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Infection and Immunity, March 1999, p. 1455-1460, Vol. 67, No. 3
The Basil and Gerald Felsenstein Medical
Research Center,
Received 5 August 1998/Accepted 3 December 1998
Neurologic manifestations, mainly convulsions, are the most
frequent extraintestinal complications of shigellosis. We used an
animal model to study the roles of tumor necrosis factor alpha (TNF- Neurologic disturbances are the most
frequent complications of acute gastroenteritis caused by bacteria of
the genus Shigella. They include convulsions, severe
headaches, hallucinations, and encephalopathy, which can be fulminant,
leading rapidly to unconsciousness and death (1, 2, 5, 10).
The pathogenesis of Shigella-associated neurologic symptoms
is unclear. Shiga toxin (ST), the main toxic product of Shigella dysenteriae, has been implicated in neurotoxicity, as its
administration caused paralysis and death in mice and rabbits
(13). Two other toxins of the same family, Shiga-like toxins
I and II (SLT I and SLT II), which are produced by enterohemorrhagic
Escherichia coli strains and are similar to ST in structure,
cell binding receptor, and biological activity (for a review see
reference 20), were also associated with
neurotoxicity. Administration of SLTs to laboratory animals or
inoculation with SLT-producing E. coli induced neurologic
symptoms (8, 9, 15, 29), and human infections with
SLT-producing strains are often accompanied by neurologic complications
(9, 12). However, the primary damage after toxin
administration is found in the vascular endothelium of the central
nervous system (CNS) rather than in the neuronal cells (13,
29), and the histopathological findings in human autopsy studies
do not always correlate with the severe manifestations (12).
Lipopolysaccharide (LPS) and the proinflammatory cytokines tumor
necrosis factor alpha (TNF- To investigate the underlying mechanisms of the neurologic disturbances
of shigellosis, we recently developed an animal model to study the
roles of host mediators and bacterial products in the induction of
seizures (35). Administration of the proconvulsant pentylenetetrazole (PTZ) to mice induces clonic-tonic seizures within
minutes of its application, owing to its antagonistic activity at the
benzodiazepine/ Employing this model, we showed that crude preparations of S. dysenteriae 60R (a producer of ST) and of E. coli H-30
(a producer of SLT I) enhanced the response to PTZ-induced seizures and
that ST and LPS acted in concert in this respect (35). In
the present study, we demonstrate that the enhancement of PTZ-induced
seizures caused by S. dysenteriae is mediated by TNF- Mice.
ICR outbred male mice 22 to 28 days of age (weight
range, 17 to 25 g) were maintained under standard conditions. The
animal experimentation guidelines followed in the animal studies were approved by the Animal Experimentation Committee of the Rabin Medical Center.
Materials.
PTZ (Sigma Chemical Co., St. Louis, Mo.) was
dissolved in pyrogen-free saline. Evans blue (Sigma) was dissolved in
sterile pyrogen-free saline before use.
Antisera.
Rabbit polyclonal anti-murine TNF- Preparation of bacterial sonicate.
Strain 60R of S. dysenteriae serotype 1 was grown in syncase broth for 48 h
with shaking, lysed by sonication, and filter sterilized as described
(22). The bacterial sonicate was analyzed for protein
content, cytotoxic activity, and lethality in mice. Cytotoxic activity
was quantitatively determined on HeLa cells as described previously
(35). Protein content was measured with the Bio-Rad protein
assay (Bio-Rad Laboratories GmbH, Munich, Germany). Lethality studies
were performed in groups of six mice injected intraperitoneally (i.p.)
with a fourfold dilution of bacterial sonicate, as described previously
(35). Death was recorded daily, and the 50% lethal dose
(LD50) was calculated according to the method of Reed and
Muench (28).
PTZ-induced convulsions.
Induction and scoring of seizures
was performed as described (35). Groups of six mice were
inoculated i.p. with 50 mg of PTZ per kg of body weight (a dose which
causes clonic-tonic seizures in 50% of animals), and their reactions
were observed for 10 min. Reactions included several phases, as
follows: unresponsiveness, myoclonic jerks, clonic seizures, and tonic
seizures (forelegs and then hind legs rigidly extended to the rear),
occasionally followed by death. Not all mice went through all the
phases. For statistical analysis, each phase was given a numerical
score, as detailed previously (19, 32): the score was 0 for
unresponsiveness, 1 for myoclonic contractions, 2 for clonic seizures,
3 for tonic seizures, and 4 for death. The response of each mouse was
scored as the highest phase reached, and a mean seizure severity score was calculated for each group. The percentages of mice that had clonic-tonic seizures in the treatment groups were also statistically compared.
