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*
Institut für Medizinische Mikrobiologie und Hygiene, Universitätsklinikum Mannheim, Universität Heidelberg, Germany;
Institut für Neuropathologie, Universitätskliniken Bonn, Bonn, Germany; and
Institut für Klinische Mikrobiologie, Immunologie und Hygiene, Universität Erlangen, Erlangen, Germany
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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40 days did not result in
an increase of the intracerebral parasitic load and a reactivation of
the disease, despite the presence of iNOS-suppressive inhibitor levels
in the brain. However, L-nitroarginine-methylester
treatment had remarkably toxic effects and induced a severe wasting
syndrome with high mortality. In contrast to BALB/c mice,
L-N6-iminoethyl-lysine treatment
rapidly exacerbated the already established chronic TE of C57BL/6 mice.
Thus, the containment of latent toxoplasms in T.
gondii-resistant BALB/c mice is independent of iNOS, whereas
the temporary control of intracerebral parasites in T.
gondii-susceptible C57BL/6 mice with chronic TE requires iNOS
activity. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The factors of the immune system that prevent reactivation of T.
gondii have only been partially identified. Studies in
experimental murine toxoplasmosis have revealed that T cells play a
critical role, because simultaneous depletion of CD4+ and
CD8+ T cells leads to reactivation of chronic
Toxoplasma encephalitis (TE) 1 . The major protective
mechanism of CD4+ and CD8+ T cells is the
production of IFN-
, and neutralization of this cytokine also results
in a lethal reactivation of chronic TE 2, 3 . Moreover, neutralization
of TNF-
, which is produced by CD4+ and CD8+
T cells, macrophages/microglial cells, and astrocytes in chronic TE,
exacerbates cerebral toxoplasmosis 4, 5 .
At present, it is unclear as to how IFN- and TNF- control
intracerebrally persisting toxoplasms. Because in vitro studies have
demonstrated that IFN- induces a TNF--dependent nitric oxide
(NO)-mediated toxoplasmastatic activity in murine macrophages 6, 7 ,
it was hypothesized that IFN- and TNF- also exert their
protective activity in toxoplasmosis in part via the induction of NO.
In fact, experiments in anti-TNF--treated mice,
IFN-R-deficient mice, or TNF receptor type 1 and type 1/2-deficient
mice have shown that these mice die of an impaired parasite control
that, apart from one study, was associated with a reduced expression of
inducible nitric oxide synthase (iNOS, NOS2) 4, 8, 9, 10 . In
addition, studies directly addressing the role of NO in murine acute
toxoplasmosis have revealed that an inhibition of iNOS with
aminoguanidine beginning at the day of infection leads to an increased
intracerebral parasitic load 11 . Furthermore, iNOS-deficient mice had
impaired parasite control and developed rapidly fatal acute cerebral
toxoplasmosis 12, 13 . In addition to this direct antiparasitic
effect, NO exerts an important immunoregulatory role in acute
toxoplasmosis by suppressing the cytokine production and proliferation
of T cells 11, 14 .
It is important to emphasize that all of the aforementioned studies on the role of iNOS in cerebral toxoplasmosis have been performed in T. gondii-susceptible mouse strains (i.e., C57BL/6 or 129Sv x C57BL/6 mice), which inevitably develop progressive and ultimately fatal TE due to a genetically determined insufficient intracerebral immune response 15, 16 . As the mice were lacking the iNOS gene or were treated with nonselective iNOS inhibitor from the very beginning of the infection 11, 12, 13 , these studies did not directly analyze the function of iNOS/NO in chronic (i.e., already established) cerebral toxoplasmosis. In fact, in susceptible mice, inhibition of iNOS from the start of infection might indirectly influence the course of the subsequent encephalitis, because it prevents the inflammation and necrosis of the small bowel otherwise occurring in these mice after oral infection 12, 17 . Experiments on the role of iNOS/NO in latent cerebral toxoplasmosis of T. gondii-resistant mouse strains (e.g., BALB/c mice) have never been reported.
