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Journal of Virology, March 1999, p. 1795-1801, Vol. 73, No. 3
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Immune Response-Mediated Protection of Adult but Not Neonatal
Mice from Neuron-Restricted Measles Virus Infection and Central
Nervous System Disease
Diane M. P.
Lawrence,
Melinda M.
Vaughn,
Alec R.
Belman,
Joan S.
Cole, and
Glenn F.
Rall*
The Fox Chase Cancer Center, Philadelphia,
Pennsylvania 19111
Received 16 September 1998/Accepted 11 November 1998
 |
ABSTRACT |
In many cases of neurological disease associated with viral
infection, such as measles virus (MV)-induced subacute sclerosing panencephalitis in children, it is unclear whether the virus or the
antiviral immune response within the brain is the cause of disease. MV
inoculation of transgenic mice expressing the human MV receptor, CD46,
exclusively in neurons resulted in neuronal infection and fatal
encephalitis within 2 weeks in neonates, while mice older than 3 weeks
of age were resistant to both infection and disease. At all ages, T
lymphocytes infiltrated the brain in response to inoculation. To
determine the role of lymphocytes in disease progression,
CD46+ mice were back-crossed to T- and B-cell-deficient
RAG-2 knockout mice. The lymphocyte deficiency did not affect the
outcome of disease in neonates, but adult CD46+
RAG-2
mice were much more susceptible to both neuronal
infection and central nervous system disease than their immunocompetent
littermates. These results indicate that CD46-dependent MV infection of
neurons, rather than the antiviral immune response in the brain,
produces neurological disease in this model system and that
immunocompetent adult mice, but not immunologically compromised or
immature mice, are protected from infection.
| |
INTRODUCTION |
The restriction of immune function
within the brain due to the presence of the blood brain barrier, a lack
of major histocompatibility complex (MHC) expression, and an absence of
lymphatic drainage has led to the presumption that the central nervous
system (CNS) is a site of immune privilege (7, 37, 43).
However, it is clear that activated leukocytes and immune mediators can
access the brain (18, 47) and that inflammatory responses
are associated with numerous CNS disorders, including multiple
sclerosis (9), Alzheimer's disease (31), and
many neurotropic viral infections (26, 36, 39, 46, 48).
While the antiviral immune response may help control infection in the
CNS, often it is this response, rather than the infection alone, that
results in disease. How the balance between neuroprotection and
immunopathogenesis is regulated in the CNS remains an unresolved, yet
clinically relevant issue.
Measles virus (MV) is a member of the paramyxovirus family which causes
an acute infection in humans and primates; usually the acute disease is
resolved uneventfully with lifelong immunity. However, in rare cases,
mostly in children, MV can persistently infect neurons and
oligodendrocytes within the CNS, leading to the progressive and fatal
CNS disease subacute sclerosing panencephalitis (SSPE) (4, 17, 21,
45). SSPE often begins months to years after the acute infection,
and postmortem specimens reveal massive CNS damage, including cell
death and astrogliosis (4, 11, 25). In addition, lymphocyte
infiltration of the brain and high titers of MV-specific antibodies are
found in SSPE; yet whether the immune response is involved in disease
progression remains unresolved (4, 11). The basis for these
MV-associated CNS diseases is unclear, and the role which the host
immune response plays in either neuroprotection or disease is not
understood. Interestingly, a study of random autopsy brain tissues
showed evidence of MV in the brains of 20% of adults who never showed symptoms of CNS disease (24). These data raise the
possibility that measles infection of the brain does not invariably
lead to CNS disease or that CNS disease mediated by MV is age dependent.
