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Journal of Virology, March 1999, p. 2563-2567, Vol. 73, No. 3
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Resistance of Interleukin-1
-Deficient Mice to
Fatal Sindbis Virus Encephalitis
Xiao Huan
Liang,1
James E.
Goldman,2
Hui Hui
Jiang,1 and
Beth
Levine1,*
Departments of
Medicine1 and
Pathology,2 Columbia University College
of Physicians & Surgeons, New York, New York 10032
Received 16 September 1998/Accepted 18 November 1998
 |
ABSTRACT |
Interleukin-1
(IL-1) concentrations are frequently elevated
in central nervous system (CNS) viral infections, but the
pathophysiologic significance of such elevations is not known. To
examine the role of IL-1 in CNS viral pathogenesis, we compared the
natural histories of IL-1-deficient and wild-type 129 SV(ev) mice
infected with a neurovirulent viral strain, neuroadapted Sindbis virus
(NSV). We found that the incidence of severe paralysis and death was markedly decreased in NSV-infected IL-1
/ mice
compared to NSV-infected wild-type mice (4 versus 88%,
P < 0.001). Despite this marked difference in
clinical outcome, no differences in numbers of apoptotic cells or
presence of histopathologic lesions in the brains of moribund wild-type
mice and those of clinically healthy IL-1/ mice
could be detected. These results suggest that IL-1 deficiency is
protective against fatal Sindbis virus infection by a mechanism that
does not involve resistance to CNS virus-induced apoptosis or histopathology.
| |
TEXT |
The proinflammatory cytokine
interleukin-1(IL-1) is a critical modulator of the host response
to microbial infections. It is induced by a wide range of microbes and
other inflammatory mediators and has pleiotropic effects on numerous
cell types, including fever and the induction of other cytokines
mediating the acute-phase response. The protective role of IL-1 in
microbial host defense has been best characterized in bacterial
infections, but at least two lines of evidence suggest that IL-1
also plays an important role in host defense against certain viral
diseases. First, mice deficient in IL-1 demonstrate increased
susceptibility to challenge with influenza virus (9).
Second, deletions of poxvirus genes whose products directly interfere
with the activation of IL-1 (e.g., poxvirus genes encoding serpins
that inhibit IL-1-converting enzyme) or the function of IL-1
(e.g., soluble IL-1 receptors that bind IL-1) lead to decreased
viral virulence and host pathology (27, 30). Thus, in
influenza virus and poxvirus animal models, viral induction of IL-1
is beneficial for the host.
However, IL-1 may have adverse pathophysiologic consequences when
levels are elevated in response to certain noninfectious stimuli,
especially those involving the central nervous system (CNS). Mature
IL-1, secreted either by intrinsic brain cells or by infiltrating
inflammatory cells, can result in neuronal dysfunction (reviewed in
reference 25) by affecting neurotransmitter synthesis, ion influxes, or nitric oxide production. Mature IL-1 can
also play a direct role in mediating irreversible brain damage. Ischemic and excitotoxic brain damage in rodents is significantly inhibited by treatment with IL-1 receptor antagonist (21,
34), and transgenic mice that are deficient in IL-1-converting
enzyme (23) or express a dominant negative mutant of
IL-1-converting enzyme (4) are protected against ischemic
brain injury. Furthermore, IL-1 may be involved in mediating
apoptotic death of neurons in response to trophic factor deprivation or
oxidative stress (5, 32).
In several different viral infections of the nervous system, elevations
of IL-1 levels have been described. These include human
immunodeficiency virus (HIV) (6, 18), simian
immunodeficiency virus (10), lymphocytic choriomeningitis
virus (3), the nerotropic JHMV strain of mouse hepatitis
virus (28), rabies virus (14), canine distemper
virus (1), Semliki Forest virus (15), and Sindbis
virus (33) infections. Despite the protective effect of
IL-1 in influenza and poxvirus infections (which are outside the
CNS), the deleterious role of IL-1 in nonviral CNS disorders raises
the possibility that IL-1 also contributes to the pathogenesis of
CNS viral diseases. A correlation between the level of IL-1 elevation and the severity of viral encephalitis has been previously noted (6, 33), but no studies have directly examined whether IL-1 plays a protective or deleterious role in CNS viral infections.
