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Infection and Immunity, October 2000, p. 5724-5730, Vol. 68, No. 10
Division of Parasitology, National Institute
for Medical Research, London NW7 1AA, United Kingdom
Received 8 May 2000/Accepted 12 July 2000
Tumor necrosis factor alpha (TNF- Tumor necrosis factor alpha
(TNF- On the other hand, TNF- TNF- We have investigated here a P. chabaudi chabaudi infection
in p55R knockout (KO) mice (p55R Mice.
p55R Infection with P. chabaudi chabaudi (AS)
parasites.
P. chabaudi chabaudi (AS) parasites were
maintained as described previously (51). Mice aged 6 to 12 weeks were infected by injecting 105 parasitized
erythrocytes intraperitoneally (i.p.). The course of infection was
monitored by examination of Giemsa-stained (Fluka) thin blood films
every 2 days throughout the experimental period. Two months after the
primary infection, surviving p55R Malaria-specific antibody responses.
Plasma samples were
collected from at least eight female p55R IFN- Malaria-associated pathology.
Erythrocyte counts, blood
glucose levels, body temperature, and weight changes were measured as
described previously (31) every 2 days during the acute
primary infection. Uninfected female p55R Cytokine expression at the mRNA level using competitive PCR.
The inducible nitric oxide synthase (iNOS) mRNA level was measured
using a competitive PCR as described previously (6, 31).
mRNA was extracted from splenocytes of male and female p55R Statistical analysis.
The Student's t test was
used to calculate the significance of the differences seen in the
course of infection in p55R Secondary P. chabaudi chabaudi infections in
p55R
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Tumor Necrosis Factor Alpha p55 Receptor Is
Important for Development of Memory Responses to Blood-Stage
Malaria Infection
ABSTRACT
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
) is associated with malarial
pathology in both humans and mice. In Plasmodium chabaudi chabaudi (AS) infections, the production of TNF- and reactive metabolites from macrophages are also thought to play a role in controlling acute parasitemia. Since many of the biological functions of TNF- are effected through the p55 receptor (p55R), mice made defective in this receptor via a targeted gene disruption
(p55R
/) have been used to study its involvement in the
immune response against P. chabaudi chabaudi and in the
pathology associated with this infection. In the absence of the p55R,
mice could overcome their primary infection, although higher
acute-blood-stage parasitemias and more significant recrudescences were
observed. Hypoglycemia, hypothermia, loss of erythrocytes, and loss of
body weight, which occur transiently in this infection, were
exacerbated by the lack of the p55R, but the differences were small,
suggesting that other factors affect these symptoms. In contrast to
wild-type (WT) mice, a second challenge infection in
p55R/ mice resulted in a course of infection similar to
a primary infection. The malaria-specific immunoglobulin G antibody
response of p55R/ mice was lower than that of WT mice
and was not increased by the second challenge infection. These data
suggest that p55R/ mice do not develop an efficient
memory B-cell response against malarial infection and that this
antibody response is important in immunity to reinfection.
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
) is thought to play a role in the development of immunity and
pathology in malaria infections in experimental models and in humans
(11). High levels of TNF- in the spleen correlate with
resistance to Plasmodium chabaudi chabaudi (AS) infections
(23). Inflammatory cytokines, including TNF-, may
contribute to the clearance of acute stage infections of P. chabaudi, P. yoelii, and P. vinckei,
possibly through the induction of mediators such as nitric oxide (NO)
and reactive oxygen intermediates (42). However, it appears
that TNF- may not be a critical cytokine for these early protective
responses, since mice deficient in the receptors through which the
biological effects of TNF- are mediated (p55R and p75R) are able to
control and reduce parasitemia (45). TNF- can bring about
killing of intraerythrocytic stages of P. falciparum and
P. vivax in vitro through the action of intermediaries such
as NO (42, 43). The level of NO in the blood, which is a
downstream product of TNF- activity, is correlated with resistance
in young children infected with P. falciparum
(1).
is clearly implicated in the pathology of
malaria (11, 17, 18, 25). It has been shown to be crucial
for the development of an experimental form of cerebral malaria induced
by P. berghei in mice (17), and high plasma TNF- levels in humans infected with P. falciparum are
associated with a poor prognosis in cases of cerebral malaria (18,
25). Treatment of P. falciparum-infected children with
anti-TNF- antibodies reduces fever (5, 26). In other
experimental models of malaria, TNF- is associated with hypoglycemia
and loss of body weight (31).
