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Centre for Medical Parasitology at Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet) and Institute for Medical Microbiology and Immunology, University of Copenhagen, Copenhagen, Denmark;
Epidemiology and
Immunology Units, Noguchi Memorial Institute, University of Ghana, Legon, Ghana; and
§
Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It is becoming increasingly apparent that acquired protective immunity to P. falciparum infection relies on Abs specifically recognizing variant parasite Ags expressed on the surface of late-stage-infected erythrocytes (LSIE) (5, 6). In this scenario, only parasites expressing variant Ags to which the host does not possess adequate specific Ab are likely to cause disease, and immunity is likely to depend on the accumulation of a large panel of Ab specificities recognizing different variants of such Ags.
PAM is often associated with sequestration of large quantities of parasites in the placenta, even when peripheral parasitemia is scant (2, 7). P. falciparum is unique among human malaria parasites in its ability to adhere to several host receptor molecules, including CD36, ICAM-1 (CD54), thrombospondin, vascular adhesion molecule 1, E-selectin, and chondroitin sulfate A (CSA) (8, 9, 10, 11, 12, 13, 14, 15, 16). Specifically, placental parasites have been shown to adhere preferentially to CSA, while parasites from nonpregnant malaria patients rarely possess this phenotype (17). Furthermore, plasma from multigravid, but not primigravid, women from endemic areas can inhibit adhesion of placental parasites to CSA (18). Nevertheless, little detailed information about the parity dependency of inhibition of CSA-specific adhesion of P. falciparum is available. In the present study we have examined plasma from 163 third-trimester pregnant women with parities from 1 to 12 from an area of hyperendemic malaria transmission. Levels of Abs recognizing a CSA-adhering parasite isolate were compared with recognition of isolates without appreciable adhesion to CSA, and the relationship between Ab binding to LSIE, on the one hand, and with parity and inhibition of adhesion to CSA in vitro, on the other. We show that levels of Abs to the CSA-specific isolate are strongly associated with parity and with the ability to inhibit parasite adhesion to CSA. The data point to interference with CSA-dependent sequestration as the basis for parity-dependent acquisition of anti-PAM immunity, and suggest it as a target for vaccination against PAM.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Plasma samples were collected from 163 third-trimester (gestational age, 34.8 ± 2.22 wk; mean ± 1 SD) pregnant women attending antenatal clinics in the village of Prampram, situated about 50 km east of Accra on the coast of Ghana. Additional samples were obtained from 40 healthy adults (20 men and 20 women) living in Gomoa Onyadze village about 50 km west of Accra. The pregnancy status of the latter group of women was not ascertained. Finally, a pool of plasma from adults living in Dodowa about 20 km outside Accra was used in some experiments (hyperimmune plasma pool).
Malaria transmission in southern Ghana is perennial, but peaks after the main wet season between July and September (19). P. falciparum is the dominant species, but P. malariae is also present (19). The entomological inoculation rate is approximately 8.5 infective bites/person/yr, and the dominant vector is Anopheles gambiae (20). Ethical clearance for the study was granted by the Ghanaian Ministry of Health (DMS-083).
Control samples were collected from healthy laboratory staff in Copenhagen. In addition, third-trimester plasma samples from 10 Danish women were included in the study. None of the control donors had any known exposure to malaria parasites, and most had never visited malaria-endemic areas.
Parasite isolates
Four P. falciparum isolates were used in the study. FCR3 is a long-term laboratory isolate (21), while isolates E2037 and E2039 were obtained from children with malaria, living in Dodowa village outside Accra. None of these isolates were subjected to in vitro selection for particular adhesion phenotypes. In addition to these unselected isolates, we used a CSA-adhering substrain (PA/CSA) of the Palo Alto strain (a gift from Jürg Gysin (Université de la Mediterranée, Marseilles, France)) selected for adhesion to CSA in vitro (15). All isolates were maintained in vitro by standard methods (22). High levels of binding to CSA in the PA/CSA isolate were secured by regular panning of infected erythrocytes on purified CSA (Sigma, St. Louis, MO) as previously described (16). All experiments on CSA-selected parasites were performed within 6 days of panning. All isolates were genotypically distinct according to PCR typing on merozoite surface protein 1, merozoite surface protein 2, and glutamate-rich protein, performed as described previously (23).
Isolation of LSIE
LSIE were separated from uninfected and ring-stage infected erythrocytes by magnet-activated cell sorting (Miltenyi BioTec, Bergisch Gladbach, Germany) or in some cases by gel flotation as described previously (24, 25, 26, 27).
Parasite adhesion and agglutination
The cytoadhesion phenotype of all isolates was determined by adhesion assays to CD36, ICAM-1, and CSA as previously described (18, 28). The purified CD36 used in these assays was a gift from David Roberts and Arnab Pain (University of Oxford, Oxford, U.K.), whereas recombinant ICAM-1 and purified CSA were purchased from R&D Systems (Abingdon, U.K.) and Sigma, respectively.
