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Immunobiology Section, Laboratory of Parasitic Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
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Abstract |
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in host defense to the intracellular
parasite, Toxoplasma gondii, was investigated in mice
lacking both the p55 and p75 receptors for this cytokine. Upon i.p.
infection with the avirulent ME49 strain, knockout mice were capable of
limiting acute i.p. infection, but succumbed within 3 to 4 wk to a
fulminant necrotizing encephalitis. Receptor-deficient mice harbored
higher cyst burdens and exhibited uncontrolled tachyzoite replication
in the brain. The lack of TNF receptors did not adversely affect the
development of a type 1 IFN-
response. In vitro studies with
peritoneal macrophages stimulated with IFN- and tachyzoites
indicated that under limiting concentrations of IFN-, nitric
oxide-mediated toxoplasmastatic activity is TNF- dependent. However,
this requirement is overcome by increasing the dose of IFN-.
Furthermore, both ex vivo and in vivo studies demonstrated that
inducible nitric oxide synthase induction in the peritoneal cavity and
brain is unimpaired in receptor-deficient mice. Thus, TNF-dependent
immune control of T. gondii expansion in the brain involves
an effector function distinct from inducible nitric oxide synthase
activation. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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secreted initially by NK cells and subsequently by CD4 and CD8 T cells
(2, 3, 4).
In addition to IFN-, TNF- has been implicated to play a major
role in both innate and acquired immunity to T. gondii.
Thus, TNF- synergizes with IL-12 in the induction of IFN- from NK
cells, thereby promoting the T cell-independent pathway of host
resistance to the parasite (5). Moreover, the production by
IFN--activated macrophages of the antimicrobial metabolite NO is
dependent on autocrine TNF- (6). Finally, the in vivo importance of
the cytokine in the host response to T. gondii is supported
by studies demonstrating that treatment of mice with neutralizing
anti-TNF- Abs results in both the abrogation of acute resistance
and reactivation of latent infection in the CNS (7, 8). On the other
hand, TNF- is also known to be a major mediator of tissue damage
and, in T. gondii infection, is associated with both acute
and chronic immunopathology (9, 10, 11).
To directly address the role played by TNF- in the host response to
T. gondii, we have studied the infection in mice produced by
gene targeting, which are deficient in the two known receptors (TNF-R
p55 and p75) for this cytokine (12, 13). Our results indicate that
TNF-receptor signaling is not required for early control of parasite
growth, but is critical for the prevention of toxoplasmic encephalitis
later in infection. Surprisingly, macrophage activation, as judged by
iNOS production and in vitro microbicidal function, appears to be
largely unimpaired in the T. gondii-exposed
receptor-deficient animals. The latter findings suggest that cells
other than macrophages are the primary effectors of TNF
receptor-dependent resistance during chronic Toxoplasma
infection in the CNS.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mice lacking both the p55 and p75 chains of the TNF receptor were generated by interbreeding singly deficient homozygous parental mice. One parental strain lacked exons 2, 3, and part of 4 of the TNF-R p55 chain (12), while the second parental strain contained a neomycin-resistance casette inserted into the second exon of the TNF-R p75 gene (13). Breeding pairs of these mice were generously provided by Mark Moore of Genentech (South San Francisco, CA). The TNF receptor-deficient mice used throughout these studies were maintained on a random C57BL/6 x 129 hybrid background. As wild-type (WT) controls, C57BL/6 x 129 F2 hybrids were utilized. Animals were sex and age matched for each experiment.
Parasites, Ags, and experimental infections
The avirulent ME49 strain of T. gondii was used to infect animals. Brain suspensions were prepared from infected C57BL/6 mice. Each experimentally infected mouse received 20 cysts in a volume of 0.5 ml by the i.p. route. For in vitro infection and stimulation of cells, tachyzoites of the RH strain, maintained by passage in human foreskin fibroblasts, were utilized. Soluble tachyzoite Ag (STAg) was prepared as previously described (3).
Histopathology
The extent of active replication of tachyzoites was assessed by harvesting peritoneal cells of mice 5 days postinfection. Methanol-fixed cytocentrifuge preparations were stained using a modified Wright Giemsa procedure, per manufacturer’s instruction (Diff-Quik, Baxter, McGraw, Park, IL).