To examine the role of IL-1 in CNS viral pathogenesis, we used an
IL-1-deficient mouse model of Sindbis virus encephalitis. We used
the strain neuroadapted Sindbis virus (NSV), which was derived from the
prototype alphavirus, wild-type Sindbis virus, by serial intracerebral
passage in mouse brain (7, 8). NSV, unlike wild-type Sindbis
virus, produces fatal disease in both suckling and weanling mice. Both
immunocompetent and severe combined immunodeficient (scid)
suckling mice are susceptible to lethal wild-type Sindbis virus
infection. In contrast, the fatal disease produced by NSV in weanling
mice requires the contribution of an immunopathological response since
weanling scid mice are resistant to NSV-induced paralysis
and death (33). Previously, it has been shown that levels of
IL-1 are higher in the brains of NSV-infected immunocompetent mice
than in the brains of NSV-infected scid mice (33). In the present study, we examined the
significance of IL-1 in the pathogenesis of fatal NSV encephalitis
by comparing the natural histories of disease in
IL-1/ and wild-type 129 SV(ev) mice.
IL-1-deficient mice are resistant to fatal NSV
infection.
To evaluate the role of IL-1 in the pathogenesis of
NSV encephalitis, we compared the natural histories of 5-week-old
IL-1-deficient 129 SV(ev) mice (36) (provided by Hui
Zheng, Merck Research Laboratories) and wild-type 129 SV(ev) mice
(Taconic Farms), both of which had been inoculated intracerebrally with
NSV. Mice were observed for a 21-day period for mortality and maximal
amount of paralysis. After NSV infection, 92% of 129 SV(ev) mice
developed severe paralysis (Table 1) and
88% died (Fig. 1). (The one mouse that
developed severe paralysis but did not die recovered completely by day
21.) In contrast, only 4% of the IL-1-deficient mice developed severe paralysis (Table 1), and only 4% of the mice died (P < 0.001, life table analysis) (Fig. 1). These results show that IL-1-deficient mice are resistant to paralysis and death induced by
NSV infection.
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FIG. 1.
Survival curves of IL-1/ (closed
circles) and wild-type (open circles) 129 SV(ev) mice infected with
NSV. Five-week-old mice were inoculated intracerebrally with 1,000 PFU
of NSV in 0.03 ml of Hanks balanced salt solution. Five to ten mice of
each strain were infected per experiment; data shown represent combined
survival probabilities for four independent infections. Significance of
survival differences determined by life table analysis.
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Kinetics of viral spread and clearance in IL-1-deficient
mice.
To assess whether IL-1 deficiency affects the CNS
replication of NSV, we performed in situ hybridization to detect
message-sense viral RNA in the brains of IL-1-deficient and
wild-type 129 SV(ev) mice. Computerized quantitative image analysis was
used to calculate the number of viral RNA-positive cells in individual
mouse brain sections at serial time points after infection
(13). At day 2 after infection, there were more RNA-positive
cells in the brains of wild-type mice than in the brains of
IL-1-deficient mice (Fig. 2A), but
this difference did not reach statistical significance (P = 0.096, t test). The number of RNA-positive cells in
wild-type-infected mice peaked at day 2 after infection, whereas the
number of RNA-positive cells in IL-1/ mice did not
peak until day 6 after infection. At day 6 after infection, when the
peak number of RNA-positive cells was observed in IL-1-deficient
mice, the number of viral RNA-positive cells in the brains of wild-type
mice had already declined markedly. This difference is illustrated in
the representative photomicrographs of hippocampal sections shown in
Fig. 3. By day 9 after infection, viral
RNA was no longer detected in the brains of IL-1/
mice.
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FIG. 2.