Although small animal models of MV infection of the CNS exist (2,
19, 28), these systems use rodent-adapted strains of measles
whose sequence, cell tropism, receptor usage, and extracellular virus
production differ markedly from wild-type infection of the CNS
(28, 29, 40). To more closely parallel the human CNS infection caused by measles, we established a transgenic mouse model
system in which the human high-affinity measles virus receptor, CD46
(12, 33), was expressed under the transcriptional control of
the neuron-specific enolase promoter (38). Intracerebral infection of NSE-CD46 transgenic mice with MV-Edmonston, a
CD46-dependent vaccine strain of measles, produced severe CNS disease
associated with extensive neuronal infection in neonates, yet adult
transgenic mice were resistant to both infection and disease
(38). Importantly, while virus clearly replicates and
spreads within the CNS of transgenic neonates, no infectious virus can
be isolated from infected brains, a phenomenon that is a hallmark
feature of SSPE (25).
In this study, a genetic approach was taken to determine the
contribution of the immune response to disease progression in infected
neonatal and adult transgenic mice. The data indicate that the adult
immune response, but not the neonatal response, can protect mice from
both infection and disease. Furthermore, the abrogation of this immune
response in adults leads to infection and CNS disease similar to that
in neonates. The implications of this work for measles infection of the
human CNS are discussed, and it is suggested that host factors,
including immunocompetence and postnatal age when infected, are major
determinants in the outcome of chronic neurotropic infections.
| |
MATERIALS AND METHODS |
Mice.
C57BL/6 (H-2b) mice were
obtained from the closed breeding facility of The Fox Chase Cancer
Center. All mice were maintained in conditions consistent with the
facility animal care regulations (AAALAC) throughout the course of investigation.
The establishment of transgenic mice expressing the human MV receptor,
CD46, in CNS neurons has been described previously (38).
Transgenic mice were identified by hybridization of tail DNA to a
transgene-specific 32P-labeled probe. DNA was isolated from
a tail biopsy and 10 µg was transferred onto a nylon filter
(Schleicher and Schuell, Keene, N.H.). Mice from two independently
derived lineages (lines 18 and 52) were used in these experiments; data
presented are from line 18 transgenic mice unless otherwise indicated.
RAG-2 knockout mice (H-2b) were a generous gift
of F. W. Alt (Howard Hughes Medical Institute, Boston, Mass.).
Homozygous NSE-CD46
+ and homozygous RAG-2
/
mice were intercrossed for two generations. RAG-2
/
progeny were identified by flow cytometry on peripheral blood
lymphocytes stained with fluorescein isothiocyanate-conjugated
antibodies to mouse CD4 and CD8 antigens. In some cases, the RAG-2
genotype was confirmed by postmortem immunohistochemical staining
of
frozen spleen sections with antibodies specific for B- and
T-lymphocyte
markers.
Virus and infection of mice.
All mice were infected with the
specified doses of MV-Edmonston (American Type Culture Collection,
Rockville, Md.). This virus was amplified three times in Vero
fibroblasts. The inoculum was diluted as needed in phosphate-buffered
saline and administered intracerebrally to metofane-anesthetized mice
along the midline, in a volume of 10 µl (for neonates) and 30 µl
(for adults) with a 27-gauge needle.
Northern blot analysis of CD46 mRNA expression.
Organs were
snap-frozen in liquid nitrogen and stored at 
70°C until homogenized
with a Virtishear (Virtis, Gardiner, N.Y.) for 30 s in 1 ml of
Tri-Reagent (Sigma, St. Louis, Mo.) per 100 mg of tissue. For Northern
blot analysis of CD46 expression, 10-µg samples of purified total RNA
were denatured and run on a 1% agarose formaldehyde gel, transferred
to nitrocellulose, UV cross-linked, and hybridized overnight at 65°C
with 32P-labeled probes specific for either CD46 or GAPDH
(glyceraldehyde-3-phosphate dehydrogenase). DNA fragments were labeled
with the Prime-It II random hexamer labeling kit (Stratagene, La Jolla,
Calif.), and probes with specific activities of at least 5 × 108 cpm/µg were used.
Immunohistochemical analysis of mouse tissues.
