (Table 1). BrdU treatment began 48 h before infection (day 0) and continued until mice were killed. Fig. 3(C) is a ypical ganglionic profile, showing approximately 10 CD45+ cells, from a mouse killed on day 3. CD45+ cell numbers were unaffected by BrdU administration in uninfected mice.


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Table 1. Numbers of BrdU+ and CD45+ cells per ganglionic profile in control, mock-infected and infected C57BL/6 mice

Sensory ganglia (T8–T13) pooled from groups of five C57BL/6 mice were analysed for the presence of BrdU+ and CD45+ cells by immunohistochemistry at several times following treatment. Control mice were either untreated, administered BrdU only, or mock-infected. Infected mice were scarified 20 times on flank skin through a droplet containing 5x105 p.f.u. of HSV-1 strain SC16. In the case of BrdU-only mice, times refer to the duration of BrdU administration. In other mice, BrdU administration commenced 48 h prior to infection and the times indicate the days after infection (i.e. infection was on day 0).

 
To quantify SC proliferation caused by HSV infection, numbers of BrdU+ and CD45+ cells per ganglionic profile were measured in infected, BrdU-treated mice on days 2, 3 and 5 and compared to mock-infected and uninfected controls. Table 1 shows the mean positive cells numbers, and standard deviations, derived from composite data from duplicate experiments. The relatively low standard deviations compared to the positive cell numbers reflect the low level of mouse-to-mouse variability in this model of infection. In mock-infected animals BrdU+ cell numbers increased in response to skin trauma. On day 3, BrdU+ cell numbers in infected animals did not differ markedly from those in mock-infected animals; however, by day 5 the number in infected animals was over three times that in mock-infected animals. Fig. 2(C) shows the typical appearance of BrdU+ cells in ganglia on day 5, with typically >150 BrdU+ cells.

Sections taken 3 and 5 days after infection provide morphological evidence of SC proliferation, e.g. in Fig. 2(D), a view of a day 5 ganglionic profile, and wherein are multiple BrdU± cells encircling a neuron (which is not visible in this immunofluorescent image). The juxtaposition of these BrdU+ cells to a sensory neuron, a feature we almost invariably observed in infected ganglia, is consistent with their being SCs.

Infection, confirmed by immunohistochemistry for HSV antigen expression in day 5 ganglia, resembled that previously described (Speck & Simmons, 1991), in that numerous antigen-positive neurons were present in each ganglionic profile (data not shown).

In infected mice, on day 2 there was a slight increase in CD45+ cell numbers compared with controls, with an appreciable increase on day 3. By day 5 CD45+ cell numbers had doubled in tissues from infected animals while remaining at baseline in mock-infected and uninfected animals.

The increase in CD45+ cells per ganglionic profile on day 3 may account for some BrdU+ cells at that time; thus on day 3 there is a relatively low level of BrdU+ CD45- cells in ganglia from infected animals. However on day 5, BrdU+ cell numbers tripled, and while numbers of CD45+ cells increased, they do not account for total BrdU+ cells. Infected animals had over double the number of BrdU+ CD45- cells per ganglionic profile, compared with mock-infected animals. Thus, while SCs proliferate in response to peripheral trauma associated with scarification, they proliferate to a greater extent in response to HSV infection. Further, calculations here are based on the scenario in which all CD45+ cells are BrdU+, which minimizes the calculated number of proliferating SCs. If some immune cells are not proliferating, a likely scenario about which we have no data, then SC proliferation occurs to a greater extent.

This study was designed to measure the SC proliferation resulting from ganglionic infection with HSV. The close apposition of SCs for neurons and their known refractory nature for HSV infection positions these cells to have a potentially key role in control of ganglionic infection.

Under normal conditions, sensory ganglia predominantly comprise neurons and SCs, contained within an outer capsule of fibroblasts (Pannese, 1960, 1981). A low level of background SC proliferation was evident, consistent with the capacity of SCs to undergo mitosis during adult life (Pannese, 1981; Shinder et al., 1999; Wen et al., 1994). Data from mock-infected mice shows that SC proliferation is triggered by only moderate peripheral trauma such as skin scarification, with 50 BrdU+ cells/ganglionic profile 5 days after infection. The proliferative response following this minor injury confirms and extends previous reports on SC reactions to neuronal injury such as axotomy and nerve crush. In HSV-infected mice, proliferation of SCs occurred with over 100 BrdU+ CD45- cells present per ganglionic profile, twice the level in mock-infected animals 5 days after infection. These findings do not demonstrate an active role for SCs in viral clearance, and determination of the full extent to which SCs participate in resolution of ganglionic infection will require further investigation.

