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Infection and Immunity, September 2001, p. 5573-5576, Vol. 69, No. 9
0019-9567/01/$04.00+0 DOI: 10.1128/IAI.69.9.5573-5576.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Gamma Interferon-Induced Inhibition of
Toxoplasma gondii in Astrocytes Is Mediated by
IGTP
Sandra K.
Halonen,1,2
Gregory A.
Taylor,3,4 and
Louis M.
Weiss2,5,*
Department of Natural Sciences, Mercy
College, Dobbs Ferry, New York 105221;
Departments of Pathology2 and
Medicine,5 Albert Einstein College of
Medicine, Bronx, New York 10461; Departments of Medicine and
Immunology and the Center for the Study of Aging and Human Development,
Duke University, Durham, North Carolina 277103;
and Geriatric Research, Education, and Clinical Center, Durham
VA Medical Center, Durham, North Carolina 277054
Received 29 March 2001/Returned for modification 24 May
2001/Accepted 14 June 2001
 |
ABSTRACT |
Toxoplasma gondii is an important pathogen in the
central nervous system, causing a severe and often fatal encephalitis
in patients with AIDS. Gamma interferon (IFN-
) is the main cytokine preventing reactivation of Toxoplasma encephalitis in
the brain. Microglia are important IFN-
-activated effector cells
controlling the growth of T. gondii in the brain via a
nitric oxide (NO)-mediated mechanism. IFN-
can also activate
astrocytes to inhibit the growth of T. gondii. Previous
studies found that the mechanism in murine astrocytes is independent of
NO and all other known anti-Toxoplasma mechanisms. In
this study we investigated the role of IGTP, a recently
identified IFN-
-regulated gene, in IFN-
inhibition of T.
gondii in murine astrocytes. Primary astrocytes were cultivated from IGTP-deficient mice, treated with IFN-
, and then tested for
anti-Toxoplasma activity. In wild-type astrocytes
T. gondii growth was significantly inhibited by IFN-
,
whereas in astrocytes from IGTP-deficient mice IFN-
did not cause a
significant inhibition of growth. Immunoblot analysis confirmed that
IFN-
induced significant levels of IGTP in wild-type murine
astrocytes within 24 h. These results indicate that IGTP plays a
central role in the IFN-
-induced inhibition of T.
gondii in murine astrocytes.
 |
INTRODUCTION |
Toxoplasma gondii is an
important pathogen in the central nervous system, where it causes a
severe and often fatal encephalitis in patients with AIDS. Cytokines
play an important role in the regulation of T. gondii
replication in the central nervous system (5, 10, 11).
Gamma interferon (IFN-
) has been shown to be the main cytokine
preventing reactivation of Toxoplasma encephalitis in the
brain (17, 18). Several studies have demonstrated that IFN-
can control the growth of T. gondii in the brain via
the activation of microglia (3, 4). The
anti-Toxoplasma activity in microglia is via a nitric oxide
(NO)-mediated mechanism (7). IFN-
can also activate
astrocytes to inhibit the growth of T. gondii
(8). The mechanism of IFN-
-mediated
anti-Toxoplasma activity in murine astrocytes has been found
to be independent of the mechanisms previously demonstrated in other
cells, e.g., mechanisms involving NO, tryptophan starvation,
reactive oxygen intermediates, and iron deprivation (9).
IFN-
is thought to exert its effects largely by activation of
IFN-
-responsive genes, of which over 200 have been identified (2). For most of these genes, their contributions in
mediating the effects of IFN-
are unknown. One recently identified
IFN-
-regulated gene is IGTP (19). It is
representative of a family of at least six genes encoding 47- to 48-kDa
proteins that contain a GTP-binding sequence and which are expressed at
high levels in immune and nonimmune cells after exposure to IFN-
.
Several of these proteins, including IGTP, localize to the
endoplasmic reticulum (ER) of cells, suggesting that they may be
involved in the processing or trafficking of immunologically relevant
proteins, such as antigens or cytokines (20). Recently it
has been found that IGTP-deficient (
IGTP) mice display a loss of
host resistance to acute infection with T. gondii
(21). In this study, we investigated the potential involvement of IGTP in IFN-
inhibition of T. gondii in
murine astrocytes using primary astrocytes cultivated from
IGTP-deficient mice.
 |
MATERIALS AND METHODS |
Primary astrocyte culture.
Murine astrocytes from
C57BL/6 × SV129 mice or syngeneic mice, deficient in IGTP (21),
were cultivated from the brains of neonatal (less-than-24-h-old) mice.