Organs were
snap-frozen in dry ice-isopentane and stored at 70°C. Horizontal
cryosections (10 µm) were air dried and stored at 70°C. On the
day of staining, sections were fixed in ice-cold 95% ethanol and
blocked for 20 min with 2% normal goat serum (Vector Laboratories,
Burlingame, Calif.) for MV staining, 0.1% bovine serum albumin (Sigma)
for CD4 and CD8 T-cell staining, or 2% calf serum (Gibco/BRL,
Gaithersburg, Md.) for B-cell staining. Avidin and biotin were used for
blocking when required (Vector Laboratories). Primary antibodies
(incubated for 2 h at room temperature, diluted in blocking buffer
as indicated) included human SSPE immune serum Vasquez (1:750) for MV,
clone RM4-5 rat anti-mouse CD4 (1:50), clone 53-6.7 rat anti-mouse
CD8
plus clone 53-5.8 rat anti-mouse CD8
(1:50 each), and clone
RA3-6B2 rat anti-mouse CD45R/B220 (1:1,000 for B cells) (Pharmingen,
San Diego, Calif.). Secondary antibodies (incubated for 1 h at
room temperature, 1:200 dilution in blocking buffer) included
biotinylated goat anti-human immunoglobulin G (IgG) for MV staining and
biotinylated rabbit anti-rat IgG for CD4, CD8, and B-cell staining
(Vector Laboratories). All sections were peroxidase labeled with the
ABC Elite kit (Vector Laboratories) and 0.7 mg of diaminobenzidine per
ml in 60 mM Tris buffer with 1.6 mg of H2O2 per
ml (Sigma). Uninfected tissues or omission of the primary antibody
served as negative controls.
| |
RESULTS |
Host age and susceptibility to MV-induced CNS disease are inversely
correlated.
We previously reported (38) that
intracerebral (i.c.) infection of NSE-CD46+ neonatal mice
with 105 PFU of MV-Edmonston caused extensive neuronal
infection, CNS disease, and death. Conversely, inoculation of
transgenic adults (greater than 4 weeks of age) failed to induce
illness (38). To further define the age dependence of
susceptibility to MV-induced disease, several litters of homozygous
NSE-CD46+ mice at various ages were inoculated i.c. with
3 × 104 PFU of MV-Edmonston. As indicated in Fig.
1A, mice inoculated on postnatal day 1 or
day 6 showed the fastest kinetics of disease, with all mice dead by 7 to 8 days postinfection. Signs of CNS disease (tremors, ataxia, a
hunched appearance, and paralysis) appeared 1 to 2 days prior to death.
None of the mice inoculated at 30 days or older showed signs of
disease, and all of them survived. Importantly, when mice were
inoculated at 14 days of age, only 50% of mice showed signs of
disease, and the average onset of disease was delayed until 10 days
postinfection. In each age group, there were no differences in outcome
between male and female mice (data not shown). Figure 1B shows that, in
transgenic mice, CD46 mRNA expression in the brain is maintained in
adult mice, suggesting that the lack of MV-induced disease in adults is
not likely due to downregulation of receptor expression.
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FIG. 1.
(A) Neuronal MV infection is lethal only in neonatal
mice. Homozygous line 18 NSE-CD46+ mice, from 1 day to 60 days of age, were inoculated i.c. with 3 × 104 PFU of
MV-Edmonston and monitored daily for disease and death. Data represent
the percent survival within each group of 7 to 9 mice. Similar results
were obtained in at least two additional experiments for each age group
and in line 52 mice. (B) CD46 mRNA expression is maintained into
adulthood in transgenic mice. Total mRNA was isolated from brains of
NSE-CD46 transgenic mice as described in Materials and Methods.
Northern blots were hybridized with 32P-labeled probes
specific for either CD46 (upper panel) or GAPDH (lower panel). For each
age group, two mice were tested in separate lanes as follows: e16,
embryonic day 16; p1, postnatal day 1; p3, postnatal day 3; p10,
postnatal day 10; and p23, postnatal day 23.