Viral growth and apoptosis in the brains of
IL-1/ (closed circles) and wild-type (open circles)
129 SV(ev) mice infected with NSV. At serial time points after NSV
infection, mice were sacrificed, and brains were fixed in 4%
paraformaldehyde and embedded in paraffin. Parasagittal brain sections
(4 µm) were cut at the level of the olfactory bulb, extending
caudally from the bulb to the cerebellum and medulla. In situ
hybridization to detect message-sense viral RNA (A) and ISEL to detect
apoptotic nucleic (B) were performed as described previously (11,
22). The numbers of virus RNA and ISEL-positive cells were
quantitated with Image-ProPlus software, exactly as previously
described for Sindbis virus-infected brains (11). Each data
point represents the mean ± the standard error of the mean of
RNA- or ISEL-positive cells per square millimeter of brain for four to
eight mice.
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FIG. 3.
Representative photomicrographs of hippocampal sections
of a moribund wild-type 129 SV(ev) mouse (A, C, and E) and a clinically
healthy IL-1/ 129 SV(ev) mouse (B, D, and F) 6 days
after infection with NSV. (A and B) H&E-stained sections showing
necrosis and numerous pyknotic nuclei in both the wild-type and
IL-1/ mice. (C and D) In situ hybridization to
detect message-sense viral RNA. The images show fewer positive cells in
the wild-type mouse than in the IL-1/ mouse. (E and
F) ISEL staining to detect apoptotic nuclei. The images show numerous
positive cells in both the wild-type and the IL-1/
mouse. Panels C to F illustrate representative fields used for
computerized quantitative image analyses of viral RNA-positive and
ISEL-positive cells (Fig. 2) and correspond to images observed with a
10× objective lens; arrowheads denote cells representative of those
that were scored as positive by the Image-ProPlus software program.
Panels A and B show images of the same hippocampal brain region
observed with a 40× objective lens.
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Apoptosis is not prevented in the brains of IL-1-deficient
mice.
To determine whether IL-1 deficiency protects against
NSV-induced apoptosis, we compared the number of apoptotic nuclei in the brains of NSV-infected IL-1/ and wild-type mice.
Computerized quantitative image analysis was used to calculate the
number of apoptotic, in situ end labeling (ISEL)-positive cells in
individual mouse brain sections at serial time points after infection
(13). At day 2 after infection, parallel to the decrease in
viral RNA-positive cells, the number of apoptotic cells was decreased
in the brains of IL-1-deficient mice (Fig. 2B), but this difference
also did not reach statistical significance. Furthermore, within
defined virus-infected brain regions, the number of apoptotic versus
RNA-positive cells appeared to be at least as high in the
IL-1-deficient mice as in the wild-type 129 SV(ev) mice (data not
shown). Thus, the decreased total number of apoptotic nuclei in the
brains of IL-1-deficient mice at day 2 after infection probably
reflects the decreased number of virus-infected cells rather than any
specific protective effects of IL-1 deficiency on virus-induced
apoptosis. At day 6 after infection, when the number of viral
RNA-positive cells was highest in NSV-infected IL-1-deficient mouse
brains, the number of apoptotic cells was also highest. At this time
point, the number of apoptotic cells observed in the brains of
IL-1/ mice was identical to that found in the brains
of wild-type 129 SV(ev) mice.
CNS histopathology and apoptosis do not correlate with clinical
status of NSV-infected mice.
To determine whether the clinical
resistance of IL-1-deficient mice to NSV-induced disease was
associated with reduced CNS histopathology, hematoxylin-and-eosin
(H&E)-stained brain sections were examined by a neuropathologist
blinded to mouse genotype. At day 6 after infection, the majority of
NSV-infected wild-type mice were lethargic, severely paralyzed, and
moribund, whereas the majority of NSV-infected IL-1-deficient mice
appeared clinically healthy. Despite these pronounced differences in
clinical status between the two groups of mice, no significant
histopathologic differences could be detected between the brain tissues
of the IL-1/ and the wild-type 129 SV(ev) mice. At
day 6 after infection, both groups of mice demonstrated histopathologic
evidence of severe encephalitis, including extensive perivascular
cuffing, microglial activation, and pyknotic cell nuclei (see
representative photomicrographs in Fig. 3A, 3B, and
4). The frequency, severity, and
distribution of such lesions did not differ between the two strains of
mice. In addition, as stated above, numbers of apoptotic brain cells in
the brains of mice in both groups were identical. Thus, the resistance
of IL-1-deficient mice to fatal NSV encephalitis cannot be
attributed to a decrease in CNS cell death, CNS inflammation, or other
apparent histopathologic changes.
