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Journal of Virology, July 1999, p. 6093-6098, Vol. 73, No. 7
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
The GDVII Strain of Theiler's Virus Spreads via Axonal
Transport
Cécile
Martinat,1
Nadine
Jarousse,1,
Marie-Christine
Prévost,2 and
Michel
Brahic1,*
Unité des Virus Lents (URA CNRS
1930)1 and Laboratoire de Microscopie
Electronique,2 Institut Pasteur, 75724 Paris
Cedex 15, France
Received 6 January 1999/Accepted 29 March 1999
 |
ABSTRACT |
Following intracerebral inoculation, the DA strain of Theiler's
virus sequentially infects neurons in the gray matter and glial cells
in the white matter of the spinal cord. It persists in the latter
throughout the life of the animal. Several observations suggest that
the virus spreads from the gray to the white matter by axonal
transport. In contrast, the neurovirulent GDVII strain causes a fatal
encephalitis with lytic infection of neurons. It does not infect the
white matter of the spinal cord efficiently and does not persist in
survivors. The inability of this virus to infect the white matter could
be due to a defect in axonal transport. Using footpad inoculations, we
showed that the GDVII strain is, in fact, transported in axons.
Transport was prevented by sectioning the sciatic nerve. The kinetics
of transport and experiments using colchicine suggested that the virus
uses microtubule-associated fast axonal transport. Our results show
that a cardiovirus can spread by fast axonal transport and suggest that
the inability of the GDVII strain to infect the white matter is not due
to a defect in axonal transport.
| |
TEXT |
Theiler's murine encephalomyelitis
virus (TMEV) belongs to the Cardiovirus genus within the
Picornaviridae family (22, 24, 27). Most strains
of TMEV, including the DA and BeAn strains, cause a biphasic disease of
the central nervous system (CNS) after intracranial inoculation
(17). The first phase, which occurs during the first 7 to 10 days, is an acute encephalomyelitis. At this time, the virus is found
in the gray matter of the CNS, predominantly in neurons and in a small
number of glial cells (2). Soon after, the virus disappears
from the gray matter and infects the white matter of the spinal cord,
where it persists, mainly in macrophage-microglial cells and, to a
lesser extent, in oligodendrocytes (19, 26). Persistence in
the white matter causes chronic inflammation and primary demyelination.
Although the routes of TMEV dissemination within the CNS have not been
fully explored, there is a good indication that the virus may use
axonal transport. Viral antigens have been found in axons by using
ultrastructural immunohistochemistry (8), and the pattern of
spread of the virus within the limbic system in mice is consistent with
axonal transport (35). Furthermore, TMEV antigens are found
rather early in the corticospinal tract, the main pathway from the
brain to the anterior horn cells (35), and infected white
matter macrophages have been found close to axons containing viral
antigens (19).
In contrast to the DA and BeAn strains, the GDVII strain is highly
neurovirulent and kills its host in a matter of days (33). It does not persist in the CNSs of the rare survivors (16). Attenuated variants of this strain have been used recently to confirm its incapacity to persist (12, 18).
Importantly, the GDVII strain, which infects the gray matter,
where it replicates almost exclusively in neurons (2, 30),
does not infect the white matter (12). Viral recombinants
between the persisting DA or BeAn strain and the virulent GDVII strain
have been constructed by several groups in order to map viral genes
responsible for persistence. The results obtained by different
laboratories are, on the whole, consistent and show that the capsids of
the DA and BeAn strains bear the main determinants of persistence
(1, 20). Studies from our group showed that the ability to
persist correlates with the ability to infect the white matter of the spinal cord (10). Thus, the capsid of the DA strain may
determine persistence by allowing the infection of white matter glial
cells. Among other possibilities, the DA capsid could allow the virus to be transported in axons. According to this hypothesis, the inability
of the GDVII virus to infect the white matter and to persist could be
due to defective axonal transport. There is a precedent for closely
related strains of the same virus differing in their abilities to be
transported in axons. Tyler et al. showed that reovirus type 3 reaches
the CNS via fast axonal transport, whereas type 1 reaches it via the
bloodstream, and that this difference maps to the gene coding for the
viral hemagglutinin (34). In the present work, we tested the
ability of the GDVII strain to be transported in axons, using the
paradigm of transport to the spinal cord through the sciatic nerve
after footpad inoculation.