Enhancement of PTZ-induced seizures.
Groups of six to eight
mice were inoculated i.p. with 1,000 50% cytotoxic doses
(CD50) (~4 LD50) of S. dysenteriae
60R sonicate. This dose caused death in 80 to 100% of the mice within
36 to 96 h. Saline-treated mice were used as controls. At 7 and
24 h after injection of S. dysenteriae sonicate or
saline, mice were injected with PTZ (50 mg/kg) and scored for their
response compared with that of controls.
Pretreatment with antibodies.
Rabbit anti-mTNF- Cytokine assay.
Plasma for TNF- Determination of BBB integrity.
Blood-brain barrier (BBB)
permeability was tested as described previously (7). Mice
were injected i.v. with 100 µl of 1% Evans blue, an albumin binding
dye, in saline. One hour later mice were anesthetized with
pentobarbital sodium (Nembutal) (60 mg/kg) and flushed with saline
introduced into the cardiac left ventricle. The brains were then
removed for photography.
Statistical analysis.
The difference in the incidence of
seizures among the various groups in each experiment was compared by
chi-square test for multiple comparisons or by Fisher's exact test, as
appropriate. Convulsion scores were compared by two-tailed unpaired
t test (for two groups) or by one-way analysis of variance
(for three or more groups).
Induction of TNF- Effects of anti-mTNF-
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Involvement of Tumor Necrosis Factor Alpha and Interleukin-1
in Enhancement of Pentylenetetrazole-Induced Seizures Caused by
Shigella dysenteriae
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
) and interleukin-1 
(IL-1) in
Shigella-related seizures. Administration of Shigella
dysenteriae 60R sonicate enhanced the sensitivity of mice to the
proconvulsant pentylenetetrazole (PTZ) within 7 h. This was
indicated by a significantly higher mean convulsion score and an
increased number of mice responding with clonic-tonic seizures in the
Shigella-pretreated group. Preinjection of mice with
anti-murine TNF- (anti-mTNF-) or anti-murine IL-1 (anti-mIL-1) 30 min prior to administration of Shigella
sonicate abolished their enhanced response to PTZ at 7 h. Mean
convulsion scores were reduced by anti-mTNF- from 1.2 to 0.8 (P = 0.017) and by anti-mIL-1 from 1.3 to 0.7 (P = 0.008). Preinjection of anti-mTNF- also
reduced the percentage of mice responding with clonic-tonic seizures,
from 48 to 29% (P = 0.002), and preinjection of
anti-mIL-1 reduced it from 53 to 21% (P = 0.012).
Neutralization of TNF- or IL-1 did not protect the mice from
death due to S. dysenteriae 60R. These findings indicate
that TNF- and IL-1 play a role in the very early sensitization of
the central nervous system to convulsive activity after S. dysenteriae administration. Similar mechanisms may trigger
neurologic disturbances in other infectious diseases.
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
) and interleukin 1 (IL-1) may also
be involved in diseases associated with ST and SLT toxicity. Barrett et
al. have shown that LPS either increased or inhibited SLT II lethality
in mice and rabbits, depending on the timing of its application, and
that the toxicity of SLT II in mice was macrophage-dependent (3,
4). TNF- and IL-1, the major mediators of LPS toxicity, are
also induced by SLTs (25). Both TNF- and IL-1
upregulate toxin receptor expression on endothelial cells and increase
SLT cytotoxicity (33). In the early stages of disease,
phagocytosis of Shigella triggers TNF release
(21), and macrophages infected with invasive
Shigella secrete large quantities of IL-1
(36). The increased production of these cytokines has been
implicated in the extensive inflammatory reaction and the severe tissue
damage of the colon (26). High concentrations of TNF- and
IL-1 may also account for systemic manifestations. Recently, we
found elevated plasma levels of TNF- in children with shigellosis,
with significantly higher concentrations in those exhibiting neurologic
complications (18).
-aminobutyric acid (GABA) receptor complex. The
ability of bacterial products to modulate the sensitivity of mice to
PTZ-induced seizures was used to study their involvement in the neural
processes that lead to convulsions.
and
IL-1.
MATERIALS AND METHODS
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
(anti-mTNF-) and rabbit polyclonal anti-murine IL-1
(anti-mIL-1) antibodies were purchased from Genzyme Corp.
(Cambridge, Mass.).
