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Infect Immun, July 1998, p. 3397-3402, Vol. 66, No. 7
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Inhibition of Binding of Malaria-Infected
Erythrocytes by a Tetradecasaccharide Fraction from Chondroitin
Sulfate A
James G.
Beeson,1
Wengang
Chai,2
Stephen J.
Rogerson,1,
Alexander M.
Lawson,2 and
Graham V.
Brown1,*
Division of Infection and Immunity, The
Walter and Eliza Hall Institute of Medical Research, Parkville,
Victoria, Australia,1 and
The
Glycosciences Laboratory, Imperial College School of Medicine,
Northwick Park Hospital, Harrow, Middlesex, United
Kingdom2
Received 17 February 1998/Returned for modification 24 March
1998/Accepted 28 April 1998
 |
ABSTRACT |
Adherence of parasite-infected erythrocytes (IEs) to the
microvascular endothelium of various organs, a process known as
sequestration, is a feature of Plasmodium falciparum
malaria. This event is mediated by specific adhesive interactions
between parasite proteins, expressed on the surface of IEs, and host
molecules. P. falciparum IEs can bind to purified
chondroitin sulfate A (CS-A), to the proteoglycan thrombomodulin
through CS-A side chains, and to CS-A present on the surface of brain
and lung endothelial cells and placental syncytiotrophoblasts. In order
to identify structural characteristics of CS-A important for binding,
oligosaccharide fragments ranging in size from 2 to 20 monosaccharide
units were isolated from CS-A and CS-C, following controlled
chondroitin lyase digestion, and used as competitive inhibitors of IE
binding to immobilized ligands. Inhibition of binding to CS-A was
highly dependent on molecular size: a CS-A tetradecasaccharide fraction
was the minimum length able to almost completely inhibit binding. The
effect was dose dependent and similar to that of the parent
polysaccharide, and the same degree of inhibition was not found with
the CS-C oligosaccharides. There was no effect on binding of IEs to
other ligands, e.g., CD36 and intercellular adhesion molecule 1. Hexadeca- and octadecasaccharide fractions of CS-A were required for
maximum inhibition of binding to thrombomodulin. Analyses of
oligosaccharide fractions and polysaccharides by electrospray mass
spectrometry and high-performance liquid chromatography suggest that
the differences between the activities of CS-A and CS-C
oligosaccharides can be attributed to differences in sulfate content
and sulfation pattern and that iduronic acid is not involved in IE
binding.
| |
INTRODUCTION |
The adherence of purified infected
erythrocytes (IEs) to the microvascular endothelium of various organs
is a key feature of Plasmodium falciparum infection and
contributes to the survival of parasites by aiding replication and
evasion of splenic clearance. This process can lead to postcapillary
venules becoming packed with adherent IEs, an important pathological
characteristic of cerebral malaria (1, 44), and to the
accumulation of IEs in the intervillous spaces of the placenta
(8). A range of cell adhesion molecules has been reported
for P. falciparum, including thrombospondin (33),
CD36 (2, 29), intercellular adhesion molecule 1 (ICAM-1)
(5), vascular cell adhesion molecule 1, E-selectin
(30), platelet/endothelial cell adhesion molecule/CD31 (41), P-selectin (42), and heparan sulfate
(14).
Previously, cell-associated or purified chondroitin sulfate A (CS-A or
chondroitin-4-sulfate) has been identified as a cell adhesion molecule
for IEs in static and flow-based assays (13, 16, 32, 35).
IEs can also bind to the proteoglycan thrombomodulin (TM), via CS-A
side chains, making it a candidate for anchoring CS-A ligands at the
cell surface (20, 36). Interest in CS-A as a cell surface
carbohydrate ligand has grown following reports that IEs can adhere to
Saimiri brain and human lung endothelial cells
(32) and placental syncytiotrophoblasts (18, 27)
in a CS-A-dependent manner. Also, binding to CS-A may be involved in
the placental sequestration of IEs and may partially explain the
increased susceptibility to malaria during pregnancy (18).
Chondroitin sulfate (CS) chains comprise repeating disaccharide units
of hexuronic acid (HexA) 
1-3 linked to
N-acetylgalactosamine (GalNAc), i.e.,
-(4HexA1-3GalNAc1)n-. However, CS chains show
heterogeneity in sulfation patterns and uronic acid compositions (glucuronic acid-iduronic acid [GlcA-IdoA]), depending on the polysaccharide source (22), due to different sulfate
substitutions and differing degrees of isomerization of GlcA to IdoA.