Clinical signs after footpad inoculation.
The GDVII virus
infects and kills CNS neurons efficiently. If it is able to spread from
the periphery to the spinal cord through the sciatic nerve, it will
cause paralysis, appearing first in the inoculated limb. Eleven 4- to
5-week-old SJL/J mice were inoculated in the left hind footpad with 50 µl of phosphate-buffered saline containing 5 × 106
PFU of the GDVII strain and were examined daily for clinical signs. All
mice showed symptoms. The typical course of the disease was paralysis
of the inoculated limb 5 to 6 days postinoculation (p.i.), followed by
paralysis of the contralateral hind limb 1 to 2 days later. Death of
the animals occurred 9 to 10 days p.i. These results were consistent
with the spread of the GDVII strain from the periphery to the CNS via
the sciatic nerve.
Detection of the virus in the sciatic nerve and the spinal
cord.
If the GDVII virus spreads from the footpad to the spinal
cord through the sciatic nerve, viral RNA should appear first in the
sciatic nerve of the inoculated leg, then in the inferior spinal
cord
the region containing the neurons innervating the skin and
muscles of the footpadand lastly in the superior spinal cord. In
contrast, if the virus reaches the CNS via the bloodstream, it should
appear in the inferior and superior regions of the spinal cord at the
same time. The pattern of the spread of TMEV to the CNS was examined by
inoculating SJL/J mice with 5 × 106 PFU of the GDVII
strain in the left hind footpad and sacrificing them on days 1 through
4 p.i. The spinal cords and sciatic nerves were removed. The
spinal cord was divided into a superior segment, which consisted of the
cervical cord, and an inferior segment, which consisted of the thoracic
and lumbosacral cords. Total RNA was extracted from tissues as
previously described (6), and viral RNA was detected by
reverse transcription (RT)-PCR. Briefly, RT was performed with 10 µg
of spinal cord RNA or with the totality of RNA extracted from the
sciatic nerve. Then, 30 cycles of PCR were performed with primers
specific for part of the capsid-coding region of the viral genome. The
primers corresponded to GDVII virus nucleotides 2889 to 2909 (5'-TGACCCCCCTGACCTACCCTT-3') and 3969 to 3989 (5'-CGCCCATGCACACGAGCATTC-3'). After separation by electrophoresis, the PCR products were transferred to nylon
membranes and hybridized with a 32P-labeled probe
consisting of nucleotides 3297 to 3319. For each tissue sample
examined, except for sciatic nerve because of the limited amount of RNA
available, the housekeeping 
-actin mRNA was amplified in parallel by
RT-PCR to confirm the integrity of the RNA (data not shown).
Viral RNA was first detected 1 day p.i. in the left sciatic nerves of
five of seven inoculated mice (Fig. 1 and
Table 1). At that time, viral RNA was not
detected in the right sciatic nerve (Fig. 1). By 2 days p.i., viral RNA
was also found in the inferior spinal cord segment. One day later,
viral RNA had disappeared from the sciatic nerve and was detected only
in the inferior spinal cord segment. By 4 days p.i., the whole spinal
cord as well as the left sciatic nerve contained viral RNA (Fig. 1). As
determined by using the Kaplan-Meier model and the log-rank test with a
standard statistical threshold of a significance of 5%, the kinetics
of appearance of viral RNA in the inferior spinal cord was
statistically different from that observed in the superior spinal cord
(P 
0.002). The reappearance of viral RNA in the left
sciatic nerve 4 days p.i. might have been due to axonal transport from
the spinal cord back to the periphery.