(30 µl/mouse), rabbit anti-mIL-1 (30 µg/mouse), or normal rabbit
serum (NRS) was injected intravenously (i.v.) in a 200-µl volume 30 min before injection of bacterial sonicate.
and IL-1 assessment
was collected at 0, 1, 3, 5, and 24 h after Shigella
sonicate administration and stored at 
70°C until assay. TNF-
levels were determined by a cytotoxicity bioassay on mouse L-929 cells
(18). Each test included a standard curve of recombinant
human TNF- (specific activity, 2.5 × 107 U/mg of
protein), kindly provided by T. Amarant (Reprogen Ltd., Rehovot,
Israel). IL-1 was measured by an enzyme-linked immunosorbent assay
kit (R&D Systems Inc., Minneapolis, Minn.).
RESULTS
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
and IL-1 production by S. dysenteriae 60R sonicate.
Injection of S. dysenteriae 60R sonicate rapidly induced circulating TNF- and
IL-1. High levels of TNF- were present 1 h after injection,
and the levels declined rapidly to undetectable concentrations at
5 h (Fig. 1); IL-1 appeared after
TNF-, the levels peaking at 3 h and returning to baseline by
24 h (Fig. 1).
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FIG. 1.
Plasma TNF- and IL-1 production in response to
S. dysenteriae 60R sonicate (60R). Mice were injected with
S. dysenteriae 60R sonicate (4 LD50, i.p.).
TNF- production was determined by bioassay and IL-1 production
was determined by enzyme-linked immunosorbent assay kit, as described
in Materials and Methods. The values are the means of at least five
determinations.
and anti-mIL-1 on enhancement of
PTZ-induced seizures by S. dysenteriae sonicate.
Administration of S. dysenteriae 60R sonicate 7 and 24 h before PTZ administration increased the susceptibility of the mice to
PTZ. This was reflected in the significantly higher mean convulsion score (Fig. 2) and the greater number of
mice responding with clonic-tonic seizures as compared to control,
saline-treated mice (Table 1).
View larger version (30K):
[in a new window]
FIG. 2.
Effect of pretreatment with anti-mTNF- or
anti-mIL-1 on the enhancement of PTZ-induced seizures by S. dysenteriae sonicate (60R). Mice were injected i.p. with saline
alone (
) or with 60R alone (
) or were pretreated with the
indicated antibodies i.v. 30 min before administration of 60R. PTZ was
applied i.p. at 7 and 24 h. Each panel shows the findings for a
different pretreatment. (A) For mice pretreated with anti-mTNF-
(), at 7 h the P value was <0.001 for the
convulsion scores in the groups treated with saline (n = 63) and with 60R (n = 67), and it was 0.017 for
the scores for the groups treated with 60R and with anti-mTNF- plus
60R (n = 68). At 24 h, the P value was
0.001 for saline- (n = 49) and 60R-treated
(n = 56) groups, and the P value was 0.170 for 60R- and anti-mTNF--plus-60R-treated (n = 48)
groups. (B) For mice pretreated with anti-mIL-1 (
), at 7 h,
P was 0.001 for the scores in the saline-treated
(n = 30) and 60R-treated (n = 30)
groups, and it was 0.008 for those in the 60R- and
anti-mIL-1-plus-60R-treated (n = 28) groups. At
24 h, P was <0.001 for saline-treated (n = 48) and 60R-treated (n = 48) groups, and
P was 0.036 for 60R- and anti-mIL-1-plus-60R-treated
(n = 47) groups. (C) For mice pretreated with NRS
(
), the
P values were 0.017 for saline-treated (n = 11) and 60R-treated (n = 12) groups and 0.1 for
60R- and NRS-plus-60R-treated groups at 7 h and <0.05 for
saline-treated (n = 18) and 60R-treated (n = 18) groups and 0.7 for saline- and NRS-plus-60R-treated groups at
24 h.
TABLE 1.
Effects of pretreatment with anti-mTNF- and
anti-mIL-1 on S. dysenteriae 60R enhancement of
PTZ-induced seizures
and IL-1 participate in the
sensitization of mice to PTZ-induced seizures by S. dysenteriae, we pretreated the mice with anti-mTNF- or
anti-mIL-1. Pretreatment with anti-mTNF- before inoculation with
S. dysenteriae 60R sonicate abolished the greater response
to PTZ at 7 h. The mean convulsion scores for control mice, mice
given S. dysenteriae 60R sonicate, and mice pretreated with
anti-mTNF- prior to inoculation with S. dysenteriae 60R
sonicate were 0.7, 1.2, and 0.8, respectively (P < 0.001 for saline versus Shigella and P = 0.017 for Shigella versus anti-mTNF- followed by
Shigella) (Fig. 2A). The incidences of seizure for the three
groups (Table 1) were 27% (17 of 67 saline-treated mice), 48% (32 of
67 Shigella sonicate-treated mice), and 29% (20 of 68 mice
treated with anti-mTNF- plus Shigella) (P = 0.002 for saline versus Shigella and P = 0.021 for Shigella versus anti-mTNF- plus
Shigella).