Typically, GalNAc is mono-O sulfated at either the 4- or the
6-O position and this differentiates the principal CS-A and
CS-C disaccharide units, respectively. CS-B (or dermatan sulfate) is
similar in sulfation to CS-A but the uronic acid is predominantly IdoA.
In order to investigate specific structural characteristics of CS-A
that are involved in binding parasitized erythrocytes, various sizes of
CS-A and CS-C oligosaccharide fragments obtained by lyase digestion
have been used to study inhibition of IE binding to immobilized CS-A
and TM, together with an analysis of sulfation and uronic acid
composition, allowing derivation of the minimum size oligosaccharide
containing the putative inhibitory motif.
| |
MATERIALS AND METHODS |
Chemicals.
CS-A (sodium salt from bovine trachea) and -C
(sodium salt from shark cartilage), chondroitin lyase ABC (EC 4.2.2.4,
from Proteus vulgaris) and disaccharide standards
UA-GalNAc (0-S), UA-GalNAc(4SO3H) (4-S),
UA-GalNAc(6SO3H) (6-S),
UA(2SO3H)-GalNAc(6SO3H) (diS-D), and
UA-GalNAc(4SO3H,6SO3H) (diS-E) were
purchased from Sigma Chemical Co. (Poole, Dorset, United Kingdom).
Preparation and characterization of CS oligosaccharide
fragments.
CS-A and -C were partially depolymerized by controlled
digestion with chondroitin lyase ABC as described previously
(9). Briefly, CS-A and CS-C (200 mg each) were incubated
with 0.5 U of chondroitin lyase ABC in 4 ml of sodium phosphate buffer
(50 mM, pH 7.0) containing 0.2 M NaCl at 30°C. Aliquots of reaction solutions were diluted and monitored by UV absorbance at 232 nm at
timed intervals. The reaction was stopped by heating the solution at
100°C for 1 min when digestion was 60% complete.
After being desalted on a short column of Sephadex G-10 (1.6 by 36 cm),
the digests were fractionated on a Bio-Gel P-4 column (1.6 by 90 cm)
and eluted with 0.2 M ammonium acetate at a flow rate of 15 ml/h. The
eluate was monitored on-line by UV at 232 nm and also by refractive
index. Di- to dodecasaccharide fractions together with the larger
oligomer pool were collected and freeze-dried. The larger oligomers
were rechromatographed on a Bio-Gel P-10 column under the same
conditions, and tetradeca- to eicosasaccharide fractions were isolated.
Ammonium acetate was removed by repeated coevaporation with water by
lyophilization.
Each oligosaccharide fraction was quantified by UV absorption at 232 nm
with CS disaccharide 6-S as a standard. The UV activity
of
oligosaccharide fragments results from 4,5-unsaturated uronic
acid
residues (
UA) that are created by lyase cleavage at the
GalNAc1-4HexA bond. UV absorption for
UA-containing CS-A and
CS-C
oligosaccharides was assumed to be equivalent, and the calculated
quantities were checked against the dry weights of the samples.
Dried
oligosaccharides were dissolved in phosphate-buffered saline
(1 mg/ml)
before use in binding assays.
The major components in Bio-Gel P-4 fractions were detected by
electrospray mass spectrometry (ES-MS) (
11,
12).
Compositions
of oligosaccharides in terms of GalNAc, HexA, and sulfate
were
derived from the measured molecular masses.
Disaccharide composition analysis.
Analysis was essentially
as described previously (10). Oligosaccharides were
freeze-dried, dissolved in 28 µl of 5 mM sodium phosphate (pH 7.0)
containing 0.2 M NaCl, and digested exhaustively at 37°C overnight
with 5 mU of chondroitin ABC lyase in 2 µl of the same phosphate
buffer. Disaccharides (0.5 to 1 nmol) were separated by strong anion
exchange high-performance liquid chromatography on an S5-SAX column
(4.6 by 250 mm; Phase Separation Ltd) with a titanium-lined Gilson
liquid chromatographic system. Disaccharides were eluted at a flow rate
of 1 ml/min with UV detection at 232 nm by using increasing
concentrations of NaCl (pH 3.5) from 0 to 0.075 M for 15 min followed
by 0.075 to 0.9 M for 25 min.