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|
MV-induced neurological disease in NSE-CD46+ transgenic
mice is dose dependent.
To assess the minimum dose of virus needed
to produce CNS disease in neonates, 5-day-old homozygous
NSE-CD46+ mice (line 18) were infected i.c. with various
doses (30 to 3 × 104 PFU) of MV-Edmonston in a
constant volume (10 µl). All neonates inoculated with the two highest
doses of MV died by 8 days postinfection (Fig.
2). At the 300-PFU dose, 5 of 6 infected
mice succumbed to MV infection, with a time course of disease similar
to the higher doses. Only at the lowest dose, 30 PFU, were the kinetics of mortality slower and more variable; death occurred in 66% of inoculated mice between 8 and 14 days postinfection, although 100% of
the animals showed signs of illness, suggesting that some of these mice
were infected but recovered. Adult mice showed no disease signs with
infectious doses 3,000-fold higher than that required to cause disease
in neonates, indicating that differences in brain volume cannot account
for the age difference in susceptibility to MV-induced CNS disease and
death (data not shown). These data, together with the age-dependent
susceptibility to illness (Fig. 1A), indicate that the outcome of CNS
infection represents a balance of multiple factors, including viral
dose, host age, and possibly immunocompetence.
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FIG. 2.
Lethality of neuronal MV infection is dose dependent.
Five-day-old homozygous line 18 NSE-CD46+ mice were
inoculated i.c. with 30 to 3 × 104 PFU of
MV-Edmonston. The mice were monitored daily for evidence of disease
(tremors, seizures, paralysis, and weight loss), and mortality was
recorded. Data represent the percent survival within each group of five
to six mice.
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|
The kinetics of disease onset and death in transgenic neonates were
highly reproducible, with either heterozygous and homozygous
mice from
independently derived lines 18 and 52, and no signs
of illness were
observed in either nontransgenic mice or transgenic
neonates infected
with UV-inactivated virus (data not
shown).
Neuronal MV infection and immune response in neonates versus
adults.
We next examined whether there were age differences in
neuronal infection and the immune response to infection. Since
extracellular MV could not be detected in infected brains
(38), we used immunohistochemical analysis to compare viral
protein expression, as well as T- and B-cell infiltration in brains
from infected neonates (5 to 6 days of age) and adults (45 to 60 days
of age), at two time points. Figure 3
shows representative micrographs of MV, CD4, and CD8 staining; Table
1 presents a quantification of infected
cells and infiltrating lymphocytes in at least four mice from multiple levels throughout the brain.
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FIG. 3.
Time course of MV infection and CD4+ and
CD8+ lymphocyte infiltration in brains of neonates and
adult NSE-CD46+ mice. Homozygous line 18 mice were
inoculated as neonates (5 to 6 days old) or adults (45 to 60 days old)
and sacrificed at either 3 or 6 days postinfection. Frozen brain
sections from these mice were peroxidase stained for MV antigen (A, D,
G, and J; ×40), CD4+ T lymphocytes (B, E, H, and K;
×100), and CD8+ T lymphocytes (C, F, I, and L; ×100) as
described in Materials and Methods. Panels: A to C, neonatal brain, 3 days postinfection; D to F, neonatal brain, 6 days postinfection; G to
I, adult brain, 3 days postinfection; J to L, adult brain, 6 days
postinfection.
|
|
By 3 days postinfection, all neonates and adults appeared healthy: body
weight, activity level, and limb mobility were normal.
MV antigen was
detected in neonatal brains (Fig.
3A) but very
rarely in adults (Fig.
3G). Patches of focal infection in neonates
appeared in the
hippocampus, cortex, inferior colliculus, and
paraventricular regions
and occasionally in the Purkinje neurons
of the cerebellum. At 6 days
postinfection, adults remained healthy
but, consistent with the
survival studies described above, most
of the neonates showed signs of
CNS disease. The magnitude of
infection in neonates had increased by
this time (Fig.
3D, Table
1) but still was not apparent in adults (Fig.