A reduced response after anti-mTNF- pretreatment was also noticed
when PTZ was administered 24 h after bacterial sonicate inoculation, but the reduction was milder and did not reach statistical significance (Fig. 2A and Table 1).
Pretreatment with anti-mIL-1 yielded results similar to those for
anti-mTNF-. The effect of anti-mIL-1 was also most evident when
PTZ was applied 7 h after bacterial sonicate inoculation (Fig.
2B). Mean convulsion scores were 0.5, 1.3, and 0.7 for saline-treated, S. dysenteriae 60R sonicate-treated, and
anti-mIL-1-plus-S. dysenteriae 60R sonicate-treated
groups, respectively (P = 0.001 for saline versus
Shigella and P = 0.010 for
Shigella versus anti-mIL-1 plus Shigella).
Preinjection of anti-mIL-1 also completely abolished the increase in
the number of mice responding to PTZ with clonic-tonic seizures; the
seizure incidences were 23% (7 of 30 mice) in the saline-treated
group, 53% (16 of 30 mice) in the Shigella sonicate-treated group, and 21% (6 of 28 mice) in the group treated with anti-mIL-1 plus Shigella) (P = 0.016 for saline versus
Shigella and P = 0.012 for
Shigella versus anti-mIL-1 plus Shigella)
(Table 1).
The effect of anti-mIL-1 on the convulsion score remained
significant when PTZ was administered 24 h after bacterial
sonicate inoculation; the scores were 0.9, 1.8, and 1.3 for the groups treated with saline, Shigella, and Shigella plus
anti-mIL-1, respectively (P < 0.001 for saline
versus Shigella and P = 0.036 for
Shigella versus anti-mIL-1 plus Shigella)
(Fig. 2B). However, there was no significant difference between the
total numbers of mice with clonic-tonic seizures in the
Shigella and anti-mIL-1-plus-Shigella groups
(Table 1).
Pretreatment of mice with NRS prior to S. dysenteriae 60R
sonicate administration did not reduce the enhanced response to PTZ
(Fig. 2C), nor did administration of anti-mTNF- or anti-mIL-1 affect the response to PTZ in mice pretreated with saline (data not shown).
BBB permeability.
Elevated levels of IL-1 and TNF- have
been associated with disruption of BBB integrity (24). To
investigate the possibility that severe BBB injury contributes to the
enhanced response to PTZ, we examined the permeability of the BBB at
various time points after S. dysenteriae 60R sonicate
injection (Fig. 3). At 7 h, only 1 of 15 brains examined was slightly stained with Evans blue, whereas at
24 and 48 h 60% (n = 10) and 100% (n = 5), respectively, were permeable.
|
Effects of anti-mTNF- and anti-mIL-1 on clinical
manifestations.
The mice that received S. dysenteriae
60R sonicate died within 5 days. Clinical symptoms, which usually
appeared after 24 h, included ruffled fur, weakness, weight loss,
and shortly before death, flaccid paralysis of the hind legs.
Pretreatment with anti-mTNF- or anti-mIL-1 neither attenuated the
clinical symptoms nor protected the mice from death. A slightly
increased mortality rate (Table 2) and
shorter survival time were observed in the mice receiving anti-mTNF-
(Fig. 4). However, both anti-mTNF- and
anti-mIL-1 prevented the massive weight loss observed at 24 h
after bacterial sonicate administration (Table 2).
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Mice show an increased susceptibility to PTZ as early as 6 to 7 h after administration of S. dysenteriae 60R sonicate. This resembles the situation in human shigellosis where, strikingly, neurologic disturbances appear very early in the course of the disease, sometimes preceding the onset of diarrhea (2). Therefore, our model is useful for studying the early neural processes that lead to convulsions in human infections.
The rapid sensitization of the mice to PTZ by Shigella
sonicate is a result of the mutual action of ST and LPS, as we have previously shown (35). TNF- and IL-1 are quickly
induced after Shigella administration by LPS and possibly by
ST itself. Both TNF- and IL-1 have been implicated in the
neurologic manifestations of infectious diseases, such as bacterial
meningitis, cerebral malaria, and human immunodeficiency viral
encephalitis (7, 16, 30), owing mainly to the correlation
between cerebrospinal fluid TNF- and IL-1 levels and the severity
of the neurologic damage. Neurologic disorders, including seizures,
have also been reported to occur during cancer therapy with TNF- or
IL-1 (27, 31) and in transgenic mice showing CNS-specific
expression of TNF- (23).