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FIG. 1.
Spread of the GDVII strain from the footpad to the
sciatic nerve and the spinal cord. Shown are the percentages of mice
inoculated in the footpad in which viral RNA was detected in the
ipsilateral ( ) or contralateral ( ) sciatic nerve and in the
inferior ( ) or superior ( ) spinal cord. The percentages were
calculated from the data shown in Table 1.
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TABLE 1.
Summary of the patterns of the spread of the GDVII strain
from the periphery to the CNS in SJL/J mice after different treatments
of the sciatic nervea
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We examined if sectioning the sciatic nerve, which is the main neural
pathway from the hind limb to the spinal cord, prevented
the virus from
reaching the CNS. Sciatic nerve transection was
done as previously
described (
29,
34). Briefly, a small incision
was made above
the superficial gluteus muscle of the left hind
leg, and the muscle
layers were moved to expose the nerve. Approximately
1 mm of nerve was
removed. Mice were checked for paresis after
surgery. Two days after
nerve transection, SJL/J mice were inoculated
in the left hind footpad
with 5 × 10
6 PFU of the GDVII strain, and they were
sacrificed on days 2 through
4 p.i. for RT-PCR analysis. The
sciatic nerves of approximately
half of the mice were examined at
necropsy. Transection was confirmed
in all cases. As shown in Fig.
2 and Table
1, sectioning the
nerve
completely inhibited the spread of the virus to the spinal
cord.
Indeed, we were unable to detect viral RNA in the inferior
spinal cord
up to 4 days p.i.
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FIG. 2.
Effect of sectioning the sciatic nerve on the spread of
the GDVII strain to the inferior spinal cord segment. Shown are the
percentages of mice inoculated in the footpad in which viral RNA was
detected in the inferior spinal cord (). The control ()
corresponds to the spread of the GDVII virus to the inferior spinal
cord in the absence of sectioning the sciatic nerve.
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The pattern of the spread of the GDVII strain from the periphery to the
spinal cord was confirmed by histological analysis
performed as
previously described (
3). Viral antigens were
first detected
in the inferior spinal cord segment 3 days p.i.
and in the superior
spinal cord 1 day later. There was a good
correlation between the
pattern of infection and clinical signs.
Five days p.i., most viral
antigens were located on one side of
the inferior spinal cord (Fig.
3). At this time, the mouse shown
in Fig.
3A demonstrated paralysis of the inoculated limb. At 8
days p.i., a
large amount of viral antigens was found on one side
of the inferior
spinal cord and some were found on the contralateral
side (Fig.
3B).
The mouse used for Fig.
3B demonstrated paralysis
of both hind limbs.
Taken together, the molecular and histological
data indicate that the
GDVII strain is able to spread from the
periphery to the spinal cord
via the sciatic nerve.
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FIG. 3.
Histological findings in longitudinal sections of the
inferior spinal cords of SJL/J mice after inoculation with 5 × 106 PFU of the GDVII strain in the left hind footpad. Viral
antigens were detected in paraffin sections by immunocytochemistry. (A)
Histological findings 5 days p.i. The top panel shows viral antigens
(arrows) present on one side of the inferior spinal cord.
Magnification, ×73. The bottom panels show higher-magnification views
of symmetric fields designated by open triangles in the top panel.
Arrowheads point to infected cells. Magnification, ×293. (B)
Histological findings 8 days p.i. Viral antigens are present on both
sides of the inferior spinal cord. Magnification, ×73.
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Effect of colchicine on the transport of the virus through the
sciatic nerve.