Therefore, we performed a comparative analysis on the functional role of iNOS/NO in established latent vs progressive cerebral toxoplasmosis using T. gondii-resistant BALB/c mice and T. gondii-susceptible C57BL/6 mice, respectively. In both strains, cerebral toxoplasmosis was characterized by intracerebral expression of iNOS protein. Inhibition of iNOS activity resulted in a rapid and lethal exacerbation of TE in C57BL/6 mice. In contrast, parasite control of BALB/c mice remained completely unaffected. These findings argue for a critical role of NO in the control of intracerebral parasites in T. gondii-susceptible mice, whereas T. gondii-resistant strains effectively contain intracerebral toxoplasms in the absence of iNOS activity.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female 6–8-wk-old BALB/c (H-2d) and C57BL/6 (H-2b) mice were obtained from Harlan Winkelmann (Borchen, Germany). The animals were kept on a normal rodent diet under conventional conditions throughout the experiments.
Parasites
Parasites were harvested from the brains of NMRI mice that had been chronically infected with the low-virulent DX strain of T. gondii. Brain tissue of these animals was dispersed in 0.9% NaCl. The final concentration of the infectious agent was adjusted to a dose of 10 cysts/0.5 ml, and this dosage was administered orally to the mice by gavage.
NO synthase (NOS) inhibitors
L-N6-iminoethyl-lysine (L-NIL), a potent selective inhibitor of iNOS 18, 19 , was either synthesized at Searle/Monsanto (St. Louis, MO) or purchased from Alexis (Läufelingen, Switzerland). Both L-nitroarginine-methylester (L-NAME), an inhibitor of all NOS isoforms 18, 20 , and the inactive analogue D-nitroarginine-methylester (D-NAME) were obtained from Alexis. Either D-NAME or water was used as a control for L-NIL, because sufficient amounts of an inactive D analogue of L-NIL are not yet commercially available. The stereospecificity of L-NIL has been demonstrated previously 18, 19 .
In vivo treatment of chronically infected mice
Genetically resistant BALB/c and susceptible C57BL/6 mice (four to six mice per group) were treated with NOS inhibitors on or after day 30 postinfection. L-NIL, L-NAME, and D-NAME were added to the drinking water (adjusted to pH 2.7 to prevent bacterial overgrowth) at a concentration of 5–10 mM and were freshly provided every other day. Survival rates, body weight, and food and water uptake were recorded.
Histopathology
At the indicated days postinfection, animals were intracardially perfused with 0.9% NaCl to remove the blood from brain vessels. The brain was dissected, embedded in Tissue Tek OCT compound (Miles Scientific, Napperville, IL), snap-frozen in isopentane (Fluka, Neu-Ulm, Germany), precooled on dry ice, and stored at -80°C.
T. gondii Ag and iNOS were detected on 5–7-µm frozen sections by incubation with rabbit anti-T. gondii antiserum (Biogenex, Duiven, The Netherlands) and rabbit anti-iNOS peptide-antiserum (obtained from Dianova, Hamburg, Germany, or kindly provided by Drs. C. Nathan and Q.-W. Xie, Cornell University Medical College, New York, NY), respectively, followed by peroxidase-labeled goat anti-rabbit IgG (Dianova). CD4+ T cells, CD8+ T cells, and B220+ B cells were stained on frozen sections with an indirect peroxidase protocol employing rat anti-CD4 (clone G.K 1.5), rat anti-CD8 (clone 2.43), and rat anti-B220 (clone RA3-3A1/6.1), respectively, as primary Abs. Thereafter, sections were incubated with peroxidase-labeled sheep anti-rat IgG. F4/80+ macrophages and microglia were detected by incubation with rat anti-F4/80 (clone F4/80), followed by biotinylated mouse anti-rat IgG F(ab')2 fragments and peroxidase-labeled streptavidin complex (Dakopatts, Hamburg, Germany). Peroxidase reaction products were visualized using 3,3'-diaminobenzidine hydrochloride (Sigma, Deisenhofen, Germany) and H2O2 as cosubstrates. Negative controls included omission of the primary Ab, incubation with an irrelevant isotype-matched control Ab, or competition of the staining by the peptide used for immunization. Sections were slightly counterstained in part with hemalum (Merck, Darmstadt, Germany).