The ability of isolates to agglutinate was determined by standard microagglutination assay as described previously (29).
Analysis of variant Ag-specific Abs by flow cytometry
Levels of plasma Abs recognizing variant LSIE surface Ags were measured by flow cytometry as described in detail previously (27). In brief, purified LSIE were labeled with ethidium bromide (0.1 mg/ml; 1 µl/1 x 105 LSIE) and sequentially exposed to test plasma (2.5 µl/1 x 105 LSIE), goat anti-human IgG (Dako, Glostrup, Denmark) diluted 1/250 in PBS, and FITC-conjugated rabbit anti-goat Ig (Dako) diluted 1/25. Samples were washed twice between each labeling step and once before analysis on a Coulter EPICS XL-MCL flow cytometer (Coulter Electronics, Luton, U.K.). For each sample, the mean fluorescence (expressed as channel number) was calculated using an ethidium bromide gate to identify LSIE. Labeling of uninfected erythrocytes was measured in a similar way, using uninfected erythrocytes rather than LSIE. All assays were performed using coded samples with no reference to donor parity, etc.
In some experiments with CSA-adhering LSIE, soluble CSA (sCSA; 10–500 µg/ml) was added either before or after labeling with plasma Ab.
Inhibition of parasite adhesion to CSA
Plasma-mediated inhibition of adhesion of parasitized erythrocytes to CSA was quantified essentially as described previously (18). In brief, 20 µl (10 µg/ml) of CSA (Sigma) was spotted onto Falcon petri dishes (Becton Dickinson, Brøndby, Denmark) and incubated for 3 h at room temperature. Subsequently, the drops were carefully removed, and the spots were blocked by 20 µl of BSA (20 mg/ml) for 30 min. After removal of the blocking buffer, 16 µl of LSIE (5% hemocrit, 5–20% parasitemia) preincubated for 60 min with 4 µl of test plasma was added to the CSA spots and incubated for 60 min at room temperature. In some assays LSIE were preincubated with sCSA (10–100 µg/ml) instead of plasma. Following incubation, unbound erythrocytes were removed by washing five times in PBS, and bound erythrocytes were counted (minimum of 15 fields) by microscopy (x400) of the glutaraldehyde-fixed (0.5%, 10 min), Giemsa-stained spots. Again, all assays were performed using coded samples, with no reference to donor parity, etc. In assays of reversal of parasite adhesion, the preincubation step was omitted, and plasma was added only after parasites had been allowed to adhere to CSA for >30 min.
Statistical analysis and data presentation
Groupwise averages were compared by Kruskal-Wallis one-way ANOVA on ranks (H) followed by Dunn’s test. Spearman’s test (rs) was used for analysis of parameter association. Analysis of possible confounding factors was performed using multiple linear regression analysis (t). p < 0.05 was considered significant. All experiments described in this paper were repeated a minimum of three times with similar results.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Late-stage (amoeboid trophozoites and schizonts) P.
falciparum-infected erythrocytes (LSIE) are able to adhere to a
number of host receptor molecules (reviewed in Ref. 30).
Most unselected parasite isolates investigated to date have shown
affinity for CD36, whereas binding of LSIE to ICAM-1 is less common,
and CSA binding is rare (31). We found that LSIE of all
three unselected isolates adhered significantly to CD36, whereas none
showed significant binding to either ICAM-1 or CSA (Table I
). In contrast, the CSA-selected isolate
PA/CSA showed strong affinity for CSA and did not bind to either CD36
or ICAM-1. The specificity of the binding to CSA was demonstrated by
concentration-dependent inhibition of this adhesion by the addition of
sCSA to the adhesion assay (data not shown). In conclusion, the
parasite isolates all displayed the expected adhesion phenotype.
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Plasma samples from individuals from malaria-endemic areas contain
Abs that recognize variant LSIE surface Ags, and such Abs can be
detected and quantified by flow cytometry (FCM) (27, 32).
For all three unselected parasite isolates studied here, plasma from
adults living in a hyperendemic malaria area (coastal Ghana) contained
significantly higher levels (p(H) < 0.01 and
p < 0.05, by Dunn’s test) of Abs recognizing LSIE
surface Ags compared with levels in plasma from nonexposed donors (Fig. 1A and data not shown). FCR3,
which has been maintained in continuous in vitro culture for many
years, was the unselected parasite isolate least recognized (not
shown). In marked contrast to the plasma Ab-mediated pan-recognition of
the unselected parasites, the CSA-selected parasite isolate PA/CSA was
only poorly recognized by plasma from the same malaria-exposed
Ghanaians (Fig. 1B). Even more strikingly, in not a single
case did plasma samples from Ghanaian men contain Ab levels above
levels in plasma from nonexposed control donors. The majority of plasma
samples from Ghanaian women displayed a similar lack of Ab-mediated
recognition of the CSA-selected parasite isolate (Fig. 1B).
