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Infection and Immunity, May 1999, p. 2306-2311, Vol. 67, No. 5
Department of Veterinary Science,
Received 6 November 1998/Returned for modification 16 December
1998/Accepted 22 February 1999
The role of transforming growth factor Malaria remains a major cause of
morbidity and mortality worldwide. Patients infected with malaria
parasites show extremely diverse clinical manifestations, and the
ability of a host to resist the infection depends on both immunological
and inherent characteristics of the host (24). Elucidation
of the mechanisms involved in protective host responses to the parasite
is essential for the development of an effective vaccine or therapeutic
method. Infection of inbred strains of mice with blood-stage murine
malaria parasites is a recognized model of human malaria
(6). Many different kinds of cytokines are produced after
infection with malaria parasites of humans and mouse models, and they
are believed to play major roles in determining the fate of the
infected hosts (14, 21, 35, 36). Although, CD4+
T cells are solely responsible for the gamma interferon
(IFN- Transforming growth factor- Levels of TGF- In the present study, by using genetically resistant and susceptible
strains of mice, we show the role of TGF- Parasite and infection of mice.
P. chabaudi
subsp. chabaudi AS was maintained by syringe passage every
week in mice (20). PRBCs were collected by heart puncture,
washed and suspended in phosphate-buffered saline (PBS). Female
C57BL/10 Sn Slc (B10) and BALB/c Cr Slc (BALB/c) mice 5 to 7 weeks old
were obtained from Japan SLC Co., Hamamatsu, Japan. Mice were infected
intraperitoneally (i.p.) with 5 × 104 PRBCs and
monitored by counting the percentage of parasitemia on
Diff-Quik-stained tail blood smears. In all of the experiments, mice
were kept under specific-pathogen-free conditions and handled according
to the guidelines for animal experimentation of the National Institute
of Infectious Diseases.
rTGF- Anti-TGF- RT-PCR of cytokine mRNAs.
Mouse spleens were obtained at
various times after infection and immediately frozen in liquid
nitrogen. Total RNA was extracted from the spleens by the guanidium
thiocyanate-phenol-chloroform method (4) by using RNAzol B
(Cinna/Biotecx, Houston, Tex.), followed by alcohol precipitation. RNA
preparations were resuspended in diethylpyrocarbonate-treated distilled
water (5 µg/20 µl). mRNA amplification was performed with reverse
transcriptase PCR (RT-PCR) (Takara RNA-PCR; Takara Biomedicals, Ohtsu,
Shiga, Japan) according to the manufacturer's instructions.
Measurement of cytokines.
Blood was obtained from the
orbital venous plexus or by cardiac puncture at various times from mice
infected with the parasite. Blood was allowed to clot for 30 min at
room temperature and centrifuged at 1,200 × g for 10 min, and the sera obtained were stored at
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Transforming Growth Factor
-Induced Failure of
Resistance to Infection with Blood-Stage Plasmodium chabaudi
in Mice
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
(TGF-) in infection
with Plasmodium chabaudi was investigated with resistant
and susceptible mouse models. C57BL/10 mice produced gamma interferon (IFN-
) and nitric oxide (NO) shortly after infection and cleared the
parasite spontaneously. In contrast, BALB/c mice showed a transient
enhancement of TGF- production, followed by a relative lack of
IFN- and NO production, and succumbed to the infection. However,
there was no correlation between levels of serum TGF- and splenic
TGF- mRNA in both mouse strains before and after infection.
Administration of recombinant TGF- (rTGF-) rendered resistant
mice susceptible because of suppression of subsequent production of
IFN- and NO. Administration of anti-TGF- antibody to the infected
BALB/c mice resulted in remarkable increases in serum IFN- and NO,
and the mice resisted the infection. Splenic CD4+ T and
CD11b+ cells of C57BL/10 mice were significantly activated
after infection, but this was completely abrogated by administration of
rTGF-. These results suggested that, in the P. chabaudi-susceptible but not resistant mice, production of
TGF- was promoted, and subsequent failure of IFN-- and
NO-dependent resistance to the parasite was induced. This study is the
first to indicate that TGF- production was the key event in failure
of resistance to mouse malaria.