Our experiments did not identify the mechanism of
transport of the GDVII virus in the sciatic nerve, although the
presence of viral RNA in the inferior spinal cord as early as 2 days
p.i. strongly suggested fast axonal transport. To examine this point in
more detail, we studied the spread of the GDVII virus to the spinal
cord after treatment of the sciatic nerve with colchicine, an agent
which causes a reversible dissociation of microtubules and inhibits
fast axonal transport (25). Briefly, 20 µg of colchicine in 40 µl of phosphate-buffered saline was injected into the left hind
footpad. The animals were inoculated with 5 × 106 PFU
of the GDVII strain 20 h later. The treatment caused a delay in
the appearance of viral RNA in the spinal cord (Table 1 and Fig.
4). Viral RNA could not be detected in
the spinal cord before 3 days p.i., and it was detected in only 2 of 11 mice. The difference between the kinetics of appearance of viral RNA in
the inferior spinal cord with colchicine treatment and that without it
was statistically significant (P 0.001).
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FIG. 4.
Effect of colchicine treatment on the axonal transport
of the GDVII strain. Colchicine was injected 1 () or 10 () days
before viral inoculation. Shown are the percentages of mice inoculated
in the footpad in which viral RNA was detected in the inferior spinal
cord. The control () corresponds to the spread of the GDVII virus to
the inferior spinal cord without colchicine treatment.
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As a control for these experiments, we examined, by electron
microscopy, the effect of colchicine on the axonal microtubules
of the
sciatic nerve. Compared with the control, the axonal cytoskeleton
showed disruption and microtubules disappeared 1.5 days after
treatment
with colchicine (Fig.
5). Another
important control
consisted of testing the effect of 500 µg of
colchicine per ml
(the concentration used for in vivo experiments) on
the infectivity
of viral particles and on viral replication in
permissive BHK-21
cells. The virus was incubated with or without
colchicine for
1 h at 37°C, and virus titers were measured
before and after treatment.
On the other hand, BHK-21 cells were
treated with 500 µg of colchicine
per ml or were left untreated, and
they were infected with the
GDVII strain of TMEV. Viral yields were
measured after 24 h. No
effect of colchicine on viral particles or
virus yield was detected
(data not shown).
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FIG. 5.
Effect of colchicine treatment on the microtubules of
the sciatic nerve as observed by electron microscopy. (A) Longitudinal
section of the sciatic nerve of an untreated mouse. The arrows point to
some of the microtubules. Magnification, ×15,470. (B) Longitudinal
section of the left sciatic nerve, 1.5 days after the injection of
colchicine in the left hind footpad. Note the absence of microtubules.
Magnification, ×15,470. Bars, 500 nm.
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High doses of colchicine can cause axonal degeneration. The dose used
in our experiments was in the range required for reversible
inhibition
of fast axonal transport and was below the threshold
for nerve
degeneration (
4). Moreover, the detection of viral
RNA in
the inferior spinal cord 3 days p.i. after colchicine treatment
suggested that colchicine did not cause nerve degeneration. However,
to
confirm this mice were inoculated with the virus 10 days after
treatment with the drug. Under these conditions the spread of
the GDVII
virus to the spinal cord was not delayed (Fig.
4 and
Table
1). The
difference in kinetics of the spread to the CNS
1 and 10 days after
colchicine treatment was statistically significant
(
P < 0.001). As expected, the difference between the kinetics
observed
10 days after colchicine treatment and that without colchicine
treatment was not statistically different (
P > 0.1).
Therefore,
our results indicate that the spread of the GDVII virus
through
the sciatic nerve is microtubule
dependent.
The axonal transport of the persisting DA and BeAn strains takes place
in the CNS. The present work describes the axonal transport
of the
nonpersisting GDVII strain in the sciatic nerve, which
belongs to the
peripheral nervous system. Although there are well-known
differences in
the myelin sheaths of the CNS and peripheral nervous
system, there is
no evidence for a difference in the mechanism
of axonal transport.
Furthermore, viruses such as herpes simplex
virus or rabies virus, for
which peripheral axonal transport is
well established, also spread
within the CNS through axons and
transneurally (
4,
5,
15,
31). Thus, our results suggest
that the inability of the GDVII
strain to infect the white matter
is not due to a defect of axonal
transport in the
CNS.