Preparation of serum, cerebrospinal fluid (CSF), and brain homogenates from NOS inhibitor-treated mice
Blood was obtained from anesthetized mice by puncture of the
retroorbital plexus with Pasteur pipets. Serum was prepared from
clotted blood by centrifugation. Clear CSF (
5–8 µl/mouse) was
obtained from mice after intracardial perfusion with 0.9% NaCl by
puncturing the cisterna cerebellomedularis with a fine glass capillary
and was mixed with an equal volume of sterile distilled water to reduce
losses. The perfused, blood-free brains (brain volume was 1
ml) were homogenized in sterile distilled water (1.25 ml per
brain) and centrifuged (36,000 x g, 30 min), and the
supernatant (1 ml per brain) was sterile-filtered (0.22 µm).
Serum, CSF, and brain homogenates were stored at -70°C before being
subjected to the NOS inhibitor analysis.
Determination of biologically active NOS inhibitor levels in serum, CSF, and brain homogenates
Serum samples and brain homogenates were initially filtered
through a 10,000 m.w. cutoff centrifuge filter (Centricon, Millipore,
Bedford, MA) to remove remaining particles from the centrifugation step
(not performed for CSF samples because of lack of volume). The
endogenous arginine in the samples was converted to urea by treatment
with arginase (100 U/ml, 1 h at 37°C; Sigma, St. Louis, MO), and
the enzyme (with a molecular mass of 130 kDa) was
subsequently removed by filtration (10,000 m.w. cutoff filter). Samples
and standards of the respective water-soluble inhibitors
(L-NIL and L-NAME, with molecular masses of
223.5 and 269.7 Da, respectively) were diluted appropriately and
assayed in a NOS enzyme reaction, wherein NOS activity was determined
by monitoring the conversion of
L-[2,3-3H]arginine to
L-[2,3-3H]citrulline. The enzyme assays were
performed with DEAE partially purified recombinant human iNOS as
detailed elsewhere 21 , except that a final concentration of 2.5 µM
L-arginine was used. The ability of treated samples to
inhibit NOS enzyme activity was compared with a standard curve from the
assay, in which defined amounts of the same inhibitor were added to the
enzyme reaction. The quantity of inhibitor present in the original
sample was calculated from this standard curve.
Statistics
Statistical evaluations of differences in mortality, in
intracerebral parasitic load, in the size of cysts, and in the number
of iNOS+ inflammatory foci between the various experimental
groups were determined by the Student t test.
p < 0.05 was accepted as significant. For a
quantitative evaluation of the intracerebral parasitic load and the
size of the T. gondii cysts, sections (10–15/brain) were
cut from various regions of the brain and immunohistochemically stained
for T. gondii Ag. The number of Toxoplasma cysts
per section was counted in 
100 high-power fields (x400) and is shown
as mean ± SEM. The size of the T. gondii cysts was
determined from the same sections using an ocular with a micrometer
scale bar, and the mean size ± SEM is shown. For the number of
iNOS+ inflammatory foci (mean ± SEM), tissue sections
from various regions of the brains of five animals per group were
analyzed.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Oral infection of BALB/c mice with low-virulent
Toxoplasma cysts induced chronic cerebral toxoplasmosis
(Fig. 1
a). A quantitation of
the intracerebral parasitic load revealed that the number of cysts was
continuously declining during the course of disease (Table I). Histopathologically,
Toxoplasma cysts were frequently and closely surrounded by a
few iNOS+ cells (Fig. 1b), but
iNOS- cysts were also found (data not shown).
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c) and
continuously increased during the course of disease (Table I). At day
60 postinfection, the amount of Toxoplasma cysts in C57BL/6
mice exceeded that of BALB/c mice by 40-fold
(p < 0.001). At the same timepoint, the cysts
(as determined by T. gondii immunostaining) were more than
twofold larger in the brains of C57BL/6 mice as compared with BALB/c
mice (Table I). Immunohistochemical staining for iNOS regularly
revealed numerous iNOS+ leukocytes in close vicinity to
T. gondii cysts (Fig. 1d). Compared with BALB/c
mice, the number of iNOS+ cells surrounding an individual
cyst was higher (Fig. 1, b vs d), and the extent
of iNOS+ inflammatory infiltrates was increased 10-fold at
day 30 postinfection (mean number (± SEM) of iNOS+
inflammatory foci per brain section was 36 ± 3 for C57BL/6 mice
and 3 ± 1 for BALB/c mice; p < 0.001). These findings illustrate that BALB/c mice effectively reduce the amount of intracerebral Toxoplasma cysts and develop latent TE, whereas C57BL/6 mice develop progressive TE. Expression of iNOS was observed in both mouse strains and correlated with the number of intracerebral Toxoplasma cysts in the respective mouse strain.