Parasitized erythrocytes.
Brazilian P. falciparum
isolate ItG2F6 was cloned to give FAF6 (7). This was
selected for binding to endothelial cells to give FAF-EA8
(6) and was subsequently selected for binding to Chinese
hamster ovary cells and immobilized CS-A to give the isolate CS2
(35). In cytoadherence assays, FAF6 binds to CD36 and
FAF-EA8 binds to CD36, ICAM-1, and (weakly) CS-A. CS2 binds at high
levels to CS-A but does not bind to ICAM-1 or CD36. HCS3 was derived
from a patient isolate by selection for binding to immobilized CS-A.
Selection was performed three times. Parasites were cultured as
previously described (38) and synchronized every 1 to 2 weeks by sorbitol lysis (23).
Purified ligands.
CS-A from porcine rib cartilage (Sigma
Chemical Co., Sydney, Australia) was covalently linked to
dipalmitoylphosphatidylethanolamine as previously described
(39) to facilitate immobilization on plastic and was used at
a concentration of 50 µg/ml. Recombinant soluble human TM containing
CS chains (a gift of B. Grinnell and B. Gerlitz, Lilly Corporate
Center, Indianapolis, Ind.) was used at a concentration of 1 µg/ml.
Platelet-derived CD36 was a gift of M. Berndt, Baker Institute,
Melbourne, Australia, and was used at a 1-µg/ml concentration.
Recombinant soluble ICAM-1 (A. Boyd, Walter and Eliza Hall Institute of
Medical Research, Parkville, Australia) was used at a 10-µg/ml
concentration.
Cytoadherence assays.
Assays were performed using
trophozoite-infected erythrocytes at 4 to 5% parasitemia and 2%
hematocrit. Similar to that of a previously described method
(21), holes were punched in a layer of plastic sealing film
(Nescofilm; Nippon Shoji Kaisha Ltd, Osaka, Japan) that was then
pressed firmly into place in a polystyrene petri dish (150 by 15 mm)
(Falcon 1058; Becton Dickinson, Lincoln Park, N.J.), creating shallow
6-mm-diameter wells. Up to 30 wells could be created with a single
piece of plastic film. Purified ligands were spotted (10 µl) into
each well and were incubated at 4°C overnight in a humid box. Prior
to performing the assay, ligand spots were aspirated and each well was
blocked with 1% bovine serum albumin for 30 to 60 min at room
temperature and subsequently washed three times with RPMI-HEPES medium.
A 45-µl suspension of IEs in RPMI-HEPES medium containing 10% pooled human serum, pH 6.8, was added to each well, and the plate was incubated for 45 min at 37°C. After the plastic film was carefully removed, plates were washed five times with RPMI-HEPES medium (pH 6.8, 37°C) to remove unbound cells by slowly adding 25 ml of medium to the
dish, gently agitating, and then aspirating the medium from the side by
using suction. Bound cells were fixed with 2% glutaraldehyde for
2 h at 4°C, stained with 10% Giemsa, and counted
microscopically. This approach enabled the testing of many samples
together in one dish, under the same conditions, favoring a more
reliable comparison of the inhibitory effects of different CS
fractions. CS oligo- and polysaccharides were tested for inhibition of
binding by adding them to the parasite suspension at a final
concentration of 90 µg/ml (unless otherwise stated) 5 min prior to
performing the assay. Phosphate-buffered saline was used as a control
and samples were randomized and coded in all experiments.
| |
RESULTS |
Inhibition of binding to immobilized CS-A by oligosaccharides.
Ten oligosaccharide fractions of 2 to 20 monosaccharide residues in
length derived from either CS-A or CS-C were tested, at a fixed
concentration of 90 µg/ml, for inhibition of binding of IEs to
immobilized CS-A by using the parasite line CS2. Figure 1 shows that the inhibitory effects of
the CS-A oligosaccharides are highly length specific. Nearly complete
inhibition of binding was found only with the CS-A-derived tetradecamer
or larger oligosaccharides and polysaccharide. Significant inhibition
was seen with the CS-A deca- and dodecasaccharide fractions, averaging
31 and 63% inhibition, respectively, but not with shorter
oligosaccharides. The same degree of inhibition was absent using the
CS-C-derived oligosaccharides, and only the CS-C polysaccharide gave an
average inhibition of more than 50%, which was never complete in any
experiment at the maximum concentration tested.
