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, TNF-
, and Inducible Nitric Oxide Synthase1
Department of Immunology and Infectious Diseases, Research Institute, Palo Alto Medical Foundation, Palo Alto, CA 94301; and Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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were detected in sera of both strains of mice. Amounts of mRNA
for IFN-, IL-10, and inducible NO synthase in the brain did not
differ between infected µMT and control mice. Expression of mRNA for
TNF-
was increased in brains of µMT mice. Administration of
polyclonal rabbit anti-T. gondii IgG Ab prevented
early mortality and pathology associated with tachyzoites in the brain
in the infected µMT mice. These results indicate that B cells play an
important role, most likely through their production of specific Abs,
in resistance to persistent active (tachyzoite) infection with
T. gondii in mice, especially in the brain and
lung. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Frenkel and Taylor (14) previously examined the effects of B cell depletion on toxoplasmosis in mice by treatment with anti-µ Ab. From their results, they suggested that Ab may not be decisive in resistance against the acute infection, but may be important in controlling the latent infection. Because of the potential side effects of injection of large quantities of xenogenic Ab (15), these studies did not provide conclusive results. Chronic anti-µ Ab treatment involves delivery of an extraordinary amount of Ab, which may alter the microenvironment and concomitant cell-cell interactions that occur during infection with T. gondii (15, 16, 17). In addition, despite the extraordinary amount of Ab used, the anti-µ Ab may not completely deplete B cell populations in vivo, and although serum IgM is reduced to undetectable levels, IgG is generally readily detectable, albeit at levels 10- to 1000-fold lower than normal (17). To elucidate whether B cells play a protective role in resistance against infection with T. gondii, additional studies using alternative approaches to deplete B lymphocytes are needed.
B cell-deficient (µMT) mice have recently been generated by
disruption of one of the membrane exons of the µ-chain gene
(18). These animals have no detectable B cells or
circulating Ab, yet display normal development of the T lymphocyte
compartment (18). Moreover, previous studies have been
shown that µMT mice have normal Ag-presenting function for priming of
CD4+ T cells to most soluble Ags as well as
unimpaired CD8+ T lymphocyte response
(19, 20, 21). Thus, µMT mice appear to be a suitable model
to analyze the role of B cells in host resistance to T.
gondii infection. In the present study, we examined susceptibility
of µMT mice to peroral infection with T. gondii. These
mice suffered early mortality associated with continuous proliferation
of tachyzoites in their brains and lungs in the absence of Ab responses
to the parasite but with unimpaired expression of IFN-, TNF-, and
inducible NO synthase
(iNOS).3
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female Swiss-Webster (Taconic Farms, Germantown, NY), C57BL/6-background B cell-deficient (µMT) (The Jackson Laboratory, Bar Harbor, ME), and control C57BL/6 mice (The Jackson Laboratory) were 6–8 wk old when used.
Infection with T. gondii
Cysts of the ME49 strain were obtained from brains of chronically infected Swiss-Webster mice as described previously (22). µMT and control mice were infected with 10 cysts perorally by gavage.
Histopathology
At 25 days after infection, mice were euthanized by asphyxiation with CO2. Their brains, lungs, hearts, livers, spleens, kidneys, and small and large intestines were removed and immediately fixed in a solution containing 10% Formalin, 70% ethanol, and 5% acetic acid. Two to four 5-µm-thick sections (50- or 100-µm distance between sections) of the organs from each mouse were stained with hematoxylin and eosin. Immunoperoxidase staining using rabbit IgG Ab against either tachyzoite-specific SAG2 or bradyzoite-specific BAG1 were used for detection of tachyzoites and cysts, respectively (23, 24). The specificity of these Abs were described previously (25, 26). Sections stained with hematoxylin and eosin were evaluated for inflammatory changes, and sections stained by the immunoperoxidase method were evaluated for the number of T. gondii cysts and areas associated with tachyzoites.