Murine pups were sacrificed, the brains were removed from the cranium,
the forebrains dissected, and the meninges were removed. The tissue was
minced and incubated in 0.25% trypsin for 5 min at 37°C. After 5 min, the trypsin was inactivated with a solution containing DNase and
soybean trypsinase inhibitors, and the tissue was further disrupted by
trituration in a 20-ml pipette. The dissociated cells were filtered
through a 74-µm-pore-size Nitex mesh, centrifuged at 200 × g, and suspended in growth medium (GIBCO-BRL, Gaithersburg,
Md.) supplemented with 20% fetal bovine serum (FBS) (GIBCO-BRL), 5%
glucose, and 1% penicillin and streptomycin (GIBCO-BRL) per ml.
The growth medium was changed every 3 days. After 7 days in vitro, a
confluent layer of 1 × 104 to 2 × 104 cells/cm was reached. By this method, cells
were found to be >95% astrocytes, as judged by positive staining for
glial fibrillary acidic protein (GFAP). Cultures contained <5%
microglia, as identified by staining with the lectin BS1-B4 (L-2895;
Sigma, St. Louis, Mo.). Astrocytes were dissociated in trypsin-EDTA,
replated onto poly-L-lysine-coated coverslips or
24-well plates at 104 cells/cm, and cultured for
7 to 10 days after replating. These astrocytes were then infected with
T. gondii ME49 as described below.
Cryopreservation of primary murine astrocytes.
Murine
astrocyte cultures prepared from mouse brain were cultivated in growth
medium as described above. At 7 to 10 days after plating, cultures were
trypsinized and then resuspended in growth medium with 10% dimethyl
sulfoxide. Cells were then frozen to
70°C at
1°C/min using a
Nalgene Cryo Freezing Container (catalog no. 5100-001; Nalge Nunc
International, Rochester, N.Y.) and were stored in liquid nitrogen.
Astrocytes frozen by this method were stable for months and routinely
could be replated to attain a monolayer within 7 days that was
GFAP positive.
Culture of T. gondii.
Parasites were
maintained by serial passage in confluent monolayers of human foreskin
fibroblasts (ATCC CCD-27SK) grown in Dulbecco's modified Eagle's
medium (pH 7.1) (GIBCO-BRL) supplemented with 10% FBS and a 1%
penicillin-streptomycin solution (GIBCO-BRL). Parasites were harvested
at 5 to 6 days postinfection, resuspended in minimal essential medium
supplemented with 10% FBS, and used for infection of murine astrocyte cultures.
Cytokine treatments.
Murine astrocytes were stimulated with
IFN-
(Calbiochem) at 64 to 500 U/ml for 72 h prior to
infection. Cultures were washed and then infected with 5 × 104 T. gondii tachyzoites per well (a
5:1 tachyzoite/host cell ratio) for 2 h. Cultures were then washed
to remove extracellular parasites and incubated for 48 h without
IFN-
. Growth of T. gondii was assessed microscopically as
detailed below. All cultures were incubated in endotoxin-free media,
and no endotoxin contamination was detected in any experimental cultures.
Microscopic analysis of T. gondii intracellular
replication.
The percentage of infected astrocytes was determined
by counting the number of infected cells per 500 cells under both phase and immunofluorescent microscopies. Each condition was determined in
triplicate. Immunofluorescence was performed using a 1:50 dilution of a
commercial polyclonal rabbit anti-Toxoplasma antibody (DAKO, Carpinteria, Calif.) followed by detection with anti-rabbit fluorescein immunoglobulin G (IgG; Boehringer-Mannheim, Indianapolis, Ind.) as
previously described (8, 9).
Western blotting.
Total cellular protein lysates were
prepared by washing the cells three times with ice-cold
phosphate-buffered saline and then scraping them into ice-cold lysis
buffer (1% [vol/vol] Nonidet P-40, 50 mM Tris [pH 7.5], 0.15 M
NaCl, 5 mM EDTA) with plastic cell scrapers. Cellular protein lysates
were separated on sodium dodecyl sulfate-10% polyacrylamide
gels; the gels were transferred to an Immobilon-P membrane (Millipore,
Bedford, Mass.) with a TEX50 wet transfer apparatus (Hoefer, San
Francisco, Calif.) using 25 mM Tris, 480 mM glycine, and 20% (vol/vol)
methanol buffer. Western blotting and detection were carried out using
the ECL Detection System (Amersham International, Buckinghamshire,
United Kingdom) according to the manufacturer's protocols. The rabbit polyclonal anti-IGTP antiserum (19-21) was used at a
1:1,000 dilution; the peroxidase-conjugated anti-rabbit IgG secondary
antibody (Boehringer Mannheim) was used at a 1:5,000 dilution.