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FIG. 1.
Inhibition of binding of CS2 parasites to immobilized
CS-A by oligosaccharides (di- to eicosamers) and polysaccharides from
CS-A and CS-C at a concentration of 90 µg/ml. Values are means (± standard errors) for quadruplicate experiments.
|
|
The inhibitory effect of the CS-A tetradecasaccharide fraction on IE
binding to immobilized CS-A was further tested over a
range of
concentrations and compared to that of CS-A polysaccharide
by using the
CS-A decamer and CS-C tetradecamer fractions as negative
controls. The
resulting concentration versus binding plot for
the CS-A
tetradecasaccharides paralleled that for the CS-A polysaccharide,
consistent with specific competitive inhibition of receptor-ligand
binding (Fig.
2). The 50% inhibitory
concentrations (IC
50) derived
for the CS-A
tetradecasaccharide and polysaccharide were similar
and were at least
10-fold lower than those of the CS-C tetradecamer
and CS-A decamer
fractions (Table
1).
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FIG. 2.
Inhibition of binding of CS2 parasites to immobilized
CS-A at increasing concentrations of oligosaccharides and
polysaccharide. Values are means ± standard errors for triplicate
experiments.
|
|
Erythrocytes infected by
P. falciparum HCS3, selected for
high binding to immobilized CS-A, could be inhibited in a
dose-dependent
manner by free CS-A but not by CS-B or CS-C, and there
was no
binding seen to immobilized CS-B used as a control (data not
shown).
As with erythrocytes infected by CS2, the inhibitory effects of
the CS-A oligosaccharides showed the same significant increases
for
tetradecamers and larger oligosaccharides. For the CS-A fractions,
binding as a percentage of that for the control averaged 75% for
the
decamer, 45% for the dodecamer, 21% for the tetradecamer,
and <10%
for each of the hexadeca-, octadeca-, and eicosamer and
for the
polysaccharide fractions. Binding averaged 60% or higher
with each of
the CS-C fractions from deca- to eicosamer and the
polysaccharide.
Inhibition of binding to TM, CD36, and ICAM-1.
The effects of
CS-A oligosaccharides on binding of CS2 IEs to immobilized TM are shown
in Fig. 3. The inhibitory effect of the
CS-A tetradecasaccharide fraction was about 50% but this effect was
significantly increased when the hexadecamer and higher fractions were
used under the same experimental conditions as those used for binding
to CS-A. Little or no inhibition was achieved with the CS-C
oligosaccharide fractions at the same concentration (data not shown).
In preliminary experiments, increasing the concentration of TM above 1 µg/ml when coating plates for binding assays significantly reduced
the degree of inhibition by CS-A oligosaccharides.
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FIG. 3.
Inhibition of binding of CS2 to immobilized recombinant
human TM by CS-A oligosaccharides and polysaccharide at a concentration
of 90 µg/ml. Values are means ± standard errors for duplicate
experiments.
|
|
The oligosaccharides and polysaccharide had little or no effect on the
binding of FAF6-infected IEs to CD36 or of FAF-EA8-infected
IEs to
ICAM-1 (Fig.
4). Specifically, the CS-A
tetradecasaccharide
fraction had no effect on binding to CD36 and
ICAM-1 compared
to that of the same length CS-C oligosaccharides. This
is consistent
with a specific interaction between CS-A and a receptor
present
only on parasite lines CS2 and HCS3.
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FIG. 4.
Effect on binding of parasite lines FAF-EA8 and FAF6 to
ICAM-1 and CD36, respectively, and of CS2 to CS-A by CS-A
oligosaccharides and polysaccharide at a concentration of 90 µg/ml.
Values are means ± standard errors for duplicate experiments.
|
|
Characterization of CS oligosaccharides.