At indicated times after infection, brain as well as lung, liver, spleen, and heart tissue samples were fixed in 4% buffered Formalin and processed for paraffin embedding and sectioning. Five-micron sections were stained using the periodic acid schiff (PAS) procedure to aid in the visualization of tissue cysts. The average number of cysts per mouse was determined from two noncontiguous sections, in a blinded fashion.
Measurement of cytokine production by spleen cells
Spleens were homogenized by passing through a sterile fine wire
mesh, and the resulting single cell suspensions were depleted of red
cells by hypotonic lysis. Three million spleen cells/ml were plated in
24-well plates and stimulated with STAg (10 µg/ml). Supernatants were
harvested 24 h later for IL-12 determination and 48 h later
for measurement of IFN-.
Determination of IFN- and IL-12 p40 levels in tissue culture
supernatants was conducted using previously described sandwich ELISA
protocols (4).
Macrophage toxoplasmastatic assay
Peritoneal exudates were harvested from WT and KO mice 4 days after elicitation, and plated at 2 x 106 cells/ml. Cells were preincubated with 100 U/ml of murine rIFN for 2 h. RH tachyzoites were then added at a multiplicity of infection of 0.2 parasites per cell. After an overnight incubation, 50 µl of supernatant was harvested from each well for determination of NO production. Cultures were then pulsed with 0.5 uCi of [3H]uracil and harvested the next day using an automatic cell harvester. Radioactivity incorporated into the cells was measured by liquid scintillation counting. The percent inhibition of tachyzoite growth was calculated as follows: {1 - [(IFN + RH) - (IFN - RH)/(medium + RH) - (medium - RH)]} x 100%.
In some experiments, a neutralizing polyclonal rabbit
anti-mouse TNF- antiserum (Genzyme Corp., Boston, MA) or
preimmune rabbit serum was added together with IFN- at a 1/100
dilution. In other experiments, 1, 10, and 100 U/ml of IFN- was used
to activate and compare the in vitro response of WT and KO peritoneal
cells.
Measurement of NO
Nitrite levels were measured in the culture supernatants of peritoneal exudate cells using the Griess reagent (14). Fifty-microliter aliquots of culture medium were mixed in 96-well plates with an equal volume of 0.5% sulfanilamide dihydrochloride and 0.05% naphthylethylenediamide dihydrochloride in 2.5% phosphoric acid. A standard curve (4–250 µM) of NaNO2 in complete medium was prepared and read together with the samples at a wavelength of 550 nm.
RT-PCR analysis
RNA was extracted from brain tissue suspended in RNAzol, as
previously described (8). RT-PCR analysis was performed to detect
changes in the mRNA levels of IFN-, iNOS, and hypoxanthine
phosphoribosyl transferase using primers and probes described
previously (8). Thirty cycles of amplification were used for IFN-
mRNA detection, and 33 cycles for the other genes.
Western blot detection of brain-associated iNOS protein
Brain tissue from uninfected or day 20 infected mice was homogenized in 1x Laemmli solubilizing buffer containing 2 µM leupeptin, 1 µM pepstatin, and 1 mM PMSF using a polytron tissue disrupter. Five microliters of solubilizing buffer were used per mg tissue. Extracts were diluted 1 to 5 in sample buffer and boiled for 5 min. Samples were separated on 4 to 12% Tris-glycine gels and blotted onto nitrocellulose paper. Membranes were blocked and probed with a rabbit anti-iNOS polyclonal Ab (0.1 µg/ml) (Upstate Biotech, Lake Placid, NY) and developed for chemiluminescence detection using horseradish peroxidase anti-rabbit IgG. Extracts from iNOS-deficient mice were included as negative controls.
Statistical analysis
An unpaired student t test was used for comparison of cyst counts and cytokine secretion in WT and TNF receptor-deficient mice.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To assess their susceptibility to T. gondii, TNF
R1/R2-deficient and WT C57BL/6 x 129/J F1 mice were
inoculated i.p. with 20 cysts of the avirulent ME49 strain, and the
survival of the animals was monitored. Whereas the WT mice survived for
at least 60 days postinfection, the receptor-deficient animals all
succumbed within 20 to 26 days (Fig. 1
).
This survival pattern, which was observed repeatedly in three
independent experiments, is clearly distinct from that of
IFN--deficient mice, which succumb to acute infection within 10 to
12 days after inoculation with the same parasite strain (4, 15). The
resistance of the TNF R1/R2-deficient animals to acute infection was
confirmed by microscopic examination of cells harvested from the
peritoneal inoculation site at day 5. In both these and WT animals,
only 0.4% of the cells was infected with tachyzoites vs greater than
25% in populations recovered at the same time point from
IFN--deficient mice.