What could be the reason(s) why the GDVII virus does not infect glial
cells in the white matter of the spinal cord, although
it can be
transported in axons? The virus infects neurons and
is highly lytic as
shown, e.g., by the presence in gray matter
of numerous fragmented
neuronal cell bodies with typical images
of neuronophagia. It is
possible that the rapid death of the neuron
does not give the virus
time to be transported down the axon.
In contrast, the persisting DA
strain exhibits a much more attenuated
phenotype in neurons
(
11), which may allow the virus to reach
the white matter by
axonal transport. Alternatively, persisting
strains may use different
receptors on neurons and glial cells,
and the GDVII strain might not
recognize the latter. This is consistent
with the presence of
determinants of persistence at the surfaces
of the capsids of the DA
and BeAn strains (
1,
20) and with
the fact that the BeAn and
GDVII virions bind differently to the
surfaces of permissive cells
(
36). Obviously, a block of replication
in glial cells, in
particular in macrophage-microglial cells,
could also occur at later
steps, after attachment of the virus
to the receptor. There is evidence
for this from work done with
macrophage cell lines. Jelachich et al.
reported that the replication
of the GDVII strain is highly restricted
in two different murine
macrophage cell lines (
13).
Moreover, recent studies showed
that the GDVII virus does not
replicate actively in another macrophage
cell line, whereas the DA
strain productively infected these cells
(
21,
32).
Since viral RNA was first detected in the lower spinal cord 2 days
after inoculation into the footpad, the rate of transport
in the
sciatic nerve was approximately 20 mm/day, which is consistent
with
fast axonal transport (for a review, see reference
9).
We confirmed that the virus uses fast axonal
transport by using
colchicine, a drug which depolymerizes microtubules.
Colchicine
has already been used to demonstrate fast axonal transport
for
reovirus type 3, herpes simplex virus, and rabies virus (
4,
5,
15,
34). It had been conjectured for a long time that
picornaviruses might use axonal transport (
7,
14). Taking
advantage of mice transgenic for the poliovirus receptor, two
studies
demonstrated axonal transport of poliovirus (
28,
29).
Recently, Ohka et al., although they did not use colchicine, also
concluded that poliovirus is transported in the sciatic nerves
of mice
transgenic for the poliovirus receptor by the fast transport
mechanism
(
23). However, several points concerning axonal transport
of
picornaviruses, such as the mechanism of entry at nerve terminals
and
of subsequent transport, remain unclear. There is evidence
that the
poliovirus receptor is required for entry at nerve terminals
and that
intact infectious virions are transported in the
nerve.
In conclusion, we report that the GDVII strain of TMEV is transported
in the sciatic nerve by a fast axonal transport mechanism.
Therefore,
the inability of this virus to infect the white matter
of the spinal
cord and to persist is most probably not due to
a defect in axonal
transport.
| |
ACKNOWLEDGMENTS |
We thank Laurence Fiette for helpful discussions and Mireille Gau
for secretarial assistance.
This work was supported by grants from the Institut Pasteur Fondation,
the Centre National de la Recherche Scientifique, the Association pour
la Recherche sur la Sclérose en Plaques, the National Multiple
Sclerosis Society, and the EC Human Capital and Mobility program
(contract no. CHRX-CT94-0670). C.M. is a recipient of a scholarship
from the Ministère de la Recherche et de l'Enseignement
Supérieur.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Unité des
Virus Lents, Institut Pasteur, 28, rue du Dr. Roux, 75724 Paris Cedex
15, France. Phone: 33 1 45 68 87 70. Fax: 33 1 40 61 31 67. E-mail: mbrahic{at}pasteur.fr.
Present address: Hormone Research Institute, University of
California San Francisco, San Francisco, CA 94143-0534.
| |
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Journal of Virology, July 1999, p. 6093-6098, Vol. 73, No. 7
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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