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
)-dependent resistance of the mouse to acute infection with
Plasmodium chabaudi subsp. chabaudi AS, mouse
strains with competent functions of CD4+ T cells, such as
BALB/c mice, often fail to resist the parasite (36). Thus,
the presence of additional mechanisms which downregulate proper
activation of CD4+ T cells of the infected mice is suggested.
(TGF-) is secreted ubiquitously by
many different cell types, including activated T cells and activated
macrophages (25). The bioactivity of TGF- is often bidirectional, depending on target cells or coexisting mediators (29). In vitro evidence indicated that TGF- upregulated
arginase activity of murine macrophages and limited
macrophage-dependent cytostasis and cytolysis (2). Human
monocyte functions such as H2O2 production and
adherence were suppressed by TGF-, but antimycobacterial activity
and O2
release were unaffected
(38). TGF- also has important roles in generation of
effector T cells (3) and Th2 cell development (1).
in serum were found to be decreased in patients
infected with Plasmodium falciparum, but returned to the
normal range after initiation of treatment (39). In vitro,
V9+ T cells from malaria-nonexposed donors expressed
TGF- mRNA when stimulated with P. falciparum schizont
antigens (13). Furthermore, TGF- and many other cytokines
were secreted into the culture supernatants when human platelets,
monocytes, and T lymphocytes were incubated with P. falciparum-parasitized erythrocytes (PRBCs) (37).
However, no role of TGF- in modulation of human malaria was
indicated by these studies. A recent publication showed that TGF-
levels during murine malaria infection were inversely correlated with
severity of disease (27). However, the downregulatory role of TGF- is indicated in resistance to infection with a variety of
microorganisms, including protozoal parasites (16, 18, 33, 40,
42). Since TGF- is a multifunctional cytokine, the
participation of this molecule in mechanisms of pathogenesis of malaria
or immune protection merits further investigation.
in resistance to infection
with P. chabaudi subsp. chabaudi AS. The results suggested that production of TGF- above the physiological level was
involved in failure of IFN-- and nitric oxide (NO)-dependent resistance of the mouse to acute infection with blood-stage malaria.
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
and its administration.
Recombinant TGF-
(rTGF-), prepared in transformed Chinese hamster ovary cells
(9), was obtained from Genentech, Inc. (South San Francisco,
Calif.). The bioactivity of the rTGF- preparation was tested by the
growth inhibition assay with CCL-64 mink lung epithelial cells
(8). The purified preparation of rTGF- showed a specific
activity of 2.3 × 107 U/mg. rTGF- was diluted in
PBS and injected i.p. (10 µg) 1 h before infection and every 2 days until day 8 postinfection.
MAb and its administration.
A Wistar rat was
immunized with a total of 400 µg of rTGF-, and spleen cells were
fused with SP2/0-Ag 14 myelomas by using polyethylene glycol 1000 (Sigma Chemical Co., Tokyo, Japan) and then cultured under standard
conditions. Antibody activity in hybridoma supernatants was detected by
an enzyme linked-immunosorbent assay (ELISA). A hybridoma which
secreted neutralizing antibody of the IgG1 isotype was obtained (clone
15-1). Clone 15-1 MAb was partially purified from the culture
supernatant by using a Procep-G column (Bioprocessing, Inc., Princeton,
N.J.). To obtain 50% inhibition of bioactivity of 1 U of rTGF-, 2.5 ng of the 15-1 MAb was required in the blocking assay of the
TGF--dependent growth inhibition of CCL-64 cells. The MAb (1.0 mg)
was injected into the mice i.p. 
2, 1, 0, 2, 4, and 6 days
postinfection. An isotype-matched rat MAb with unrelated specificity
was used as a control.