Oral uptake of NOS inhibitors L-NIL and L-NAME leads to iNOS-suppressive inhibitor levels in serum, CSF, and brain tissue of T. gondii-infected mice
To analyze the functional role of iNOS/NO in chronic TE, it is a
prerequisite that the NOS inhibitors gain access to the CNS. Therefore,
we determined the concentration of biologically active
L-NIL and L-NAME in the serum, the CSF, and the
brains of chronically infected BALB/c mice, which had received drinking
water supplemented with either of the two inhibitors for 12 consecutive
days, using an assay based on the suppression of the activity of
recombinant iNOS. L-NIL is a potent and nontoxic inhibitor
with a 30-fold selectivity for the inducible form of NOS, whereas
L-NAME suppresses all isoforms of NOS with a preference for
the constitutive neuronal and endothelial enzymes 18, 19, 20 . As shown in
Table II, the concentration of
L-NIL in the brain reached 50% of the respective serum
levels, thus exceeding the reported concentration required for a 50%
inhibition (IC50) of iNOS in vitro (0.4–3 µM) by a
factor of 10–80 18 . Although the concentration of L-NAME
in the brain homogenates was similar (23 ± 6.3 µM), its known
IC50 against iNOS is considerably higher (20 µM),
whereas it potently inhibits neuronal NOS (IC50 = 0.5 µM)
18 . Low concentrations of both inhibitors were also found in the 1/1
prediluted CSF.
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Inhibition of iNOS does not lead to reactivation of latent TE in BALB/c mice
To test the hypothesis that iNOS is involved in parasite control
in chronically infected BALB/c mice, these mice were treated orally
with the iNOS inhibitor L-NIL. L-NIL treatment
(10 mM in the drinking water) was started at various timepoints during
chronic TE (i.e., at days 30 and 70 postinfection) and performed for
40 days. L-NIL treatment did not cause mortality, reduced
food and water uptake, weight loss, or any clinically overt disease in
BALB/c mice (Fig. 2, Table III). In addition, immunohistopathology
at days 24, 27, 33, 34, 35, and 40 of treatment revealed that the
intracerebral parasite burden did not increase upon L-NIL
application in a total of eight mice analyzed, but remained equally low
as observed in control mice (Table III, and data not shown).
Furthermore, immunostaining for CD4+ T cells,
CD8+ T cells, B cells, and macrophages revealed no evidence
for differences in the distribution and number of these immune cells
between L-NIL-treated and D-NAME-treated
control mice (data not shown).
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). We conclude that the presence of a biologically active iNOS inhibitor (L-NIL) in the CNS does not reactivate chronic cerebral toxoplasmosis in BALB/c mice. The isoform-nonselective NOS inhibitor L-NAME has severe toxic side effects that are probably due to the inhibition of constitutive neuronal and endothelial NOS. Thus, in accordance with previous results obtained in Leishmania major-infected mice 19, 22 , this compound is not suitable for exploring the function of iNOS in experimental in vivo models.
Inhibition of iNOS exacerbates chronic TE in T. gondii-susceptible C57BL/6 mice
To analyze the function of iNOS in the chronic progressive
toxoplasmosis of T. gondii-susceptible mice, T.
gondii-infected C57BL/6 mice were treated with L-NIL.
Inhibition of iNOS induced a rapidly fatal course of disease, and all
L-NIL-treated C57BL/6 mice succumbed to the infection
within 14 days (Fig. 2). Clinically, an exacerbation of TE in
L-NIL-treated C57BL/6 mice was characterized by a severe
wasting syndrome, and these mice showed prominent weight loss compared
with control mice (Table IV).