Detection of mRNA for cytokines and tachyzoite-specific SAG1
RNA was isolated from brains of infected µMT and control mice
by using RNA Stat60 (Tel-Test, Friendswood, TX) by following the
commercial insert. cDNA was synthesized using the RNA as described
previously (22, 27). PCR for cytokines was performed with
5 µl of either a 1:10 dilution or 1:50 dilution of the original cDNA
reaction mixture with a Geneamp 9700 thermocycler (Perkin-Elmer,
Emeryville, CA) using 30 cycles to produce the amount of DNA within a
linear range as described previously (22, 27). This number
of cycles was determined in preliminary studies using different amounts
of cDNA of the sample. Specific primers for ß-actin, IFN-,
TNF-, IL-10 (Clontech, Palo Alto, CA), and iNOS (28)
designed to span at least one intron allowed differentiation of
amplified target DNA derived from either cDNA or genomic DNA in the
PCR. PCR for SAG1 were performed using 1 µl of the original cDNA
reaction mixture, as described by Gazzinelli et al. (28).
For each gene product, the number of cycles was determined
experimentally and was defined as that number of cycles that would
achieve a detectable concentration that was well below the saturating
conditions. In these conditions, 3-fold differences in cDNA
concentrations showed clear differences in the amounts of PCR
products.
Detection of PCR products
Ten-microliter aliquots of the final PCR mixtures were
electrophoresed at 100 V for 1 h on a 1.5% agarose gel and
denatured (22, 27). The DNA was then transferred to a
Duralon-UV membrane (Stratagene, La Jolla, CA) by standard blotting
procedures (29) and UV cross-linked. Oligonucleotide
probes for ß-actin, IFN-, TNF-, IL-10 (Clontech), and iNOS
(26), which hybridize to the PCR products wholly within
the region amplified by the primers, were end labeled as described for
the 3'-end labeling and signal amplification system for a FluorImager
(Amersham, Little Chalfont, England), and hybridization was detected by
scanning of the membranes with a FluorImager Storm 860 (Molecular
Dynamics, Sunnyvale, CA) as described previously (30).
Quantification of mRNA was performed by densitometry analysis with the
FluorImager and normalized to the ß-actin level.
Serum levels of IFN-
Mice were bled at 25 days after infection and the concentrations
of IFN- in their sera were measured by ELISA using mAbs against
IFN- (R4–6A2 as capture, XMG 1.2 as secondary) obtained from
PharMingen (San Diego, CA).
Toxoplasma Ab
Toxoplasma Ab titers in sera of animals obtained at 25 days after infection were measured by the Sabin-Feldman dye test (31).
Flow cytometry
Spleen cells were obtained from µMT and control mice before
and 23 days after infection. A total of 1 x
106 of spleen cells was pretreated on ice for 10
min with 10 µl of a predetermined optimal concentration of
anti-FcII/III receptors (2.4G2) to block non-Ag-specific binding
of Abs to the FcII/III receptors. Thereafter, the cells were
incubated on ice for 30 min with 10 µl of optimal concentrations of
FITC-conjugated anti-CD8 mAb (53-6.7) and PE-conjugated
anti-CD4 mAb (RM4-5), or PE-conjugated anti-NK1.1 mAb (PK136).
The mAbs were obtained from PharMingen. Analysis of stained cells was
performed with a FACScan (Becton Dickinson, Mountain View, CA). Dead
cells were gated out on the basis of propidium iodide staining.
Administration of anti-T. gondii IgG Ab
T. gondii-specific IgG Abs were purified by using a
protein A column from sera of rabbits that had been infected i.p. with
50 cysts of the ME49 strain 5 wk earlier. µMT mice were injected i.p.
with 0.12 ml (0.8 mg of protein) of the purified IgG solution (dye test
tier, 
1:16,000) every 3 days beginning at 2 days after infection for
40 days. Control mice were injected with the same amounts of normal
rabbit IgG purified from seronegative rabbits in the same manner.