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A). Whereas the
tissues from the WT animals at these time points showed only intact
cysts and inflammatory nodules (Fig. 2B), active
tachyzoite replication (Fig. 2C), combined with
extensive parenchymal cell necrosis (Fig. 2D), was
clearly evident within the brain sections from infected TNF
R1/R2-deficient mice. Moreover, numerous extracellular tachyzoites were
evident within the fully developed necrotizing lesions (Fig. 2E). Examination of other organs, including the
lungs, spleen, and liver of moribund mutant mice, failed to reveal
systemic dissemination of the infection (data not shown). Thus, the
dominant pathologic lesion in the TNF R1/R2-deficient animals appears
to be the development of a fulminant toxoplasmic encephalitis.
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As IL-12-dependent IFN- production is the major response that
controls T. gondii infection, we asked whether both
cytokines are produced normally in the absence of TNF receptor
signaling. As shown in Figure 3, spleen
cells from WT and receptor-deficient mice spontaneously produced
comparable levels of IFN- and IL-12p40 on day 5 postinfection.
Moreover, when restimulated in vitro with STAg, the control and mutant
splenocytes synthesized indistinguishable quantities of IFN- both
before and on days 5, 15, and 20 after parasite inoculation. Similarly,
no difference was apparent in the STAg-induced IL-12 p40 responses of
the WT and TNF R1/R2-deficient mice on day 5 postinfection.
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response development in vivo, the cytokine was
measured by RT-PCR in the brains of mice on days 5, 15, and 21
postinfection. As shown in Figure 5A, on day 5, little or no
cytokine message was detected. By days 15 and 21, high levels of
IFN- mRNA were present in brain tissue from both receptor-deficient
and WT mice, and no consistent quantitative differences were evident.
Thus, T. gondii-infected TNF R1/R2-deficient mice display
unimpaired IFN- and IL-12 synthesis, and therefore, their inability
to control tachyzoite replication in the CNS cannot be explained by a
defect in type 1 cytokine expression.
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The in vitro toxoplasmastatic activity of IFN--activated
macrophages is strictly dependent upon the antimicrobial metabolite,
NO, a product of the iNOS enzyme (16, 17). Previous studies have
reported that iNOS activation requires autocrine stimulation by TNF-
(6). We, therefore, assessed whether NO production and in vitro control
of tachyzoite replication can be triggered in macrophages in the
absence of TNF receptors. In the absence of tachyzoite infection,
exposure of thioglycolate-elicited macrophages from WT mice to 100 U/ml
of IFN- for 18 h resulted in the induction of low, but
significant, NO synthesis, whereas the same cell populations from TNF
R1/R2-deficient mice failed to respond (Table I). Nevertheless, upon addition of RH
tachyzoites to macrophage preincubated with 100 U/ml of IFN-, NO
production was stimulated equally in cultures from WT or
receptor-deficient mice, and both macrophage populations were
equivalent in their ability to restrict the growth of the parasite in
vitro. These results suggest that in the absence of TNF receptor
function, the parasite itself may provide compensatory signals needed
to activate iNOS. However, when cells were activated with only 1 U/ml
of IFN-, NO production and toxoplasmastatic activity were found to
be impaired significantly in the cells from mutant animals. In
agreement with this observation, addition of neutralizing
anti-TNF- Ab diminished NO production and toxoplasmastatic
activity by WT macrophages in response to IFN- and RH only when the
lower dose (1 U/ml) of IFN- was used. Taken together, the above
results suggest that under limiting concentrations of IFN-,
signaling by autocrine TNF- emerges as a requirement for iNOS
induction in macrophages.
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If the concentrations of IFN- are indeed not limiting in vivo,
macrophages from infected TNF R1/R2-deficient mice should exhibit the
same level of toxoplasmastatic activity as cells from infected WT mice
when examined ex vivo. As shown in Figure 4, resident peritoneal cells from either
mutant or WT animals both supported growth of the parasite and were
activated by 100 U/ml of IFN- to suppress tachyzoite replication. In
contrast, tachyzoites grew only marginally in ex vivo derived
peritoneal cell populations from 5 day infected mice, regardless of
further in vitro activation with IFN-. The cells from infected TNF
R1/R2-deficient mice were indistinguishable from WT peritoneal
populations in their ability to restrict parasite growth, both
spontaneously as well as after in vitro activation with IFN-. Thus,
during the acute stage of infection, macrophages from TNF
R1/R2-deficient animals appear to have unimpaired microbistatic
activity against T. gondii in vivo.