,
5'-TGGACCGCAACAACGCCATCTATGANTIGENAAAACC-3' and
5'-TGGANTIGENCTGAANTIGENCAATANTIGENTTGGTATCCANTIGENGGCT-3' (Clontech Laboratories, Inc., Palo Alto, Calif.); IFN-,
5'-TGGANTIGENGAACTGGCAAAANTIGENGATGGT-3' and
5'-TTGGGACAATCTCTTCCCCAC-3' (26); inducible NO
synthase (iNOS), 5'-CATGGCTTGCCCCTGGAANTIGENTTTCTCTTCAAANTIGEN-3'
and 5'-GCANTIGENCATCCCCTCTGATGGTGCCATCG-3' (12); and glyceraldehyde-3'-phosphate dehydrogenase
(G3PDH), 5'-CTGGTGCTGANTIGENTATGTCGTG-3' and
5'-CANTIGENTCTTCTGANTIGENTGGCANTIGENTG-3' (17).
The PCR was performed in the presence of 0.2 µM each primer, 1.25 U
of Taq polymerase (Takara), and PCR buffer supplied in a
total volume of 50 µl. Thirty cycles of amplification were run under
conditions of denaturation at 94°C for 0.5 min, annealing at 60°C
for 1.5 min, and elongation at 68°C for 1 min. The PCR products were
electrophoresed on a 1.5% agarose gel and stained by ethidium bromide.
20°C.
and IFN- levels were determined with ELISA kits with
antihuman TGF- MAb (Morinantigena Bioscience Institute, Yokohama, Kanagawa, Japan) or antimouse IFN- MAb (Genzyme, Cambridge, Mass.) according to the manufacturers' instructions Sera were acid activated for determination of TGF-.
and NO3 in the
mouse sera (30). Briefly, infected mouse serum was mixed with distilled water (for measurement of NO2)
or NADPH and nitrate reductase (both from Sigma, for measurement of
NO3) and kept at room temperature for 20 to
30 min, followed by addition of the Griess reagent (15).
Precipitates were removed by addition of 10% trichloracetic acid and
centrifugation and the A540 of the supernatant
was read. Standards of nitrite and nitrate were prepared in pooled
normal mouse serum.
Flow cytometry (FACS) analysis. Mouse spleen cells were washed in RPMI 1640 and suspended in PBS containing 5% bovine serum albumin and 0.01% NaN3. Fluorescein isothiocyanate (FITC)-labeled MAb against mouse CD4 (clone RM4-5) and I-A (clone AF6-120.1), phycoerythrin-labeled MAb to mouse Ly6A/E (clone D7) and CD11b (clone M1/70) were obtained from Pharmingen (San Diego, Calif.). The cells (2 × 105/0.1 ml) were double stained with 1 µg of MAb clones RM-4-5 and D-7 or AF6-120.1 and M1/70 on ice for 20 min, washed, and analyzed on a FACScan fluorescence-activated cell sorter (FACS) by using Lysis II software (Becton Dickinson, San Jose, Calif.). CD4+ T cells or CD11b+ cells were gated, and the amounts of Ly6A/E and I-A antigens were compared in the histogram, respectively.
Mean fluorescein intensity (MFI) (linear conversion of log10 fluorescence) was determined after correction for nonspecific fluorescence of controls by using Lysis II software.Reproducibility and statistical analysis. Similar experiments were repeated more than three times, and a representative result is shown. Data are expressed as means ± standard deviations. Differences were analyzed by one-way analysis of variance (ANOVA) or Student's t test. P values of <0.05, <0.01, or <0.001 were considered to be significant.
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RESULTS |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Time course of infection and production of IFN- and NO.
B10
and BALB/c mice presented resistant and susceptible profiles in
response to P. chabaudi subsp. chabaudi AS
infection, respectively (Fig. 1). B10
mice experienced a transient peak parasitemia 9 days postinfection, but
the infection was controlled spontaneously. In contrast, BALB/c mice
developed a higher level of parasitemia, and all animals died within 12 days postinfection. In the resistant B10 mice, a significant amount of
IFN- was revealed in the serum 7 days postinfection, and it was
followed by the appearance of NO (approximately 220 nM) 3 days later
(Fig. 2). In contrast, the amount of
IFN- in the serum of the infected BALB/c mouse was only 3 ng/ml at
the peak (7 days after infection), in contrast to 40 ng/ml in the
infected B10 mouse serum. Furthermore, NO was undetectable in the serum
of BALB/c mice throughout the infection period.