Statistical analysis
Levels of significance for differences between groups of mice were determined by Student’s t or Mann-Whitney U test. Mann-Whitney U test was applied when SDs were significantly different between groups tested. Differences which provided p < 0.05 were considered to be significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Following infection with 10 cysts of the ME49 strain, µMT mice
all died between 21 and 28 days after infection (Fig. 1
). In contrast, all control mice were
alive at 59 days after infection, and thereafter began dying; all died
by 85 days after infection (p = 0.0007,
Fig. 1).
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Because of the remarkable difference in mortality between infected
µMT and control mice, we examined their brains, hearts, lungs,
livers, kidneys, and small and large intestines at 25 days after
infection (when some µMT mice had already died). The most remarkable
histological changes were observed in brains of µMT mice.
Significantly greater numbers of areas associated with T.
gondii tachyzoites were observed in brains of µMT than in
control mice (p = 0.0001, Fig. 2B). In µMT mice, there were
many small areas of acute focal inflammation with the parasites (Fig. 3A). Large areas of necrosis
of brain tissue associated with numerous tachyzoites were observed in
µMT but not in control mice (Fig. 3B). Numbers of cysts
were also significantly greater in brains of µMT than in control mice
(p = 0.019, Fig. 2A). These facts
indicate that continuous proliferation of tachyzoites and formation of
greater numbers of cysts occur in brains of µMT mice following
infection.
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C). Neither tachyzoites nor cysts were detectable in lungs
of control mice (n = 7). Despite these differences in
the presence of the parasite between µMT and control mice,
infiltration of inflammatory cells in the lungs was similar in both
groups. Although the tachyzoites were not detected, mild infiltration of inflammatory cells was observed in the liver and heart of both µMT and control mice. Neither the parasite nor inflammatory responses were observed in the kidneys or intestines of µMT mice or controls.
Tachyzoite-specific SAG1 mRNA in brains of infected mice
At 25 days after infection, amounts of tachyzoite-specific mRNA
encoding SAG1 in the total RNA fractions were measured by reverse
transcripting the RNA, followed by amplification of SAG1-specific cDNA
using PCR (RT-PCR). Significantly greater amounts of SAG1 mRNA were
detected in total RNA obtained from brains of infected µMT mice than
control mice (p = 0.0002), although there were
variations between individual µMT mice (Fig. 4).
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It was recently reported that spleen cells from Chlamydia
trachomatis-infected B cell-deficient mice failed to produce
Th1-related (IFN-) or Th2-related (IL-6 and IL-10) cytokines after
C. trachomatis-specific in vitro restimulation
(16). Since an IFN--mediated immune response has been
shown to be critical for resistance against development of toxoplasmic
encephalitis (5, 6, 7, 8, 9, 32), we examined whether expression of
IFN-, TNF-, and iNOS is impaired in brains of µMT mice infected
with T. gondii. We also examined expression of IL-10 in
brains of these mice because this cytokine has been reported to inhibit
T. gondii microbicidal activity of macrophages activated by
IFN- (33). Amount of mRNA for the cytokines and iNOS
were measured by RT-PCR in the total RNA fractions obtained from brains
of mice at 25 days after infection. The amounts of mRNA for IFN-,
IL-10, and iNOS did not differ between these mice (Fig. 4). The amounts
of mRNA for TNF- were significantly greater in µMT than in control
mice (TNF-:ß-actin ratio, 0.191 ± 0.081 vs 0.052 ±
0.013, p = 0.0021) (Fig. 4). In uninfected µMT or
control mice, the amounts of mRNA for each of these molecules were very
low and mostly undetectable (ratios to ß-actin were below 0.001).
IFN- levels in sera of infected µMT and control mice
To compare systemic IFN- production between µMT and control
mice, we measured serum levels of this cytokine at 25 days after
infection. Levels of IFN- did not differ between these mice
(1.95 ± 0.54 ng/ml in controls (n = 7) vs
2.35 ± 0.53 ng/ml in µMT (n = 9)). The results
were reproducible in two separate experiments.