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FIG. 4.
Perivascular inflammation in the anterior thalamus of a
wild-type 129 SV(ev) mouse (A) and a IL-1/ 129 SV(ev) mouse (B) 6 days after NSV infection.
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|
In summary, we found that wild-type 129 SV(ev) mice developed severe
paralysis and death, whereas the majority of IL-1
/
129 SV(ev) mice remained clinically healthy, following intracerebral
NSV infection. At day 2 after infection, there were decreases
in the
numbers of virus RNA-positive cells and apoptotic cells
in
IL-1
-deficient mice compared to wild-type 129 SV(ev) mice;
these
values did not reach statistical significance. Moreover,
at 6 days
after infection, when IL-1
-deficient mice were clinically
healthy
and wild-type mice were moribund, the brains of both groups
of mice
demonstrated extensive apoptosis and severe histopathology.
These
findings suggest that IL-1
deficiency protects against
fatal NSV
encephalitis by a mechanism that does not involve the
blockade of
virus-induced CNS apoptosis or histopathology. To
our knowledge, these
findings provide the first direct demonstration
of a deleterious role
of IL-1
in a CNS viral
infection.
The mechanism by which IL-1
exerts deleterious effects in NSV
encephalitis appears to differ somewhat from that postulated
for
nonviral CNS disorders. In ischemic and excitotoxic models
of CNS
diseases, IL-1
is thought to contribute directly to neuronal
death
(reviewed in reference
20). In contrast, in the NSV
encephalitis
model, IL-1
deficiency did not protect animals
from virus-induced
neuronal death. At a time after intracerebral NSV
inoculation
when infected wild-type animals were terminally ill and
infected
IL-1
/ animals were clinically healthy, the
number of pyknotic neuronal
nuclei observed by H&E staining and the
number of apoptotic nuclei
observed by ISEL staining were similar in
IL-1
-deficient and
wild-type
mice.
In addition to the lack of a role for IL-1
in NSV-induced
neuronal death, our results also suggest the lack of a role for
IL-1
-dependent tissue inflammation in the pathogenesis of fatal
NSV
encephalitis. Histopathologic hallmark lesions of viral encephalitis
(e.g., perivascular cuffs and glial nodules) were present with
equal
frequencies and severities in the brains of NSV-infected,
terminally
ill wild-type mice and NSV-infected, clinically healthy
IL-1
-deficient mice. This finding suggests that the occurrence
of
these lesions in NSV encephalitis is not mechanically related
to the
clinical manifestations of the disease and that IL-1
is
not an
essential cytokine for mediating virally induced CNS-inflammatory
responses. Zheng et al. also found no difference in the histologic
nature or the severity of inflammatory lesions between wild-type
and
IL-1
/ mice in the turpentine model of inflammation,
despite the failure
of IL-1
/ mice to produce
elevations in levels of acute-phase reaction
proteins (
36).
We cannot exclude the possibility that the resistance of IL-1
mice
to fatal NSV encephalitis is due to slower CNS replication
of NSV in
these animals. There was an approximately twofold decrease
in the
number of viral RNA-positive cells in IL-1
/ mice
compared to wild-type 129 SV(ev) mice at day 2 after infection;
this
difference did not reach statistical significance. The effects
of
IL-1
on alphavirus replication have not been studied, but
neurons
(the primary target of Sindbis virus infection in the
CNS) have surface
IL-1 receptors, and IL-1
is known to stimulate
the replication of
other, unrelated viruses. IL-1
can potentiate
HIV replication in T
cells (
19) through a signalling pathway
that likely involves
p38 mitogen-activated protein kinase (
26)
and NF-
B
transcriptional stimulation of the HIV long terminal
repeat
(
17). IL-1
can also increase the susceptibility of
respiratory
epithelial cells to human rhinovirus infection by
upregulating
levels of the rhinovirus receptor, ICAM-1 (
29).