Statistics.
Within each experiment all conditions were
repeated in triplicate wells, and each experiment was replicated two to
three times (as indicated in the tables). Data were analyzed by the
Student t test method using Sigma Stat Version 1.0 (Jandel
Scientific, San Rafael, Calif.).
 |
RESULTS |
Growth of Toxoplasma in IFN-
-stimulated wild-type
astrocytes versus growth in
IGTP astrocytes.
Wild-type and
IGTP murine astrocytes were stimulated with IFN-
for 72 h
and infected with T. gondii, and growth of the parasite was
assessed 24 h after infection. There was no difference in the rate
of infection or growth of T. gondii in the untreated
IGTP
astrocytes compared to that of the wild-type astrocytes. At 48 h
after infection, both wild-type and
IGTP untreated astrocytes contained vacuoles with numerous tachyzoites (Fig.
1A versus C). In the IFN-
-treated
astrocytes, however, a significant difference was observed between
wild-type astrocytes and
IGTP astrocytes. At 48 h after
infection, the IFN-
-treated wild-type astrocytes had few visible
parasites, while the IFN-
-treated
IGTP astrocytes had numerous
parasites and cells contained vacuoles with numerous tachyzoites (Fig.
1B versus D). The growth of T. gondii in IFN-
-treated
IGTP astrocytes was comparable to that of untreated wild-type astrocytes, indicating that the IFN-
-mediated inhibition was reversed in
IGTP astrocytes.

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FIG. 1.
Phase contrast of untreated and IFN- -treated
wild-type astrocytes versus untreated and IFN- -treated IGTP
murine astrocytes. (A) Untreated wild-type astrocytes; (B)
IFN- -treated wild-type astrocytes; (C) untreated IGTP astrocytes;
(D) IFN- -treated IGTP astrocytes, 48 h after infection.
Almost no organisms were present in IFN- -treated control astrocytes,
but extensive replication was present in IFN- -treated IGTP
astrocytes.
|
|
Immunoblotting of IFN-
induction of IGTP in wild-type
astrocytes.
Wild-type astrocytes were stimulated with IFN-
(100 U/ml) for 24 and 72 h and tested for induction of IGTP via Western
blotting. IGTP was not detected either under control conditions or
following infection with T. gondii (Fig.
2). However, wild-type astrocytes treated
with 100 U of IFN-
for 24 or 72 h demonstrated strong IGTP
induction (Fig. 2, lanes 3 and 4).

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|
FIG. 2.
Accumulation of IGTP in astrocytes exposed to IFN- .
Primary astrocytes were infected with T. gondii for
24 h at a multiplicity of infection of 5:1, were exposed to
100 U of IFN- /ml for 24 or 72 h, or were exposed to control
conditions. Protein lysates were then prepared and used for sodium
dodecyl sulfate-10% polyacrylamide gel electrophoresis and
blotting with IGTP antisera.
|
|
Dose response of treated wild-type versus IFN-
-treated
IGTP
astrocytes.
A dose response of IFN-
stimulation in wild-type
versus
IGTP astrocytes was done to further investigate if
IFN-
-mediated inhibition occurred in
IGTP astrocytes at higher
doses of IFN-
. Wild-type and
IGTP astrocytes were pretreated with
IFN-
at 64, 125, 250, and 500 U/ml for 72 h prior to infection.
In wild-type astrocytes, T. gondii growth was significantly
inhibited (10.6% of control) at 64 U/ml, whereas in
IGTP
astrocytes, 64 to 500 U of IFN-
/ml caused a minimal inhibition of
growth (75 to 88% of control) (Table 1).
 |
DISCUSSION |
IFN-
has been shown to be the main cytokine preventing
reactivation of Toxoplasma encephalitis in the brain
(17, 18). Macrophages and microglia are phagocytic cells
of hemopoietic origin and are important IFN-
-activated effector
cells against T. gondii that exert potent
anti-Toxoplasma activity via the induction of inducible NO
synthase and the production of NO (1, 3, 4). NO is
believed to be directly toxoplasmacidal, resulting in intracellular
killing and/or stasis of parasites. IFN-
has been shown to induce
anti-Toxoplasma activity in a variety of nonhemopoietic
cells via NO-independent mechanisms. For example, in human fibroblasts
and retinal epithelial cells and rat retinal epithelial cells, IFN-
inhibition is due to the induction of indoleamine 2,3-dioxygenase, an
enzyme that degrades intracellular tryptophan (14, 15,
16). In rat enterocytes, IFN-
inhibition was found to be due
to iron starvation (6), while in human endothelial cells,
IFN-
inhibition was found to be independent of reactive nitrogen
intermediates, reactive oxygen species, or tryptophan starvation
(22). In murine astrocytes we have found IFN-
inhibition was independent of all of the above mechanisms (8,
9). The anti-Toxoplasma mechanism operating in murine astrocytes, and possibly in other nonhemopoietic effector cells, remains to be elucidated.