The molecular sizes
and compositions of the major components in oligosaccharide fractions
from gel filtration chromatography of CS polysaccharide digests were
determined by ES-MS analysis. The principal ions in spectra of deca-
and tetradecasaccharide fractions from both CS-A and CS-C are given in
Table 2. In CS-A fractions, the dominant
mass ions were consistent with
UA-[GalNAc(SO3H)-HexA]n-1-GalNAc(SO3H), where n equals the number of disaccharide repeats. The
relative abundance of mono-undersulfated species (
SO3) in
the CS-A fractions was 25%. In CS-C fractions, the major
UA-[GalNAc(SO3H)-HexA]n-1-GalNAc(SO3H) components were accompanied by mono-oversulfated (+SO3) and
mono-undersulfated species with relative abundances of 35 and 15%,
respectively. This indicates that CS-C has an overall higher sulfate
content than CS-A.
Disaccharide composition analyses of the tetradecasaccharide fractions
and polysaccharides (Table
3) were in
agreement with
the compositions derived from ES-MS of intact
oligosaccharides.
The CS-A tetradecasaccharide fraction produced more
nonsulfated
disaccharide (0-S) (11%) than that of CS-C (2%), whereas
CS-C
gave rise to more disulfated disaccharide (diS-D) (7%) than CS-A
(1%). As expected, there was a higher proportion of mono-4-sulfated
disaccharides in the CS-A fraction (44%) than in the CS-C fraction
(15%). A trace amount of diS-E was also present in both
tetradecasaccharide
fractions. GlcA-IdoA composition analysis by
high-resolution
1H nuclear magnetic resonance (NMR)
(
40) of CS-A and CS-C polysaccharide
fractions gave no
detectable signals from IdoA residues (data
not shown).
| |
DISCUSSION |
Using competitive inhibition assays with oligosaccharide fragments
of defined molecular size, this study has shown that a CS-A
tetradecasaccharide is the minimum-length fraction to cause complete
inhibition of binding of parasitized erythrocytes to immobilized CS-A
polysaccharides. The inhibition of binding by oligosaccharides was
highly dependent on chain length and CS type, consistent with the
presence of a unique sequence(s), comprising the CS-A binding epitope
of IEs, found only in the tetradecasaccharide and higher
oligosaccharide fractions. This effect was demonstrated with IEs of two
different P. falciparum strains, CS2 and HCS3. Specificity
was further confirmed by results indicating that inhibition with the
tetradecasaccharide fraction was dose dependent and saturable, with a
derived IC50 similar to that of the parent polysaccharide and more than 10-fold lower than that of the corresponding CS-C tetradecamer or CS-A decamer. Additionally, there was little or no
effect on binding of IEs to CD36 or ICAM-1, reflecting a specific interaction between CS-A and parasite strains CS2 and HCS3. Finally, the response was restricted to the CS-A oligosaccharides. The CS-C used
in this study contains up to 15% CS-A, which may explain the modest
inhibition of binding seen with the larger CS-C oligosaccharide fractions and polysaccharide.
In the present study, we used CS-A from bovine trachea rather than from
porcine rib cartilage, as was used in a previous study (35),
because it contains predominantly GlcA with little or no IdoA, allowing
a more direct comparison with CS-C. The major difference between the
inhibitory activities of CS-A and CS-C tetradecasaccharides can,
therefore, be attributed to differences in sulfate content and
sulfation pattern. ES-MS and high-performance liquid chromatography
disaccharide composition analyses showed fewer sulfates and a higher
proportion of 4-O- than 6-O-sulfated GalNAc in
the components of the CS-A tetradecasaccharide fraction than in those
of the CS-C tetradecasaccharide fraction, and by high-resolution NMR
analysis undetectable levels of IdoA were found in both the CS-A and
CS-C polysaccharides used. The extra sulfate in the oversulfated region
of CS-C was at the 2-O- position of GlcA residues as in the
disaccharide UA(2SO3H)-GalNAc(6SO3H) and as
previously identified in the unique trisaccharide motif -GalNAc(4SO3H)-GlcA(2SO3H)-GalNAc(6SO3H)-
(10). Hence, 2-O- sulfation appears not to be
required for IE binding. CS-A from porcine rib cartilage, containing
approximately equal amounts of IdoA and GlcA, has been shown to
directly bind IEs and to inhibit binding of IEs to cell-associated
CS-A, whereas CS-B, which has a sulfation pattern similar to that of to
CS-A but contains mostly IdoA, does not (35). Taken together
with the results from the present study, this suggests that IdoA is not
involved in binding IEs; rather IE binding is dependent on an
oligosaccharide sequence(s) with a backbone of -4GlcA1-3GalNAc1- and
a unique sulfation pattern. Fractionation and detailed analysis of
individual oligosaccharides in the tetradecamer and adjacent fractions,
together with evaluation of their inhibitory activities, may further
define structural features of CS-A binding motifs.