Toxoplasma Ab titers
Toxoplasma dye test Ab titers were examined in sera obtained at 25 days after infection. Whereas high Ab titers (dye test titers ranged from 1:1024 to 1:4096) were observed in sera of control mice, they were undetectable in sera of µMT animals.
Changes in relative percentages of T cell subsets and NK cells in the spleen in µMT and control mice following infection
We examined relative percentages of T cell subsets and NK cells in the spleen of µMT and control mice by flow cytometry before and 23 days after infection. Relative percentages of CD8+ T cells significantly increased following infection in both µMT (from 37.6 ± 4.0% to 50.1 ± 4.9%; p = 0.014) and control mice (from 12.0 ± 0.5% to 18.3 ± 4.1%; p = 0.032). In contrast, relative percentages of NK cells significantly decreased following infection in both µMT (from 8.3 ± 1.7% to 2.9 ± 0.8%; p = 0.0015) and control mice (from 3.3 ± 0.4% to 1.1 ± 0.4%; p = 0.0006). Relative percentages of CD4+ T cells did not differ before and after infection in both groups of animals (data not shown). Because of the absence of B cells in µMT mice, relative percentages of T cells and NK cells were higher in µMT than in control mice.
Passive transfer of anti-T. gondii IgG to infected µMT mice
To examine whether the cause of early death in infected µMT mice
was due to the absence of Ab responses, we treated these mice with
rabbit anti-T. gondii IgG Abs every 3 days beginning 2
days after infection. Control µMT mice were treated with normal
rabbit IgG in the same manner. All control µMT mice died from 21 to
25 days after infection (Fig. 5). µMT
mice treated with anti-T. gondii IgG Abs were all alive
at the end of observation period (42 days after infection) (Fig. 5).
Histological studies were performed on brains and lungs of µMT
animals in both groups at 23 days after infection. Significantly fewer
numbers of T. gondii cysts and inflammatory areas associated
with tachyzoites were observed in brains of mice treated with
anti-T. gondii IgG Abs than those treated with normal
IgG (p = 0.017 for either the number of cysts
or inflammatory areas) (Fig. 6). Small
numbers of tachyzoites were detected in lungs of animals only treated
with normal IgG (data not shown). Toxoplasma Abs were
detected in sera of mice treated with anti-T. gondii IgG
Abs (dye test titer at 1:2048) but not in those treated with
normal IgG.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Histological study revealed large numbers of tachyzoites in brains of µMT mice but not of control mice at the time when µMT mice had begun to die. Tachyzoites were also demonstrable in the lung of only µMT mice but the numbers of the organisms in their lungs were markedly fewer than in their brains. These results indicate that B cells, most likely Ab production by these cells, are important for preventing persistence of tachyzoite replication in the brain and lung in mice during the late stage of the infection. This is further supported by the evidence that treatment with anti-T. gondii IgG Abs markedly decreased the parasite load in these organs. Since tachyzoites were not detectable in hearts, livers, kidneys, or intestines of the µMT mice when they had begun to die, the mechanism of host defense against T. gondii appears to differ in different organs.
In addition to greater tachyzoite load in brains and lungs of µMT mice, we observed differences in the numbers of T. gondii cysts in these organs. Markedly and significantly greater numbers of cysts were detected in brains of µMT than in control mice. In addition, cysts were detectable only in lungs of µMT mice although the numbers of cysts were small. In our previous experience, formation of T. gondii cysts in the lung is unusual. Persistent proliferation of tachyzoites in the brain and lung of µMT mice may have contributed to formation of greater numbers of cysts in these organs.
Frenkel and Taylor (14) previously addressed the role of B cells in resistance against T. gondii by examining the occurrence of reactivation of latent infection in anti-µ Ab-treated mice infected with a virulent strain and treated with sulfadiazine. They observed mortality associated with toxoplasmic pneumonia and/or encephalitis in chronically infected anti-µ-treated animals after discontinuation of sulfadiazine treatment. In the present study, persistence of tachyzoite proliferation was observed in brains and lungs of µMT mice during the late stage of the primary infection. Thus, Ab appears to play a critical role in prevention of proliferation of tachyzoites in these organs in both primary infection and reactivation of latent infection. In addition to the brain and lung, myocarditis was also reported in the anti-µ-treated mice (14). However, this pathology was not evident in µMT mice in the present study. This difference may be due to the side effects of treatment with large amounts of xenogenic anti-µ Ab on the immune system in the previous study, the presence or absence of sulfadiazine treatment, differences in virulence of the parasite and mouse strains, and/or different infection conditions (primary vs reactivation).