acts through two receptors, p55R and p75R, which it shares with
the functionally related TNF-
(3, 4, 30). The majority of
the biological functions of TNF-/, such as those associated with
inflammatory pathology and endotoxic shock, however, are attributed to
signaling through p55R (13, 39, 44, 56). p75R preferentially
binds membrane bound TNF- (38), and its role in
inflammation is unclear. However, in the absence of p55R, TNF-p75R
interactions can eventually lead to macrophage activation and NO
production (16). TNF-p55R interactions have been shown to be
important not only for inflammatory responses and for host immunity
against a variety of pathogens (7, 13, 15, 16, 39, 44, 58)
but also for the architecture of lymphoid organs and the correct
localization of B cells to the follicles (33, 55). On the
other hand, TNF-p75R interactions have been shown to be involved in
lymphocyte proliferation (19) and the migration of
Langerhans cells (57).
/) to determine whether
signaling through this receptor plays a role in the development of
pathology associated with an acute primary infection and also whether
TNF-p55R interactions have any impact on the acquisition of protective
immunity. In agreement with previous observations in p55R-p75R
double-KO mice (23), p55R/ mice can overcome
a primary infection of P. chabaudi chabaudi (AS) with little
obvious alteration in accompanying acute-phase pathology. However, a
secondary challenge infection of these mice results in a course of
infection indistinguishable from that of a primary infection and little
development of a malaria-specific immunoglobulin G (IgG) antibody
response. These experiments suggest that TNF-p55R interactions are
essential for an effective memory response and underline the
requirement for antibody and B cells in protective immunity to reinfection.
MATERIALS AND METHODS
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
/ and wild-type (WT) mice
(44) on a mixed background of 129sv and C57BL/6 mice were a
kind gift from H. Blüthmann (Hoffmann-La Roche, Basel,
Switzerland) and were maintained by interbreeding homozygous males and
females in the animal facilities at Imperial College, London, United
Kingdom. All mice were maintained with sterile bedding, food, and
water. The genotype of all experimental animals was confirmed by PCR
before infection. The defective TNF- p55R gene was detected by PCR
of tail DNA using the following specific primers: sense, 5'-CTC TCT TGT
GAT CAG CAC TG-3'; antisense, 5'-CTG GAA GTG TGT CTC AC-3'; and neo-34,
5'-TCC CGC TTC AGC AAC GTC-3'. The combination of a sense and antisense
primer set amplified the WT p55R gene and gave a PCR product of 1.4 kb,
whereas the sense and neo-34 primer combination detected the mutate
p55R gene at 1.0 kb (H. Blüthmann, personal communication).
/ and WT mice were
rechallenged with 105 P. chabaudi chabaudi (AS)
parasites i.p. Naive p55R/ and WT mice were infected at
the same time as the controls.
/ and WT mice
before infection, weekly for 6 weeks after the primary infection, and
weekly for 4 weeks after the secondary infection. The amounts of
malaria-specific antibodies were measured by using a direct
enzyme-linked immunosorbent assay (ELISA) as described previously
(27). Briefly, a lysate of P. chabaudi chabaudi
blood-stage parasites was used to capture the specific antibody present
in plasma samples. The isotype of bound specific antibody was revealed by using anti-mouse isotype antibodies conjugated with alkaline phosphatase (Southern Biotechnology, Cambridge, England). A pooled immune plasma sample obtained from mice that had recovered from more
than five challenge infections of P. chabaudi chabaudi was used as a standard and was given an arbitrary value of 1,000 U/ml for
each of the isotypes. The concentration of each specific isotype was
calculated according to the standard curve generated from the immune
plasma. Plasma from uninfected p55R/ and WT mice were
also included as controls.
and TNF- in the plasma of infected mice.