In all these pathological conditions, however, TNF- and IL-1 are
present for a prolonged time. Here, we demonstrate that the
administration of antibodies to TNF- or IL-1 abolishes the enhanced S. dysenteriae-induced sensitivity to PTZ which
occurs rapidly (within 7 h) after bacterial administration. Yet,
since by the time mice exhibit the increased sensitivity TNF- and
IL-1 are no longer detectable in the circulation, it is possible
that other factors induced by TNF- and IL-1 may also contribute
to the sensitization of the CNS. To the best of our knowledge, this is
the first time that a causal relationship between TNF- or IL-1
and the induction of seizures has been demonstrated in an animal model
of an infectious disease.
There are several possible pathways by which TNF- and IL-1 can
affect brain function. TNF- and IL-1 can modulate the CNS from
the periphery. There is a line of evidence showing that a variety of
illness responses, such as fever, headache, slow-wave sleep, and
behavioral changes, which are governed by the brain, are mediated by
cytokines produced in the periphery, which stimulate the CNS through
afferent nerves (34). Alternatively, as some studies have
demonstrated, TNF- and IL-1 can cross the BBB (11). They are also produced within the brain by glial cells. Elevated brain
mRNA levels for TNF- and IL-1 were shown after systemic administration of LPS (34). It is possible, therefore, that TNF- and IL-1 produced locally in the brain are also involved in
the sensitization to PTZ-induced seizures by S. dysenteriae. These cytokines affect many functions in the CNS, including
neurotransmission and neurotoxicity (reviewed in reference
30). Some of their activities are modulated by the
induction of secondary messengers, such as nitric oxide (NO). It has
been reported that TNF- and IL-1 synergistically mediate
neurotoxicity through NO induction (6). NO acts also as a
neurotransmitter, and its overproduction has been linked to induction
of seizures (17). Another gene upregulated in the brain
after systemic administration of either LPS or IL-1 is the
immediate-early gene c-fos, which is activated during
seizures (14, 34). TNF- and IL-1 may also act
indirectly by increasing ST toxicity. ST is transported very rapidly to
the CNS, where it binds to specific receptors on endothelial cells (29). It can be postulated that both TNF- and IL-1
upregulate ST receptors and increase ST cytotoxicity, as they do in vitro.
Which one of the diverse activities of TNF- and IL-1 in the CNS
is relevant to the enhancement of seizures by S. dysenteriae remains an enigma. In any case, since the increased sensitivity to the
proconvulsant PTZ requires the presence of both LPS and ST, as we have
previously shown (35), some kind of cooperative mechanism
must exist. The fact that neutralization of either TNF- or IL-1
was sufficient to reduce seizure incidence indicates that both
cytokines play an essential role in the processes that lead to the
increased susceptibility to proconvulsants.
The inhibition of TNF- or IL-1 was much less effective in
reducing the incidence of enhanced seizures when PTZ was applied 24 h after Shigella sonicate. This implies that at this
later stage, the enhancement of seizures is mediated by additional
mechanisms. Moreover, the neutralization of TNF- or IL-1 did not
protect the mice from death, which indicates that S. dysenteriae is capable of inducing neuronal damage and death by
mechanisms that do not involve induction of circulatory TNF- and
IL-1. In fact, administration of TNF- slightly increased the
mortality rate and shortened the life span. This points to the complex
effects, both protective and deleterious, of TNF- during the course
of the disease.
In conclusion, using the model of PTZ-induced seizures, we showed that
both TNF- and IL-1 sensitize the CNS to convulsive activity very
shortly after S. dysenteriae administration. Similar mechanisms may trigger the early neurologic disturbances observed in
human shigellosis and enterohemorrhagic E. coli infections. This model may be used to elucidate the pathogenesis of neurologic symptoms associated with other infectious diseases.
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ACKNOWLEDGMENTS |
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We thank Amiram Ravid, The Felsenstein Medical Research Center, for fruitful discussions of the results.
This study was supported by Tel Aviv University Research Foundation grant 572/96.
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FOOTNOTES |
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* Corresponding author. Mailing address: P.O.B. 8145, Petah Tikva 49181, Israel. Phone: 972-3-9253680/1. Fax: 972-3-9253056/3899. E-mail: shkenazi{at}post.tau.ac.il.
Editor: E. I. Tuomanen
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Infection and Immunity, March 1999, p. 1455-1460, Vol. 67, No. 3
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