3J, Table
1).
Replicating virus, viral RNA, and viral proteins were
never detected
in nonneuronal tissues by plaque assay, Northern blot
analysis,
and immunohistochemistry, respectively (data not shown).
Thus,
the neuronal infection progressed over time in neonates but not
in adults, and CNS disease signs only occurred in mice with neuronal
MV
infection. The lack of infection in adults could be explained
either by
a resistance of the adult neurons to infection or by
rapid clearance of
MV from the infected
CNS.
In contrast to the age difference in neuronal infection, T lymphocytes
were detected in the brains of mice at any age (Fig.
3B and C, E and F,
H and I, and K and L) for several weeks after
inoculation. In most
cases, CD4
+ cells were more abundant than CD8
+
cells, and the numbers of both T-cell subsets increased over
time in
neonatal and adult brain (Table
1). The magnitude of
the antiviral
T-lymphocyte infiltration in adults was greater
than in neonates at
both time points (Table
1). B cells were
never detected in brain tissue
after inoculation (data not shown).
Inoculation of nontransgenic
neonates, as well as UV-inactivated
virus inoculation of transgenic
neonates, produced no T-cell infiltration
within the brain (data not
shown). Thus, CD4
+ and CD8
+ T-lymphocyte
infiltration of neonatal brains occurred in response
to neuronal MV
infection rather than as a general inflammatory
response to i.c.
inoculation. These results demonstrate that both
adult and neonatal
mice are infected but that viral spread and
subsequent CNS disease
occur only in
neonates.
T lymphocytes protect against MV-induced disease in adults but not
in neonates.
Although T lymphocytes infiltrated the brain in
response to neuronal infection at all ages, it was unclear whether
lymphocytes played any role in disease progression. If so, differences
must exist between the neonatal and adult T-cell response: either
neonatal lymphocytes contribute to disease signs or the adult
lymphocyte response prevents disease. To establish the role of
lymphocytes in MV-induced CNS disease, NSE-CD46+ mice were
backcrossed for two generations to RAG-2/ mice, which
lack mature T and B cells due to a deletion of recombination activating
gene-2 (3). The resulting F2 litters consisted
of four genotype combinations: transgenic immunocompetent
(CD46+/, RAG-2+/), transgenic lymphocyte
deficient (CD46+/, RAG-2/), nontransgenic
immunocompetent (CD46/, RAG-2+/), and
nontransgenic lymphocyte deficient (CD46/,
RAG-2/). These litters were infected at various ages
and monitored daily; scoring of sickness was completed without prior
knowledge of each mouse's genotype. Mice were sacrificed when they
showed signs of disease, and brain tissue was analyzed by
immunohistochemistry for MV antigen, as well as for CD4+
and CD8+ lymphocytes. Mice that did not become sick were
sacrificed at 3 to 5 weeks postinfection. As expected, none of the
nontransgenic mice became sick; the summary for NSE-CD46+
mice, both RAG-2+/ and RAG-2/, is shown
in Table 2.
RAG-2
+/ and RAG-2
/ neonates developed CNS
disease with the same kinetics. However, unlike the immunocompetent
mice, most of the
"adolescents" (infected at 11 to 17 days of age)
and adults (infected
at >26 days of age) in the RAG-2
/
category also became moribund (Table
2). Immunohistochemical
analysis
of brain sections from RAG-2
/ adolescent and adult mice
showed extensive neuronal MV infection
(Fig.
4A), which was not detected in
age-matched RAG-2
+/ mice (Fig.
4B) or surviving
RAG-2
/ mice. These results confirm that neuronal MV
infection, and not
the presence of an antiviral response within the
brain, is directly
associated with CNS disease. In addition, these
studies show that
an intact immune system provided protection from this
infection
in adults but not in neonates. Finally, comparison of
RAG-2
/ mice of different ages showed a delayed disease
onset and enhanced
survival in adolescent and adult mice compared to
neonates (Table
2). This observation suggests that other factors, in
addition
to the lymphocyte-mediated protection in adults, such as
components
of the innate immune response or the developmental status of
the
brain, also contribute to the pathogenesis of MV-induced CNS
disease.