Plasma
samples were taken using heparinized sterile pipettes from at least
four mice daily from day 5 to day 10 and then weekly until week 4 of
the infection. The samples were collected at the same time each day to
ensure that the time of schizogony did not differentially affect the
level of cytokines in the mice. Plasma gamma interferon (IFN-)
levels were measured using a sandwich ELISA described previously
(47). Briefly, R4-6A2 (48) was used as the
capture antibody, and biotin-labeled AN-18 (41) was used as
the detection antibody. Plasma TNF- levels were measured using a
TNF- ELISA kit (PharMingen/Becton Dickinson). The sensitivities of
the IFN- and TNF- ELISAs were 20 pg/ml and 40 pg/ml, respectively.
/ and WT mice
were also included during the experiments to control for the variation
in these parameters that were not associated with the malaria
infection. The number of erythrocytes was counted using hemocytometer.
The blood glucose level was measured using a commercial glucose machine
and glucose strips (BM-40; Boehringer Mannheim, East Sussex, United
Kingdom). Body temperature was measured using a rectal thermoprobe.
Body weight was measured using a top-pan electronic balance.
/ and WT mice before and at weekly intervals during
the primary infection. cDNA from reverse transcription of mRNA was
competed with an internal competitive fragment, pNIL (46).
The concentration of sample cDNA was calculated when the
log10 ratio of band intensity equaled zero (i.e., those
bands giving equal intensity). The concentration equaled the number of
molecules of the competitive fragment. Levels of measured cytokines
were then normalized against 106 2
microglobulin molecules.
/ and WT mice. The
Mann-Whitney U test was carried out to analyze the difference in
pathology parameters, malaria-specific antibody, and cytokine levels
between the p55R/ and the WT mice.
RESULTS
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
/ mice are more pronounced than in WT mice.
Twenty female p55R/ and littermate WT mice and fifteen
male p55R/ and littermate WT mice were infected with
105 infected erythrocytes by i.p. injection (Fig.
1). Both male and female WT control mice
had a typical P. chabaudi chabaudi (AS) infection
(51). Parasites were first detectable at day 3 of infection,
with a mean peak parasitemia of 19% between days 7 and 9. Parasites
were then cleared rapidly from the circulation and, by day 18, parasitemia decreased to <0.1%. Two small patent recrudescences with
parasitemias of approximately 1% occurred at days 12 and 36 of
infection in female WT mice; these recrudescences became undetectable
after day 40 in both male and female WT mice. In contrast, male and
female p55R/ mice had significantly higher peak levels
of parasitemia (30 and 37%, respectively) compared to WT mice
(P < 0.001, Student's t test). Two
significantly higher recrudescences with parasitemias of 20% occurred
at days 15 and 32 in female p55R/ mice (P < 0.001, Student t test), whereas in male
p55R/ mice, two recrudescences with parasitemias of
lesser magnitude were also measured at day 15 and day 35 postinfection.
All mice survived the primary infection.
View larger version (19K):
[in a new window]
FIG. 1.
The primary and secondary course of a P. chabaudi
chabaudi (AS) infection in p55R / and WT mice
(BL6 × 129sv). Male and female p55R/ (
and
, respectively) and WT mice (
and 
, respectively) were
infected with 105 parasites i.p. The course of infection
was monitored by examination of Giemsa-stained blood films. Two months
after primary infection, p55R/ and WT mice were
rechallenged with 105 parasites i.p. The graphs represent
the means of 15 male and 20 female p55R/ and WT mice
(from three independent experiments). The error bars represent the
standard error of the geometric mean of parasitemia (SEM). For clarity,
the SEM values of <10% of the mean are not shown.
/ and WT mice were given a second P. chabaudi
chabaudi infection 2 months after clearance of the primary
infection. A parasitemia of <0.5% was detected in WT mice.
Surprisingly, the second challenge infection of p55R/
mice resulted in a significantly higher level of parasitemia than seen
in the WT mice. Parasites were detectable in the blood 7 to 8 days
after injection of 105 infected erythrocytes and resulted
in peak parasitemias of 12 to 15% in females and males, respectively,
between days 11 and 12. Parasitemia became subpatent by day 20 postchallenge. All animals recovered from the challenge infection.
Malaria-associated pathology in p55R/ and WT mice
during the acute primary infection.