Histopathology of terminally ill L-NIL-treated mice showed
that these mice had a significantly increased amount of intracerebral
cysts compared with control treated mice (Table IV). In addition,
L-NIL-treated mice had slightly more necrotic foci, whereas
immunohistochemistry showed no significant differences in the
distribution and quantity of intracerebral CD4+ T cells,
CD8+ T cells, B cells, and macrophages between
L-NIL- and control-treated mice (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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These findings extend previous in vitro studies on the role of NO for
the control of intracellular toxoplasms. NO inhibits the growth of
T. gondii in IFN--stimulated human astrocytes as well as
murine macrophages and microglia 6, 7, 23, 24 . However, in several
other human cell types, including fibroblasts, glioblastoma cells,
macrophages, and retinal pigment epithelial cells, indoleamine
2,3-dioxygenase (IDO)-mediated tryptophan degradation inhibits the
growth of T. gondii 25, 26, 27, 28, 29 . With respect to murine cells,
a decisive role for IDO in the control of T. gondii has not
been described thus far. However, there is evidence for a
cross-regulation between NO and IDO. Mouse cells, when expressing high
levels of NO, show a drastically reduced activity of IDO 30, 31 . In
contrast, IDO levels increase under conditions with low NO
concentrations; therefore, in chronically infected BALB/c mice, which
express low amounts of iNOS, IDO-mediated tryptophan starvation may
become clinically relevant and contribute to the control of latent
toxoplasms. An alternative pathway that might also participate in the
control of persisting toxoplasms is the production of oxygen
intermediates by activated macrophages 32, 33 .
The observation that the control of latent intracerebral toxoplasms is independent of iNOS in T. gondii-resistant mice contrasts with findings in other experimental infectious diseases with persisting pathogens. In murine leishmaniasis, resistant mice control Leishmania persisting in lymph nodes via iNOS, and inhibition of iNOS employing exactly the same protocol as in the present study caused clinical recrudescence of the disease 22 . In addition, in latent murine tuberculosis, NO controls the infectious organism in the lung, and inhibition of iNOS with L-NIL or aminoguanidine reactivated the disease 34, 35 . These divergent findings on the role of NO for the control of persisting pathogens may be explained by pathogen-specific features or by an influence of organ-specific factors on the ensuing immune response.
What makes NO so important in chronic TE of T.
gondii-susceptible C57BL/6 mice? Previous studies have shown that
T. gondii-susceptible mice succumb to chronic progressive TE
due to an insufficient intracerebral immune response; this response is
characterized by significantly lower levels of intracerebral IFN-
and TNF- as compared with BALB/c mice 36, 37, 38 . An analysis of the
host genes responsible for the impaired intracerebral immune response
of C57BL/6 mice has revealed that genes within the MHC complex as well
as genes outside of the MHC are involved 16, 36, 39 . The MHC class I
LD molecule, which is expressed in BALB/c but not in
C57BL/6 mice, confers protection against T. gondii 40, 41 . The importance of MHC class I-restricted CD8+ T
cell responses in chronic TE is further supported by the observations
that CD8+ T cells determine the number of intracerebral
Toxoplasma cysts 39 and that T.
gondii-susceptible C57BL/6 mice have reduced numbers of
intracerebral CD8+ T cells compared with T.
gondii-resistant mice 36 . In contrast, C57BL/6 mice have
increased numbers of intracerebral macrophages 38 , which have been
identified as the cellular source for iNOS in TE 5 . Thus, the
increased production of iNOS in C57BL/6 mice that was observed in the
present study most likely reflects a compensatory mechanism for the
insufficient intracerebral T cell response in this strain. Inhibition
of this compensatory NO production results in a rapid multiplication of
the parasite and in death of the animals.