TM contains one or two CS-A chains (17, 19), to which
parasites may bind, and its distribution in brain (45) and
placenta (37), where parasite sequestration is known to
occur, makes TM a likely target for IE adhesion. The CS chains of human
TM are predominantly constituted of 4-O-sulfated GalNAc
with GlcA (28). Inhibition of binding of IEs to immobilized
human TM by oligosaccharides in the present study was dependent on size
and CS type, being strongly inhibited by CS-A hexadecasaccharide and higher oligosaccharide fractions, similar to results obtained with CS-A
as the binding ligand. Previous work demonstrated that CS-A
polysaccharides of differing GlcA-IdoA contents had different inhibitory effects on binding of IEs to TM (36). However,
the sulfate contents and sulfation patterns of these CS-As were unknown and may have accounted for inhibitory differences. TM may be the principal cell surface proteoglycan containing CS-A; however, glycosylation of TM can be variable (25), which may affect
the pattern of sequestration in vivo. Additionally, the possible
heterogeneity of CS chains present on cell surfaces in the human
population may affect susceptibility to infection and/or severe
disease.
Further studies are needed to clarify the role of adhesion of IEs to
CS-A in parasite sequestration in organs such as the placenta and the
brain. If specific structural motifs in CS-A chains are implicated,
defined oligosaccharides may provide reagents to target sequestered
parasites or to prevent sequestration of circulating IEs. In
Saimiri monkeys, intramuscular administration of CS-A
polysaccharides was found to inhibit and reverse parasite sequestration
following infection with a CS-A-binding P. falciparum strain
(31). CSs have also been safely administered to humans, both
orally and parenterally, achieving levels in serum equivalent to those
that inhibit binding of IEs in vitro (15). CS is normally present in human serum at a concentration of >1 µg/ml and is made up
of approximately 60% nonsulfated disaccharides and 40%
mono-4-sulfated disaccharides, with GlcA being the principal uronic
acid (43). It may be useful to examine changes in serum CS
levels that occur with malaria infection and in pregnancy.
The receptor on the surface of IEs that binds to CS-A remains to be
identified but is likely to be the P. falciparum erythrocyte membrane protein 1 (PfEMP1) (34). As a strain-specific
variant protein (6), PfEMP1 is expressed on the surface of
IEs (24, 26) and binds to CD36, thrombospondin, ICAM-1
(3, 4), heparan sulfate (14), and perhaps other
host molecules. The possibility that the CS-A tetradecasaccharides are
inhibitory by specifically binding to PfEMP1 on the surface of IEs will
be the focus of further investigation. Identification of a protein receptor for defined CS-A oligosaccharides will enable elucidation of
the cytoadherence receptor-ligand interaction and should lead to a
better understanding of cytoadherence in relation to the pathogenesis
of disease.
| |
ACKNOWLEDGMENTS |
We thank Kathy Davern and John Reeder for technical assistance
and helpful discussions provided during this study and J. Luo (MRC
Toxicology Unit, Leicester, United Kingdom) and H. Kogelberg (The
Glycosciences Laboratory) for performing the ES-MS and NMR analyses,
respectively. Human erythrocytes and serum were kindly provided by the
Red Cross Blood Bank of Victoria, Australia.
The work of the Division of Infection and Immunity is supported by
grants from the National Health and Medical Research Council (NHMRC) of
Australia, and The Glycosciences Laboratory is supported by a program
grant (E400/6221) from the U.K. Medical Research Council. J.G.B. is a
recipient of an NHMRC Medical Postgraduate Scholarship. S.J.R. is
supported by a Wellcome Trust Career Development Fellowship in Clinical
Tropical Medicine.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Division of
Infection and Immunity, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. Phone: 61 3 9345 2555. Fax:
61 3 9347 0852. E-mail: brown_g{at}wehi.edu.au.
Present address: Wellcome Trust Centre and Malaria Research
Project, Queen Elizabeth Central Hospital, Blantyre, Malawi.
Editor: S. H. E. Kaufmann
| |
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Infect Immun, July 1998, p. 3397-3402, Vol. 66, No. 7
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Copyright © 1998, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