Four common parameters of
pathology (anemia, hypothermia, hypoglycemia, and weight loss) were
measured. All p55R/ and WT mice displayed these
pathological signs during the acute phase of infection (the data for
female mice are shown in Fig. 2). Weight
loss in p55R/ and WT mice occurred between days 8 and
12 of infection (Fig. 2A). At day 10 postinfection,
p55R/ mice had lost 15% of their body weight compared
to 5% in WT mice (P < 0.01, Mann-Whitney U test). By
day 12, body weight in p55R/ mice had recovered to
normal uninfected levels. WT mice also regained their lost body weight
during this time.
|
/ and WT mice
diminished within 2 days of infection. However, the decrease was more
marked in the p55R/ mice (Fig. 2B), which became
significantly more hypoglycemic than WT mice from day 6 postinfection
throughout the measurement period (P < 0.01,
Mann-Whitney U test).
Erythrocyte counts decreased to a similar minimum level in both WT and
p55R/ mice at day 8 of the primary infection (Fig. 2C).
However, anemia was of a shorter duration in the p55R/
mice, where lower erythrocyte counts were not observed until day 6 postinfection (P < 0.01, Mann-Whitney U test).
Both p55R/ and WT mice experienced hypothermia.
Although there was no significant difference in the lowest temperature
between p55R/ and WT mice at day 8 postinfection (Fig.
2D), between days 10 and 12 p55R/ mice had
significantly lower body temperatures (P < 0.01,
Mann-Whitney U test).
The differences between p55R/ and WT male mice were
similar to those shown for female mice and are not shown.
IgG antibody responses in p55/ and WT mice during a
second challenge infection.
Plasma samples were taken from eight
female p55R/ mice and WT littermate controls once
before and weekly during a primary and secondary infection and were
tested for the presence of malaria-specific antibodies. The level of
malaria-specific immunoglobulin (Fig. 3)
was significantly higher in the plasma of WT mice compared with
p55R/ mice after 4 weeks of infection (P < 0.01, Mann-Whitney U test). When the isotype composition of the
malaria-specific antibody response was analyzed, it was apparent that
this difference was due to a lower amount of IgG antibodies. Initially
(weeks 2 and 3), there was no significant difference in the amount of
IgG antibody between p55R/ and WT mice. However, at
week 4 of the infection the levels of specific IgG1, IgG2b, and IgG3
were significantly lower in p55R/ mice compared with WT
controls (P < 0.01, Mann-Whitney U test), and at 5 weeks the levels of IgG2a, IgG2b, and IgG3 were significantly lower
(P < 0.01, Mann-Whitney U test). This suggests that
the p55R/ mice were unable to maintain an IgG response.
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/ and
WT mice was different, but the amount of antibody present in the plasma was similar. IgM antibody levels were maximal at 2 weeks postinfection in the p55R/ mice and significantly greater than in WT
mice (P < 0.01, Mann-Whitney U test), whereas overall
the greatest response was seen in WT mice at week 4.
Mice received a second infection 2 months after the primary infection.
At the time of challenge, the antibody levels of all isotypes, IgG2a
and IgM, were substantially lower in the p55R/ mice
than in the WT mice (day 0, Fig. 4). By 2 weeks postchallenge, a striking difference in the amounts of
malaria-specific antibodies was observed (Fig. 4). Specific IgG1,
IgG2a, IgG2b, and IgG3 could not be detected until week 2 of the second
infection in the p55R/ mice and did not exceed the
amounts measured during the primary infection. In contrast, the levels
of all the IgG isotypes in the WT mice increased at least 10-fold
compared to those observed in the primary infection. These results,
together with a significantly higher IgM response in the
p55R/ mice, suggest that p55R/ mice are
not able to make an effective secondary antibody response to P. chabaudi chabaudi.
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Decreased IFN- and TNF- in plasma of p55R/
and WT mice.
IFN- and TNF- were detectable in the plasma of
male and female WT mice on days 6 and 7 following a primary infection
(Fig. 5). The plasma IFN- levels of
female mice were greater than those in male mice and were at
concentrations similar to those described previously for C57BL/6 mice
infected with P. chabaudi chabaudi (AS) (47). In
contrast, IFN- and TNF- were only detectable in a small
proportion of p55R/ mice at these times (one out of
eight was positive for TNF-, and two out of eight were positive for
IFN-). We were unable to detect nitric oxide in the blood in plasma
during infection. However, the levels of iNOS mRNA in the spleens of
p55R/ and WT mice were comparable during weeks 1 and 2 postinfection (data not shown), suggesting that this enzyme can be
induced in the absence of the p55R.