In addition,
soluble IL-1 receptors that antagonize IL-1
reduce
viral replication
in BALB/c mice infected with murine cytomegalovirus
(
35). Further
studies to examine the effects of IL-1
on
NSV replication in
mouse brain are
warranted.
IL-1
may play a pathophysiologic role in fatal NSV encephalitis
through mechanisms other than those affecting neuronal death,
CNS
inflammation, or viral replication. Given that neuronal death
and CNS
histopathology lack a relationship to animal mortality
in NSV
encephalitis, one possibility is that animal mortality
in these cases
results from IL-1
-dependent neuronal dysfunction
and/or
alterations in neurohormonal function. IL-1
stimulates
the release
of several neurotransmitters, including norepinephrine,
dopamine,
5-hydroxytryptophan, and nitric oxide; induces alterations
in the
electrophysiologic properties of neurons; stimulates the
hypothalamic-pituitary-thyroid axis, resulting in a systemic stress
response; and modulates autonomic function, including body temperature
and cardiovascular regulation (reviewed in reference
24). The
reversibility of severe NSV-induced
paralysis in mice that do
not die supports the concept that at least
some of the disease
manifestations are due to potentially reversible
neuronal dysfunction,
which could be mediated by effects of IL-1
on
neurotransmission
or neuroelectrophysiology. In addition, it has
been postulated
that the systemic stress responses resulting from
intracerebral
production of IL-1
and other cytokines are
important in the pathogenesis
of encephalitis caused by neurovirulent
strains of Sindbis virus
(
31) and herpes simplex virus
(
2).
The lack of a correlation between clinical outcome and amount of CNS
apoptosis in NSV-infected IL-1
/ and wild-type 129 SV(ev) mice may have important implications
for understanding the role
of apoptosis in CNS viral pathogenesis.
Previously, we and others
hypothesized that apoptosis plays a
direct role in the pathogenesis of
fatal Sindbis virus encephalitis.
This hypothesis was based upon
observations that the overexpression
of antiapoptotic genes (e.g.,
bcl-2,
beclin, and
crm-A) in virally
infected neurons protects 1- to 10-day-old mice from fatal Sindbis
virus infection (
11,
13,
16). In addition, Lewis et al.
reported a close relationship between CNS apoptosis and fatal
disease
in older mice infected with different strains of Sindbis
virus
(
12). However, the findings of the present study suggest
that, at least in the NSV weanling-mouse model of alphavirus
encephalitis,
extensive CNS apoptosis may be present without adversely
affecting
the clinical status of the animal. The nature of the
pathogenetically
relevant IL-1
-dependent factors that are
responsible for NSV-induced
paralysis and death remains to be
elucidated.
| |
ACKNOWLEDGMENTS |
We thank H. Zheng and L. H. T. Van der Ploeg (Merck
Research Laboratories) for providing IL-1/ 129 SV(ev) mice and Milton Packer for helpful comments.
This work was supported by a James S. McDonnell Foundation
Scholar Award (B.L.) and NIH grants AI01217 (B.L.) and AI40246 (B.L.).
B.L. was supported by an Irma T. Hirschl Trust Career Scientist Award.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Medicine, Columbia University College of Physicians & Surgeons, P & S 8-444, 630 W. 168th St., New York, NY 10032. Phone: (212) 305-7312. Fax: (212) 305-7290. E-mail:
Levine{at}cuccfa.ccc.columbia.edu.
| |
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Journal of Virology, March 1999, p. 2563-2567, Vol. 73, No. 3
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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