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A, iNOS
transcripts increased substantially after 15 and 21 days of infection
in both WT and mutant mice. Similarly, induction of the iNOS protein in
both strains of infected animals was observed by Western blot analysis
of brain extracts probed with an iNOS-specific polyclonal antiserum
(Fig. 5B). Thus, during T. gondii
infection, the induction of iNOS activation in vivo can occur
independently of signals delivered by the TNF receptor. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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in host resistance to T. gondii in vivo. Toward this end, we
studied avirulent infection in mice lacking both the p55 and p75 TNF
receptors. Our results indicate that TNF receptor signaling is
essential for survival of the infected animals. Thus, WT mice
inoculated i.p. with the ME49 strain of T. gondii survived
beyond 60 days, while TNF receptor-deficient mice succumbed within 20
to 26 days postinfection and exhibited gross as well as histopathologic
manifestations characteristic of necrotizing encephalitis. This
observation is consistent with previous findings indicating that
administration of neutralizing anti-TNF Abs to chronically exposed
mice results in rapid reactivation of latent infection and death due to
encephalitis (8). Surprisingly, however, at 5 days postinoculation, we
failed to observe increased parasite numbers in peritoneal cells of
receptor-deficient vs WT animals. These parasitologic findings in
infected TNF receptor-deficient mice are reminiscent of those recently
reported for iNOS-deficient mice, which also survive acute, but not
chronic, toxoplasmosis (17). The latter phenotype is quite distinct
from that observed in IFN--deficient mice that succumb within 10 to
12 days after parasite inoculation (4). Taken together, the above
findings indicate that TNF receptor signaling and iNOS activity are not
required for early resistance to T. gondii, but are
essential for control of chronic infection in the CNS.
Do the similarities in the resistance phenotype of the TNF receptor-
and iNOS-deficient mice simply reflect lesions in a common or
convergent effector pathway? A prevailing paradigm of macrophage
activation suggests that this may indeed be the case. Thus, autocrine
production of TNF- has been shown to be required for IFN- to
fully activate macrophages based on both iNOS induction and in vitro
microbicidal activity against a variety of pathogens (18). Indeed, when
tested under conditions of low dose IFN- priming, TNF
R1/R2-deficient macrophages or macrophages from WT mice treated in
vitro with neutralizing TNF-specific Ab displayed defective NO and
toxoplasmastatic responses (Table I). Nevertheless, this requirement
for TNF- triggering is by no means obligatory, since it is overcome
readily when the parasites are added to the cultures along with
increased concentrations of IFN-. The latter observation is
seemingly in conflict with a previous report describing a requirement
for TNF- in the toxoplasmastatic activity of macrophages activated
with high doses (1000 U) of IFN- (6). Nonetheless, in that study,
the tachyzoites were added after 24 h of preincubation with
IFN-, whereas in our studies, infection was initiated 2 h after
IFN- treatment. Thus, in the former series of experiments, it is
possible that the initial priming signal provided by IFN- may have
decayed by the time parasites were introduced into the cultures. This
interpretation is consistent with the observations of Sibley et al.
(19), that concomitant treatment with TNF- or LPS is necessary for
triggering of toxoplasmastatic activity in IFN--primed macrophages.
In the same experiments, neutralization of TNF- resulted in loss of
microbicidal function in cultures triggered by TNF-, but not by
LPS.
The concept that T. gondii can provide its own triggering
signal is supported by the finding that a STAg induces NF-
B
DNA-binding activity in inflammatory macrophages (20), even when
TNF- is neutralized. Thus, the requirement for endogenous TNF-
signaling in the NF-B-dependent transcriptional activation of the
iNOS promoter (21) appears to be bypassed effectively by the parasite
itself, or possibly through the induction of other cytokines. That this
same bypass of TNF function occurs in vivo is supported by our
observation of unimpaired iNOS induction and ex vivo macrophage
toxoplasmastatic activity in infected TNF R1/R2-deficient
mice.