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|
Production of TGF- by AS-susceptible but not AS-resistant
mice.
Figure 3 indicates the amounts
of TGF- in the sera of the infected mouse. When uninfected, both
malaria-resistant B10 mice and malaria-susceptible BALB/c mice showed
similar levels of serum TGF- (9.1 ± 1.9 and 8.8 ± 1.6 ng/ml, respectively). In B10 mice, this physiological level of TGF-
did not change until day 6 postinfection. However, the TGF- level of
B10 mice decreased significantly after a marked level of IFN-
production was revealed in the serum (7 days postinfection and
later). In the susceptible BALB/c mice, the amount of TGF- increased
remarkably, with a peak at day 5 postinfection, and then returned to
the physiological range by day 7 postinfection. The peak level of
TGF- in the infected BALB/c mice was approximately 2.4 times the
control level.
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production was induced
over the physiological level, sequential production of IFN- and NO
was induced, while in BALB/c mice, increased production of TGF- led
to a relative lack of IFN- and NO production.
Splenic expression of mRNA of TGF-, IFN-, and iNOS.
mRNA
levels of TGF-, IFN-, and iNOS in the mouse spleen were
determined by RT-PCR at a variety of times after infection (Fig.
4). When uninfected, neither IFN- nor
iNOS mRNA could be detected in the spleens. IFN- and iNOS mRNAs were
detected in the spleens of B10 mice 6 to 8 days postinfection. The time
of expression of IFN- and iNOS mRNAs preceded detection of IFN- and NO in the serum of the B10 mouse by 1 to 2 days. In the susceptible BALB/c mice, there was marginal expression of IFN- mRNA only on day
6 after infection, whereas iNOS mRNA was undetectable at all times.
|
mRNA was demonstrated in the spleens
of both strains of uninfected mice. Interestingly, these physiological
levels of TGF- transcripts of resistant as well as susceptible
strains of mice did not change throughout the infection period,
irrespective of heightened (4 to 6 days postinfection in BALB/c mice)
or lowered (7 days postinfection and later in B10 mice) levels of
TGF- production in the serum.
Effects of rTGF- administration in the resistant mouse.
Administration of rTGF- to the infected C57BL/10 mice resulted in a
marked reduction of IFN- production (Fig.
5A). The amount of IFN- produced was
only 7% of that produced by the PBS-injected control B10 mice 7 days
after infection. IFN- could not be detected in the serum 5 and 10 days after infection (data not shown), indicating that administration
of TGF- did not alter the time of IFN- production. In the
rTGF--administered B10 mice, the amount of serum NO was also
significantly suppressed to 16% of that of the control mice 10 days
after infection (Fig. 5B). Administration of rTGF- rendered B10 mice
susceptible to infection, as indicated by unrelenting parasitemia and
100% mortality by 12 days after infection (Fig. 5C).
|
Effect of anti-TGF- MAb administration in the susceptible
mice.
To neutralize the activity of endogenously produced TGF-
of infected BALB/c mice, an excess amount of anti-TGF--neutralizing MAb was injected. This treatment resulted in significant increases in
IFN- (P < 0.05) and NO (P < 0.001)
production in the serum of BALB/c mice 7 and 10 days after infection,
respectively (Fig. 6A and B). Although a
considerable amount of IFN- was also demonstrated in the serum of
the control MAb-injected BALB/c mice (8.1 ± 2.1 ng/ml), the
amount of IFN- appeared to be insufficient to induce detectable
levels of NO. Neutralization of the endogenously produced TGF- of
the susceptible BALB/c mice resulted in a delay in the development of
parasitemia, spontaneous decline of the parasitemia, and survival of
the infection (Fig. 6C). The infection profile closely resembled that
of the resistant mice.
|
Activation of CD4+ T and CD11b+ cells in
the infected mouse and their blockade by rTGF-.