Despite the absence of humoral immunity, we observed significant
increases in relative percentages of CD8+ T cells
and decreases in relative percentages of NK cells in spleens of both
µMT and control mice following infection. We also observed unimpaired
IFN- expression in T. gondii-infected µMT mice.
Cellular immunity mediated by IFN- (5, 6, 32), TNF-
(7, 8, 27, 28), and iNOS (9, 34) have been
reported to be critical for resistance against development of
toxoplasmic encephalitis in mice. Although infected µMT mice
developed severe encephalitis, expression of these molecules in their
brains were similar to or higher than those in control mice. Serum
levels of IFN- were also similar in both groups of mice. In
addition, expression of IL-10 in the brain did not differ between µMT
and control mice. These results further support the likelihood that
absence of Ab production is a major factor in the reduced resistance to
T. gondii in these mice.
Eperon et al. (35) recently reported that following
infection with Neospora caninum, µMT mice developed focal
necrotic cerebral lesions which were absent in control mice. In their
studies, IFN- production by spleen cells was lower in µMT than in
control mice during the early stage of infection; however, it did not
differ between these animals during the later stage when cerebral
pathology was observed in µMT mice (35). Yang and
Brunham (16) recently reported that production of both
Th1- and Th2-type cytokines were suppressed in µMT mice following
C. trachomotis infection. In infection with lymphocytic
choriomeningitis virus, µMT mice were found to have a CD4 helper
defect (36). A regulatory role of B cells on T cell
responses may differ depending on infectious agents which stimulate the
immune system, the stages of infection, and subsets of T cells.
In the presence of specific Abs, T. gondii tachyzoites are rapidly lysed by activation of complement through the classical pathway in vitro (37, 38), although the parasites are resistant to complement in the absence of Abs (39). This Ab-dependent complement-mediated killing may play an important role in resistance of mice to the infection. Abs also appear to play a protective role in collaboration with macrophages. Macrophages have been shown to kill Ab-coated tachyzoites in vitro (40, 41). Since the present study revealed persistent proliferation of tachyzoites in brains and lungs of µMT mice, Ab coating of the parasite to allow for phagocytosis and killing by resident macrophages (microglia and alveolar macrophages) in the brain and lung may be an important protective mechanism. In addition, Ab may inhibit intracellular proliferation of tachyzoites. Mineo and Kasper (42) reported that treatment of tachyzoites with a mAb to T. gondii in the absence of complement did not inhibit either attachment or invasion of the parasite into human fibroblasts but inhibited their intracellular proliferation.
It has been well documented that IFN--mediated cellular immunity is
required for survival of mice during both the acute and chronic stages
of the infection with T. gondii (1, 2, 3, 4, 5, 6, 7, 8, 9). The
results of the present study indicate the importance of the B cell Ab
response for prevention of persistent proliferation of tachyzoites in
the brain and lung during the chronic stage of infection. Thus, humoral
and cellular immunity act in concert in host resistance against
T. gondii. The role of each immune response appears to
differ depending on the stage of the infection and its anatomical
location.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Yasuhiro Suzuki, Department of Immunology and Infectious Diseases, Research Institute, Palo Alto Medical Foundation, AMES Building, 795 El Camino Real, Palo Alto, CA 94301. E-mail address:
3 Abbreviation used in this paper: iNOS, inducible NO synthase.
Received for publication August 23, 1999. Accepted for publication December 16, 1999.
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) or normal IgG Ab (•) every 3
days beginning at 2 days after infection for 40 days. The data shown
involved four to five mice per group.