Previous studies on the function of NO in acute murine toxoplasmosis of C57BL/6 mice also revealed that either inhibition of iNOS with aminoguanidine or infection of iNOS-deficient mice resulted in an increased parasite burden of the brain and of peripheral organs 11, 12, 13 . Interestingly, these studies showed that, although the number of parasites was initially increased in peripheral organs of T. gondii-susceptible mice, the protective role of NO in these organs seemed to be less important than in the brain, because T. gondii could be cleared efficiently from peripheral organs despite the absence of iNOS activity, whereas parasite growth was not restricted in the brain. With respect to resistant BALB/c mice, the role of NO in acute toxoplasmosis has not been evaluated. It cannot be excluded that NO also contributes to parasite control in these mice before the onset of an efficient intracerebral immune response.
In acute murine toxoplasmosis, the function of NO is not solely
confined to a direct antiparasitic effect. Within the first 14 days of
T. gondii-infection, NO inhibits the proliferation of
splenic T cells, which may contribute to the escape of the parasite
from the host immune response 11, 14 . Thus, NO has two effects in
acute toxoplasmosis, namely a direct antiparasitic effect and an
additional immunoregulatory function, which might also indirectly
influence parasite control. A recent study of murine leishmaniasis
further illustrates that iNOS not only influences the Ag-specific T
cell response but also regulates the innate immune response by inducing
IFN- production and NK cell responses 42 . In our study on the role
of iNOS in chronic TE, inhibition of iNOS was initiated when a
parasite-specific intracerebral immune response had already been
established. A careful histopathological analysis of brain tissue from
L-NIL-treated and control BALB/c mice as well as C57BL/6
mice demonstrated that there were no differences in the number,
composition, and topographical distribution of inflammatory leukocytes,
including CD4+ cells, CD8+ T cells, B cells,
and macrophages. Therefore, in contrast to acute toxoplasmosis, there
is no evidence for a decisive immunoregulatory function of iNOS in
chronic TE.
In addition to its antiparasitic and immunoregulatory functions, NO also has immunopathological effects. In acute toxoplasmosis of T.gondii-susceptible mouse strains, NO induces tissue necrosis in the gut and liver after peroral infection 12 . Moreover, it has also been suggested that NO might exert a neurotoxic effect in CNS disorders. This assumption is primarily based on the observations that in vitro NO has a remarkable capacity to kill neurons 43, 44 , that iNOS is detectable in some neurodegenerative diseases (e.g., Alzheimer’s disease) 45 , and that the expression of iNOS correlates inversely with the outcome of the disease and leads to neuronal loss in several infectious CNS disorders 46, 47, 48, 49 . From these findings, the question arises as to whether the increased iNOS expression of T. gondii-infected C57BL/6 mice plays an immunopathological role and is, at least in part, responsible for the aggravated course of disease in these animals. However, TE of T. gondii-susceptible mice is not characterized by neuronal loss, indicating that the continuous increase of intracerebral toxoplasms is the major driving force of progressive TE. In addition, the lethal reactivation of TE by the inhibition of iNOS illustrates that the antiparasitic activity is clearly the predominant effect of NO in chronic TE of susceptible mice.
In conclusion, we demonstrate that iNOS is expressed in the brains of mice chronically infected with T. gondii. Inhibition of iNOS leads to a rapid lethal exacerbation of TE in susceptible mice but not in T. gondii-resistant mice. Thus, in contrast to previous assumptions, control of intracerebrally persisting Toxoplasma in a truly latent phase of the infection does not require iNOS activity. Considering the tightly regulated and limited expression of iNOS in human diseases 50 , this observation suggests that latent toxoplasmosis in immunocompetent humans could also be controlled in an iNOS/NO-independent manner.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Christian Bogdan, Institut für Klinische Mikrobiologie, Immunologie und Hygiene, Universität Erlangen-Nürnberg, Wasserturmstr. 3, D-91054 Erlangen, Germany. E-mail address:
3 Abbreviations used in this paper: CNS, central nervous system; TE, Toxoplasma encephalitis; NO, nitric oxide; NOS, NO synthase; iNOS, inducible NOS; L-NIL, L-N6-iminoethyl-lysine; L-NAME, L-nitroarginine-methylester; D-NAME, D-nitroarginine-methylester; CSF, cerebrospinal fluid; IC50, 50% inhibiting concentration; IDO, indoleamine 2,3-dioxygenase.
Received for publication August 19, 1998. Accepted for publication December 16, 1998.
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References |
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