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FIG. 4.
MV infection in RAG-2/ versus
immunocompetent adult transgenic mice. F2 litters of CD46
mice backcrossed to RAG-2/ mice were inoculated as
adults and sacrificed at 15 days postinfection. Frozen brain sections
from these mice were peroxidase stained for MV antigen. Panels: A,
RAG-2/ adult, showing signs of CNS disease; B,
immunocompetent, healthy adult.
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|
| |
DISCUSSION |
Three conclusions can be drawn from the work presented here. (i)
MV-Edmonston inoculation of NSE-CD46 transgenic mice produces a
dose-dependent, CD46-dependent neuronal infection with concomitant CNS
disease and death in neonates but not in immunocompetent adults. (ii)
CD4+ and CD8+ T lymphocytes infiltrate the
brain parenchyma in response to neuronal measles infection at all ages.
(iii) Lymphocyte-deficient NSE-CD46 transgenic adult mice are
susceptible to neuronal MV infection and disease. Thus, although the
immune response contributes to CNS disease in other model systems of
neurotropic viral infections (18, 20, 30, 47), in this model
of neuronal MV infection, T cells appear to serve a solely beneficial
function in adult mice.
Our genetic approach for evaluating the role of the lymphocyte response
in neuropathology after MV infection of the brain employed
RAG-2/ mice, which are deficient in both T and B cells
(3). Based on our immunohistochemical findings, it is
unlikely that B-cell responses are involved in the protection in
transgenic adults, since no B cells enter the brain after infection,
and in humans and in mouse models of MV encephalitis the antibody
response to MV infection is too slow to prevent infection by 3 days, as
observed in our adult mice (17, 28). Our finding that only T
cells enter the brain parenchyma also supports the hypothesis that
infection leads to specific infiltration of T lymphocytes; if a
breakdown of the blood-brain barrier were responsible for lymphocyte
entry into the brain, intraparenchymal B cells would be expected as well. Thus, the T-lymphocyte response, consisting of CD4+
helper T cells and/or CD8+ cytotoxic T cells, is
responsible for the protection of adult mice.
In general, human and mouse lymphocytes are thought to be functionally
immature at birth (5, 32), so it was surprising to see any
immune response in the brains of infected neonatal mice. However,
recent studies have shown that neonatal immune responses can be raised
but may require extra stimulation and are biased toward a Th2 cytokine
profile (1, 27), leaving neonates potentially more
susceptible to infections which can be controlled in adults by a Th1
response. This concept is applicable to the CNS in that gamma
interferon, a Th1 cytokine, is critical for resistance to a number of
neurotropic viral infections (13, 14). It is unclear whether
the Th1-Th2 balance is involved in the protection from measles
infection in our model system, but our results suggest that age
differences in either the magnitude or the function of the antiviral
lymphocyte response, possibly cytokine production or the cytotoxic
T-cell (CTL) response, may explain the age dependence of susceptibility
to neuronal MV infection. Cytotoxic T cells are needed for protection
against a number of neurotropic infections, including those caused by
HSV-1 (34) and mouse-adapted strains of MV (35).
CTL recognition of viral antigen requires MHC class I expression, which
is generally thought to be absent in neurons (23); however,
there is evidence for upregulation of class I expression in neurons of
SSPE patients and in a rat model of experimental subacute measles
encephalitis (15), as well as in mouse neuroblastoma cells
persistently infected with measles virus (16). Current
studies in our laboratory with NSE-CD46+ mice backcrossed
with 2-microglobulin/ mice will help to
elucidate the roles of MHC class I and CTL in response to neuronal
measles infection.