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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TNF- is implicated in the pathology of malaria in both humans
and animals (11, 17, 18, 25). Most of the biological functions of TNF- induced during infections are considered to be the
result of its interaction with the p55R (13, 39, 44, 56).
Therefore, we have used mice lacking this receptor to investigate the
development of disease and protective immunity during the course of a
P. chabaudi chabaudi (AS) infection.
Despite the reports linking TNF- with changes in body temperature
and hypoglycemia in experimental and human malaria (18, 25),
the inability to signal through the p55R did not ameliorate these
symptoms in mice infected with P. chabaudi chabaudi (AS). In
contrast, loss of body weight and hypoglycemia were generally significantly more pronounced in the gene-targeted mice. As described previously in resistant and susceptible mice infected with P. chabaudi chabaudi (AS) (12), these symptoms were
strongly associated more with the level of parasitemia than with the
amount of TNF- produced. The lack of effect of p55R inactivation on
the development of hypoglycemia supports the view that hypoglycemia in
mouse malaria infections is not caused by increased levels of TNF-
but rather is an event secondary to hyperinsulinemia (14),
which may be stimulated directly by parasite products (53).
The inability to signal through the p55R did have some effect on the
erythrocyte count in peripheral blood in a P. chabaudi chabaudi (AS) infection. Reduction in the number of red cells occurred in both p55R/ and WT mice during the acute
infection. However, in the absence of the p55R, the erythrocyte counts
in the p55R/ mice corresponded to those in uninfected
WT mice during the first 5 days of infection. At the maximum level of
parasitemia, when erythrocyte loss was greatest, the erythrocyte count
in the p55R/ mice was equivalent to that of the
infected WT mice despite a significantly higher parasitemia level
during the acute infection. The causes of severe anemia in mouse
malaria models and in human P. falciparum infections are
probably multifactorial (9, 20, 34, 35, 40, 54) and may be
the result of red cell destruction (hemolysis and phagocytosis) and
decreased erythropoesis (9, 34). TNF- may be involved in
one or more of these processes. In this regard, dyserythropoesis and
enhanced erythrophagocytosis associated with anemia can be induced in
different rodent models by the administration of TNF-
(9). Our data suggest that signaling through the p55R may
play a minor role in reducing the number of erythrocytes in this model
of malaria but that other factors are clearly involved as well.
Although the lack of a functioning p55R had little impact on the
development of the various disease parameters during a P. chabaudi chabaudi (AS) infection, TNF- or TNF- signaling
through this receptor was involved in controlling parasitemia in the
primary and challenge infections. Our data agree in part with previous findings using TNFp55Rp75R/ double-KO mice infected
with P. chabaudi chabaudi (AS), where a significantly higher
peak of parasitemia was observed only in female KO mice, and there were
no differences between double KO and WT mice in subsequent recrudescent
parasitemias (45). Although in our studies the differences
between KO and WT mice were greater in female mice, parasitemias were
also significantly elevated in male mice. The discrepancies may lie in
differences in the genetic backgrounds of the mice used in the two
studies. We have shown previously that there are small differences in
the course of P. chabaudi chabaudi (AS) infection in the
C57BL/6 and 129sv strains of mice (31). In addition, the
mixture of C57BL/6 and 129sv genes in the two experiments is unlikely
to be the same.
The experiments described here support previous studies showing an
effect of TNF- on the parasitemia in transgenic mice expressing human TNF-, which can only bind to the p55R in mice (52),
and in mice given recombinant TNF- in vivo (49, 50). The
most striking difference in parasitemia between p55R/
and WT mice was observed after a second challenge infection given 2 months after the initial infection. Unlike the WT mice, which developed
a peak parasitemia level of <0.1%, p55R/ mice had a
secondary infection with a peak parasitemia level of 12 to 15%, but
with a delay in the day of maximum parasitemia and no patent
recrudescence. This suggests that there is some partial immunity
existing at the time of challenge, but compared with WT mice it is
impaired. In spite of the lack of a TNF-p55R interaction, these
deficient mice could clear their parasites from the bloodstream. This
result supports the idea that several mechanisms are involved in
parasite clearance and that either TNF is eventually able to signal
through p75R or mechanisms unrelated to TNF and TNF receptor are able
to mediate the downstream events necessary to eliminate the parasite.