FACS analysis
of the splenic CD4+ T cells from a B10 mouse 4 days
postinfection showed a significantly higher level of expression of
Ly6A/E antigen, which is known to increase on activated
CD4+ T cells (5). A representative result is
shown in Fig. 7A. MFI increased to 493 (498 ± 36 in three experiments), in contrast to 232 (236 ± 11) in uninfected mouse spleen cells, indicating that CD4+
T cells were strongly activated after infection. However, this CD4+ T-cell activation was completely prevented by
injection of rTGF- into the infected mice (MFI = 231 [233 ± 18]). The ANOVA showed a statistically significant difference
(P < 0.001) between MFI values of the PBS-treated
group and those of the uninfected or TGF--administered group. In
contrast to the infected B10 mice, no CD4+ T-cell
activation was revealed in BALB/c mice 4 days after infection (data not
shown).
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(MFI = 148 [139 ± 30]). ANOVA showed a statistically significant difference
(P < 0.001) between the MFI values of the PBS group
and those of the uninfected or TGF--administered group. In contrast
to the infected B10 mice, we failed to show increased expression of I-A
antigen on the surface of Mac-1+ cells of BALB/c mice 4 days after infection (data not shown).
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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In clinical and epidemiological studies, it was evident that the
level of TGF- in serum was significantly depressed in the acute
phase of P. falciparum infection (39) and that a
higher level of TGF- was present in the placentas of women living in an area in which malaria is holoendemic (11). However, no
precise mechanism or role of TGF- in regulation of manifestation of
human malaria was indicated in these studies. In the present study, the
role of TGF- in induction of failure to protect against infection with blood-stage P. chabaudi subsp. chabaudi AS
was demonstrated with resistant and susceptible mouse models.
Strain variations in the level of resistance to infection with AS have been investigated, and it was shown that, when survival time was used as criterion, C57BL/6J and other strains of mice were resistant to the parasite, whereas BALB/c and other strains of mice were susceptible (34, 41). We studied the level of resistance and susceptibility to infection with several strains of mouse malaria parasites in a wide variety of inbred, outbred, and congenic strains of mice (unpublished observations) and found that C57BL/10 Sn Slc (B10) and BALB/c Cr Slc (BALB/c) mice were representative strains of resistance and susceptibility to infection with AS, respectively.
P. chabaudi-susceptible mice produced low to background
levels of IFN- (41), whereas resistant B10 mice produced
a remarkably large amount of IFN- shortly after infection, followed
by NO, which is known to have a potent antiparasitic effect
(19). However, the precise role of IFN- in resistance to
the infection is still controversial. Both susceptible and resistant
mouse strains produced IFN- after infection, suggesting that
susceptibility was not due to a defect in IFN- production
(23). It was suggested that IFN- exerted the effect on
the course of parasitemia and the outcome of infection by different
mechanisms (7). Loci controlling peak parasitemia in
susceptible and resistant mice were investigated, and several
chromosomal regions were identified as suggestive linkages
(10). Among them, a locus on chromosome 8 contained genes
associated with host response to infection, interleukin-15, and the
class A scavenger receptor-encoding Scvr locus. We have shown that the
IFN-- and NO-dependent resistance to AS was regulated by
CD4+ T cells alone in the resistant B10 mice. In contrast,
despite their normal CD4+ T-cell activity, BALB/c mice
failed to produce meaningful amounts of IFN- and NO, and, hence,
continuous multiplication of the parasites was induced, resulting in a
fatal outcome (36).
Although TGF- and TGF- mRNA showed similar levels in both strains
of mice when uninfected, a marked difference was induced after
infection. For levels of TGF-, a transient increase was induced only
in susceptible BALB/c mice, while in B10 mice, a significant decrease
was induced after the appearance of IFN- in the serum. Unexpectedly,
however, the level of TGF- in serum of both strains of the infected
mouse did not reflect quantitatively differential levels of cellular
TGF- mRNA. In fact, splenic mRNA of TGF- showed similar levels in
both susceptible and resistant strains of mice when uninfected, and
these levels of expression of physiological TGF- transcripts were
not affected by infection. These results are in agreement with the
concept that the expression of TGF- transcripts is unlikely to be
indicative of actual protein secretion. TGF- is secreted as a
biologically inactive form, and posttranscriptional events are pivotal
in regulating the production of biologically active TGF-
(18). In the present paper, when sera were not acid
activated, no TGF- or a very low level, if any, of TGF- was
detected in sera from both strains of mice before and after infection
(data not shown).