In this paper we investigated the role of IGTP, a recently
identified IFN-
-regulated gene, in the IFN-
-induced inhibition of
T. gondii in murine astrocytes. We found that the inhibitory effect of IFN-
is ablated in astrocytes lacking the protein IGTP. In
wild-type astrocytes, T. gondii growth was significantly
inhibited at 64 U/ml, whereas in
IGTP astrocytes, concentrations of
up to 500 U of IFN-
/ml caused minimal growth inhibition. IGTP was highly expressed in wild-type astrocytes within 24 h of exposure to IFN-
, and expression remained high to at least 72 h. These data suggest that IGTP plays a central role in the IFN-
-induced inhibition of T. gondii in murine astrocytes. It is possible
that small amounts of IFN-
in the central nervous system are
important in maintaining astrocytes in an activated condition.
The function of IGTP is not known. IGTP is expressed at high levels in
many IFN-
-stimulated cells, including immune cells such as
macrophages, T cells, and B cells as well as nonimmune effector cells
such as fibroblasts, hepatocytes (18), and as we have
shown in this paper, astrocytes. IGTP is a GTP-binding protein that is
membrane bound, and it localizes predominantly to the ER
(20). There are many families of GTPases that associate with the ER and that are involved in protein processing or
trafficking; therefore, it has been suggested that IGTP may
regulate vesicular trafficking within the cell (20, 21).
T. gondii has a unique relationship with its host cell.
Unlike other intracellular pathogens that reside in the cytoplasm, endosome, or lysosomal compartments, T. gondii resides
within an intracellular compartment called the parasitophorous vacuole. The parasitophorous vacuole is a nonfusogenic compartment that does not
intersect with the host cell endocytic or exocytic pathways (13). The nonfusogenic nature of the parasitophorous
vacuole is crucial to survival of the intracellular stage, as fusion
with lysosomes results in degradation of the parasite. Alterations in
the host cell that induce trafficking of the host cell endocytic or
exocytic pathways to the parasitophorous vacuole could conceivably be
detrimental to intracellular survival. IGTP, for example, may control
parasite clearance through regulation of vesicular movement of antigen,
cytokines, or other molecules to the parasitophorous vacuole.
The ability of nonhematopoietic cells to control T. gondii
in vivo has, until recently, been unclear. A study employing chimeric mice demonstrated that resistance to the acute and chronic phases of
T. gondii requires nonhematopoietic cells as well as those of hematopoietic origin (23). Host control of T. gondii and other pathogens is dependent on the induction of
diverse effector molecules by IFN-
in a variety of nonhematopoietic
cells. Consequently, murine knockouts of different IFN-
-induced
effectors display various pathogen-specific susceptibilities, depending
on the cells targeted by the pathogen and the cells in which the
effectors are expressed. For example, IGTP-deficient mice are
susceptible to T. gondii but not to Listeria. Our
data demonstrate that IGTP is particularly important for
astrocyte-mediated control of T. gondii, and they further
underscore the critical importance of nonhematopoietic cells in
resistance to toxoplasmosis. T. gondii infects several types
of nonhematopoietic cells, including epithelial, endothelial,
mesodermal, and neuronal cells, and the ability of the host to elicit
effector mechanisms in these cells may relate to the pathogenesis of
toxoplasmosis. For example, epithelial cells may be important effector
cells in the acute phase of infection, endothelial cells in congenital
toxoplasmosis, and astrocytes in cerebral toxoplasmosis. A better
understanding of IFN-
-induced mechanisms in these cell types may be
important in devising better treatment strategies for toxoplasmosis.
 |
ACKNOWLEDGMENTS |
This work was supported by National Institutes of Health grant
AI39454 (L.M.W.).
We thank Yan Fen Ma for assistance with tissue culture.
 |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Pathology, Division of Parasitology and Tropical Medicine, Albert
Einstein College of Medicine, Bronx, NY 10461. Phone: (718) 430-2142. Fax: (718) 430-8543. E-mail: lmweiss{at}aecom.yu.edu.
Editor:
W. A. Petri Jr.
 |
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Infection and Immunity, September 2001, p. 5573-5576, Vol. 69, No. 9
0019-9567/01/$04.00+0 DOI: 10.1128/IAI.69.9.5573-5576.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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