Although a role for NO and O2 in the control
of Plasmodium infections in vivo is controversial (8,
10), there are several studies showing that NO can kill parasites
in vitro (21, 43). The induction of NO and
O2 in vivo is mainly due to signaling through
the p55R. However, TNF-TNFp75R interaction has been shown to induce
iNOS after some delay in mycobacterial (16) and other
parasitic infections (7, 36, 45, 58), and NO has been
detected in p55Rp75R/ mice with P. chabaudi
chabaudi (AS) infection (45). In line with these
reports, the detection of mRNA for iNOS in the spleens of
p55R/ mice at 1 and 2 weeks of infection does not
therefore rule out the possibility of a parasiticidal role for NO at
this time.
There are few studies which have investigated memory responses or
immune mechanisms in secondary infections with malaria parasites in
rodent models. It is widely accepted that immunity following the acute
phase of infection is maintained by specific antibodies (29). Passive transfer of immune serum into naive mice can
protect them from malaria infection (24), and mice depleted
of CD4+T cells after production of parasite-specific
antibodies are able to control parasites as long as a high specific
antibody titer is maintained (28). Exacerbated secondary
infections observed in B-cell-deficient mice after drug treatment to
eliminate the primary infection (29) and in interleukin-4 KO
mice (L. Packwood and J. Langhorne, manuscript in preparation) also
indicate the importance of B cells and antibody in immunity to
reinfection. These data suggest that the significant secondary
infection seen in p55R/ mice may be related to low
levels of specific antibody production. The amount of specific IgG was
significantly lower in p55R/ mice than in WT mice, and
the difference was most striking just prior to and early during
secondary infection, when the titer and the kinetics of specific IgG
response in p55R/ mice were comparable with those in
the primary infection.
Defects in antibody responses in p55R/ mice have
previously been reported (7) and have been ascribed to the
essential role of the p55R in germinal center formation within lymphoid
follicles (33), where activated B cells undergo
hypermutation to produce high-affinity antibodies and become memory B
cells. The interaction between TNF- (lymphotoxin) and p55R is
responsible for the migration of B cells into the follicles in the
spleen (33), and the presence of p55R is crucial for
maintaining the structure of the spleen (33, 55). Upon
activation, naive B cells can produce low-affinity antigen-specific
antibodies of both the IgM and the IgG isotypes in the extrafollicular
environment (22). However, migration to germinal centers is
necessary for a long-lived memory B-cell response producing antibodies
of high affinity (32, 37). Malaria-specific IgG was produced
during the primary P. chabaudi chabaudi (AS) infection.
However, the antibody response was of relatively low titer and of short
duration. Upon rechallenge, an antibody response of the same
composition, magnitude, and duration as that seen in the primary
infection was elicited. This suggests that the defect in p55R signaling
may have an effect on the development of memory B cells in the
infection. B-cell development, germinal-center formation, and the
relative affinity of the antibodies produced during a P. chabaudi
chabaudi (AS) infection in p55R/ mice is currently
under investigation.
These results strongly support an important role for specific antibodies in the development and maintenance of immunity against P. chabaudi chabaudi (AS) infections and may have relevance to human malaria infections. Natural immunity in humans is generally achieved through multiple infection and is thought to be short-lived in the absence of continuous reinfection (2). Although antigenic variation may be partly responsible for this phenomenon, it is also possible that generation of immunological memory is impaired during an infection, thus affecting both the longevity of the antibody response and its affinity.
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ACKNOWLEDGMENTS |
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We thank Mike Blackman, Stuart Quin, Latifu Sanni, and Ariel
Achtman for their helpful discussions and critical reading of the
manuscript and Horst Blüthmann, Hoffmann-La Roche, for the kind
gift of the p55R/ mice.
This work was funded by the Medical Research Council (United Kingdom) and The Wellcome Trust (United Kingdom).
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FOOTNOTES |
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* Corresponding author. Mailing address: Division of Parasitology, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, United Kingdom. Phone: 44-208-959-3666, ext. 2588. Fax: 44-0208-913-8605. E-mail: jlangho{at}nimr.mrc.ac.uk.
Editor: W. A. Petri Jr.
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REFERENCES |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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