In contrast, close associations were demonstrated between expression of
splenic mRNAs of IFN- and iNOS and levels of IFN- and NO in
serum. In B10 mice, but not BALB/c mice, levels of mRNA of IFN- and
iNOS in the spleens increased remarkably 1 to 2 days prior to
enhancement of serum IFN- and NO levels, respectively.
Administration of rTGF- rendered resistant B10 mice unable to
control the infection. These mice showed a relative lack of IFN- and
NO production, a higher level of parasitemia, and a fatal outcome. In
contrast in the AS-infected BALB/c mice, neutralization of endogenous
TGF- activity by administration of anti-TGF- MAb resulted in
marked production of IFN- and NO and acquisition of resistance to
the infection. The infection profile of the TGF--neutralized BALB/c
mice was similar to that of genetically resistant B10 mice. These
results provided direct evidence that TGF- is the key molecule in
induction of mouse susceptibility to blood-stage AS.
Resistance of C57BL/10 mice to the parasite was mediated solely by a
CD4+ T-cell-dependent mechanism (36), and
activated CD4+ T cells expressed an increased amount of
Ly6A/E antigen (5). The number of spleen cells increased to
about twofold or more 4 to 5 days postinfection, and one of the major
populations of the increased spleen cells was CD11b+ cells
(data not shown). CD11b+ cells played a role in protection
against malaria infection (21) and expressed an increased
amount of MHC class II antigen when activated (28). In this
paper, it was demonstrated by FACS analyses that CD4+ T
cells and CD11b+ cells of the infected B10 mice were
activated shortly after infection, and this could be suppressed
completely by administration of rTGF-. In contrast, in BALB/c mice,
no such activations were demonstrated. Thus, it was suggested that, in
the infected BALB/c mice, endogenously produced TGF- suppressed
activation of CD4+ T cells and CD11b+ cells and
production of meaningful amounts of IFN- and NO and hence led to the
failure of resistance to AS.
In accordance with the observations presented in this paper, the
downregulatory role of TGF- was shown in mouse leishmaniasis, in
which production of active TGF- contributed to the blunting of
CD4+ T cells, to the subsequent lack of Th1 cell
development and promotion of the development of Th2 cells, and to
activation of latent infection (1, 31, 32). Also, TGF-
has been indicated to have a downregulatory role in resistance to
infection by a variety of microorganisms, including protozoal parasites
(16, 18, 33, 40, 42). In Trypanosoma cruzi
infection, many TGF--producing cells were revealed in tissues
throughout the acute and chronic phases of infection in both the
resistant and susceptible models (33, 42). In a recent
publication, Omer and Riley (27) indicated that, in mice
infected with variety of murine Plasmodium species, lethal
infections were accompanied by low levels of TGF-, while self-resolving infections were accompanied by high levels of TGF-. BALB/c mice used by Omer and Riley were given aminobenzoic acid in
drinking water and survived the infection for more than 3 weeks. However, the BALB/c mice we used showed a typical profile of
susceptibility to infection with AS. These differences might result in
discrepancies between the findings obtained in this paper and those
obtained by Omer and Riley. TGF- controls immune responses by a
complex and often context-dependent manner (22). These
findings together suggested an involvement of TGF in pathogenesis and
resistance of the infected hosts by complicated mechanisms.
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FOOTNOTES |
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* Corresponding author. Mailing address: Department of Veterinary Science, National Institute of Infectious Diseases, Toyama 1-23-1, Shinjuku-ku, Tokyo 162-8640, Japan. Phone: 81-3-5285-1111, ext. 2622. Fax: 81-5285-1179. E-mail: kamiyama{at}nih.go.jp.
Editor: J. M. Mansfield
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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