Because BrdU is also taken up by HSV, the apparent BrdU+ SCs could reflect the theoretical possibility that these cells contain replicating viral genomes. However it can be strongly argued that this is not so, for the following reasons. First, extensive examination of ganglionic sections taken at multiple times during acute HSV infection has consistently shown an almost complete lack of immunohistochemical staining for viral antigens in the small, perineuronal cells despite abundant antigen expression in neurons (Speck & Simmons, 1991, 1998). Second, temporal studies show that circles of small, BrdU+ perineuronal cells, such as in Fig. 2(D), were first detected in ganglia 2·5 days after skin inoculation with virus (data not shown), which in this model precedes the appearance of viral antigens and infectious virus in ganglia (Speck & Simmons, 1998). Third, BrdU+ neurons were not observed, even at the peak of ganglionic infection, when many of these cells show abundant expression of viral antigens. From this we infer that the quantum of BrdU uptake into viral genomes, such as occurs in neurons, is, in this system, insufficient to be detected. Fourth, electron microscope studies have shown SCs to contain only unenveloped virions (Cook & Stevens, 1973) or no virions at all (Dillard et al., 1972).

Neuronal injury induces recruitment and/or proliferation of macrophages, 2–4 days after injury, (Lu & Richardson, 1993; Monaco et al., 1992) in the corresponding sensory ganglia. However, these studies employed nerve cut or crush trauma, and in this study there was no appreciable increase in CD45+ cell numbers (which includes macrophages) following peripheral trauma at any time-point tested. Macrophages exist in a perineural position and proliferate if degenerative changes occur in ganglia (Graus et al., 1990). While a proportion of the BrdU+ cells may be proliferating macrophages, consistent with the observed increase in CD45+ cells numbers, CD45+ cell numbers account only for the minority of BrdU+ cell numbers. Further, the distinctive circles of fluorescent cells such as in Fig. 2(d) were also observed in response to mock infection, which did not involve any increase in CD45+ cell numbers. From this we conclude that the bulk of the proliferating cells are SCs.

SCs resemble Schwann cells in their phagocytic capacity, in that they fragment and engulf degenerated neurons (Pannese, 1981; Wilkinson et al., 1999). This ability, common to CNS glia, may permit SCs to function in PNS recovery from injury by clearing debris (Bechmann & Nitsch, 1997; Stoll et al., 1989). How SCs detect neuronal infection remains to be determined. In explant culture experiments, proliferation was enhanced by blocking protein synthesis 0–3 h after explant and suppressed by blocking 3·5–7 h after explant (Wen et al., 1994). Conditioned media experiments mimicked these responses showing that the signals are labile, and elimination of the response by heating suggested the factors are proteins, leading to the proposal (Wen et al., 1994) that non-proliferating SCs are under inhibitory control and that proliferation of SCs may result from neuron-produced mitogenic signals that perturb this negative control.

There are several possible mechanisms for HSV infection inducing SC proliferation. For example: (i) viral factors could directly stimulate SCs to proliferate; (ii) viral infection could perturb the neuron–SC relationship, leading to SC proliferation; or (iii) HSV-induced damage in the infected cell triggers the proliferation. While these possibilities are not mutually exclusive, we believe that the findings of Wen et al. (1994), as described above, of non-proliferating SCs being under inhibitory control, are consistent with the second alternative. Future experiments will be required to distinguish these possibilities.

Those cellular genes activated or repressed during SC proliferation remain unidentified. Factors promoting SC replication may protect neurons from damage or promote repair of damaged neurons. In view of the increasing significance ascribed to glia in nervous system disease, the implications may be applicable to the development of therapies for neuronal degenerative disorders.


   ACKNOWLEDGEMENTS
 
This work was supported by grant no. 104880 from the National Health and Medical Research Council of Australia. Peter Speck and Anthony Simmons are equal senier authors of this paper.


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Received 10 December 2002; accepted 6 January 2003.



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