Although not necessarily involving the same mechanisms, studies on host
resistance to other pathogens in TNF receptor-deficient animals also
argue that the requirement for TNF- in macrophage activation and
iNOS expression can be circumvented in vivo. For example, while p55 TNF
receptor-deficient mice are less resistant to Mycobacterium
tuberculosis, they nevertheless are able to up-regulate iNOS
expression in vivo (22). Similarly, the same TNF receptor-deficient
animals were able to clear cutaneous infections with Leishmania
major and exhibited unimpaired NO-dependent macrophage
leishmanicidal activity in vitro (23). Interestingly, in the latter
study, in common with our findings, a defect in the macrophage
activation could be revealed by lowering the dose of IFN- used for
in vitro priming. Since there are two known receptors for TNF-,
these previous studies do not preclude the possible use of the second,
p75 receptor for macrophage triggering. The latter objection is not a
concern in the experiments performed in this study on T.
gondii, in which mice lacking both receptors were used, nor in a
recent study, in which the same animals were infected with
Mycobacterium avium and no impairment of host resistance was
observed (24).
Although in the murine T. gondii infection model iNOS and
TNF receptor deficiencies appear to have different effects on
macrophage activation, they nevertheless result in the same host
resistance phenotype in vivo. In attempting to understand the function
of TNF vs iNOS in control of T. gondii infection, two points
are worth considering. First, TNF receptors are known to be distributed
ubiquitously in a wide range of nucleated cell types (25) as opposed to
the more restricted expression of the iNOS gene primarily in
macrophage-lineage and endothelial cells (26, 27). Secondly, the
promiscuous host cell infectivity of T. gondii predicts that
essentially all of the cell types encountered by the parasite, as well
as controlling its growth, will express TNF receptors. Thus, it is
likely that TNF--dependent resistance to T. gondii
involves effector functions unrelated to iNOS activity. For instance,
effector T cells synthesizing both IFN- and TNF- (28) may trigger
control of parasite growth in infected neurons, a cell type that does
not express iNOS (29, 30), but that serves as a unique reservoir for
bradyzoites in the brain (31). Since iNOS is also required for control
of chronic infection (17), such a neuronal effector mechanism is likely
to act in concert with iNOS-dependent effector functions expressed
selectively by CNS-associated macrophages/microglial cells and/or
endothelial cells. This model would explain why mice lacking TNF
receptors remain susceptible to chronic toxoplasmosis despite
apparently normal induction of iNOS in vivo. Further analysis of the
cellular basis of the defect in parasite control in TNF
receptor-deficient mice should provide a useful approach for
identifying this tissue-specific and perhaps stage-specific mechanism
of host resistance. One candidate effector function is the depletion of
intracellular tryptophan pools by the enzyme, indoleamine dioxygenase,
which is known to be synergistically induced by IFN- and TNF- in
cells of neuroglial origin (32).
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: CNS, central nervous system; iNOS, inducible nitric oxide synthase; KO, knockout; NO, nitric oxide; RT-PCR, reverse-transcriptase polymerase chain reaction; STAg, soluble tachyzoite antigen; WT, wild-type.
Received for publication July 22, 1997. Accepted for publication October 21, 1997.
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H. W. Murray, A. Jungbluth, E. Ritter, C. Montelibano, and M. W. Marino Visceral Leishmaniasis in Mice Devoid of Tumor Necrosis Factor and Response to Treatment Infect. Immun., November 1, 2000; 68(11): 6289 - 6293. [Abstract] [Full Text] [PDF]
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C. Li and J. Langhorne Tumor Necrosis Factor Alpha p55 Receptor Is Important for Development of Memory Responses to Blood-Stage Malaria Infection Infect. Immun., October 1, 2000; 68(10): 5724 - 5730. [Abstract] [Full Text] [PDF]
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R. Allendoerfer and G. S. Deepe Jr. Regulation of Infection with Histoplasma capsulatum by TNFR1 and -2 J. Immunol., September 1, 2000; 165(5): 2657 - 2664. [Abstract] [Full Text] [PDF]
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Y.-X. Zhao, G. Lajoie, H. Zhang, B. Chiu, U. Payne, and R. D. Inman Tumor Necrosis Factor Receptor p55-Deficient Mice Respond to Acute Yersinia enterocolitica Infection with Less Apoptosis and More Effective Host Resistance Infect. Immun., March 1, 2000; 68(3): 1243 - 1251. [Abstract] [Full Text] |