If there are no age differences found in the antiviral immune response
to infection, an alternative hypothesis to explain the age dependence
of susceptibility is that the neonatal response is functionally
indistinguishable from the adult response but that viral spread within
the neonatal CNS may occur more rapidly than the neonatal immune
response can clear virus, shifting the balance in favor of viral
replication. Adoptive-transfer experiments of adult T cells into
virally infected neonates would help establish whether the "adult"
response can protect infected neonates. If so, this would further
support the concept that the outcome of a viral infection is predicated
on the interaction of multiple factors, including viral replication
rate, mechanism of cell-to-cell spread, tissue type infected, host age,
and host immunocompetence.
In RAG-2/ mice, there was a difference between neonates
and adults in the percentage of mice experiencing disease signs (91 versus 71%, respectively) and in the latency of disease onset (7 versus 19 days postinfection, respectively) (Table 2). In addition, the
number of infected neurons was significantly reduced in adult mice
compared to neonates by as early as 3 days postinfection (Table 1).
Thus, some factor other than lymphocyte-mediated protection delays
disease progression in adults and allows more mice to survive. This
factor may be a component of the innate immune system which is intact
in the RAG-2/ mice, such as natural killer cell
cytotoxicity or inflammatory cytokine secretion by macrophages or
microglia. Alternatively, brain developmental factors or age
differences in neuronal function may affect the rate of viral
replication and/or spread within the CNS. Neuronal maturation has been
implicated in age-dependent outcomes of other CNS infections, such as
hamster-adapted MV infection of neurons in mice (41),
reovirus encephalitis in mice (44), and encephalomyocarditis
virus infection in rat brain (22). Finally, we need to
consider the possibility that the CNS disease in neonates and
immunocompromised adult mice may be different and that the difference
in disease kinetics reflects the distinct pathogeneses of these
infections. In support of this hypothesis, preliminary data from our
laboratory suggest that the adult RAG-2/ spinal cord,
but not the neonatal spinal cord, is susceptible to infection; whether
spinal cord lesions such as demyelination influence the adult disease
remains to be determined.
SSPE, the human disease associated with protracted MV infection of CNS
neurons, is a very rare disease of children. Interestingly, very few
adults have been diagnosed with SSPE, despite extensive acute measles
infections in people of all ages. Sequence analysis of viral RNA
isolated from brain biopsies of children with SSPE has revealed a large
number of point mutations within the envelope-associated genes (6,
8, 10, 42), and it has been proposed that these viral mutants may
be either more neurotropic or neuropathogenic than wild-type strains.
While we are currently testing the effects of neuronal infection by
wild-type strains of MV, in our model system infection of the adult or
neonatal CNS by the vaccine strain MV-Edmonston was sufficient to cause
disease. Protection from infection and disease was conferred by a
mature and competent lymphocyte response. Perhaps the association of
SSPE with MV infection in children is not due to an age-dependent
access of the virus to the CNS or to the selection for neurotropic or
neurotoxic viral variants but rather to the ability of the host immune
response to appropriately recognize and resolve neuronal infection.
Future studies should take into account the contribution of both immune and CNS developmental differences in the pathogenesis of measles and
other neurotropic viral infections.
| |
ACKNOWLEDGMENTS |
This work was supported by Public Health Service grants MH56951
and CA06927, as well as by an NIH postdoctoral fellowship, T32-AI07429
(D.M.P.L.), and a grant from the Kirby Foundation (G.F.R.).
We wish to thank Frederick Alt for providing RAG-2 knockout mice, Sarah
Berman for secretarial assistance, and Mari Manchester, Michael B. A. Oldstone, Bill Mason, Erica Golemis, Dave Wiest, and John Taylor for
helpful discussions.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Institute for
Cancer Research, Fox Chase Cancer Center, 7701 Burholme Ave.,
Philadelphia, PA 19111. Phone: (215) 728-3617. Fax: (215) 728-3616. E-mail: gf_rall{at}fccc.edu.
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Journal of Virology, March 1999, p. 1795-1801, Vol. 73, No. 3
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Copyright © 1999, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