As a result, the recognition of CSA-selected parasites by the Ghanaian
men or women did not differ significantly from that of plasma from
donors without malaria exposure (p(H) = 0.09),
and similarly, the recognition of CSA-selected parasites by a
hyperimmune plasma pool was much less than the recognition of
unselected parasites (Fig. 1). However, despite this general
nonrecognition, a proportion of the plasma samples from the Ghanaian
women did contain Abs specifically recognizing the CSA-selected
parasites, and some at remarkably high levels (Fig. 1B). No
reliable information regarding the pregnancy status of any of the
Ghanaian women at the time of the collection of these blood samples was
available, but with hindsight (see further below) it is tempting to
speculate that these women either were pregnant or had recently been
pregnant.
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To investigate the relationship between plasma Ab-mediated
recognition of CSA-selected parasites and pregnancy in more detail we
proceeded to analyze the levels of LSIE surface Ag-specific Abs in
plasma from 163 malaria-exposed third-trimester pregnant women. In
these samples the median level of Abs specific for the CSA-selected
isolate was significantly higher (p(H)<0.001 and
p < 0.05 for all pairwise differences (Dunn’s test))
than for any of the unselected parasite isolates (Fig. 2A). This indicates that
malaria-exposed third-trimester pregnant women have much higher titers
of Abs recognizing LSIE infected by CSA-selected compared with
unselected parasites. When CSA-selected and unselected LSIE were
labeled by 2-fold dilutions of a pool of plasma from malaria-exposed
pregnant women, significant labeling of CSA-selected LSIE remained at
plasma dilutions where Abs recognizing any of the unselected parasite
isolates were undetectable (Fig. 2B and data not shown).
This supports the hypothesis of higher titers of Abs to CSA-adhering
compared with unselected parasites in the pregnant women.
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C) by sCSA at concentrations ranging from 10–500
µg/ml. The finding of very high levels of Abs in plasma from malaria-exposed pregnant women, specifically recognizing variant Ags expressed by CSA-selected parasites prompted us to examine in more detail the apparently general inability of immune plasma to agglutinate CSA-selected LSIE (33) (our unpublished observations). When examining unselected parasite isolates, our FCM assay corresponds well to the conventional agglutination assay of Abs to variant-infected erythrocyte surface Ags (29). We thus speculated that the lack of agglutination of CSA-selected parasites might be due to an Ag-Ab ratio that is unfavorable for an agglutination reaction. However, agglutination assays using plasma from third-trimester pregnant women in 2-fold dilutions down to 1/2048 did not support this hypothesis, as the only (small) agglutinates observed when using CSA-selected LSIE were seen at low dilutions (1/1 to 1/4; data not shown). It thus appears that the general absence of agglutination CSA-selected LSIE is not simply due to the high plasma levels of potentially agglutinating Ab species.
Recognition of CSA-selected parasites by Abs in plasma from third-trimester pregnant women correlates with donor parity
The marked parity dependency of PAM in endemic areas has been
proposed to reflect acquisition of protective Abs that specifically
recognize placenta-adhering parasites (18). To investigate
whether the high levels of third-trimester plasma Abs recognizing
CSA-selected LSIE in our FCM assay were related to donor parity, we
stratified the levels of Abs recognizing unselected and CSA-selected
LSIE according to the parity of the plasma donor. The parity of the 163
plasma donors ranged from 1–12 (see Table II for details).
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, levels of Abs
recognizing CSA-selected parasites were significantly correlated to
parity (p(rs) = 0.0008),
whereas this was not the case with respect to any of the three
unselected parasite isolates (0.09 <
p(rs) < 0.9). Analysis of the Ab
recognition of CSA-selected LSIE by multiple linear regression analysis
considering parity and possible confounding factors, such as donor age,
tribe, residence, gestational age, and malaria prophylaxis (Table II),
identified parity as the only significant explanatory variable
(p(t) < 0.04). Similar
results were obtained if we reduced the number of independent variables
included in the modeling. In contrast, parity did not contribute
significantly to explaining sample variation when similar analyses were
applied to the datasets obtained with unselected parasites
(p(t) > 0.5 in all cases). Thus, the data
clearly show that the level of plasma Abs recognizing Ags on the
surface of CSA-selected, but not of unselected, parasite isolates
depended on the parity of the plasma donors.
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It has been reported previously that Abs capable of inhibiting
CSA-specific adhesion of unselected P. falciparum parasites
obtained from the placenta and peripheral blood of pregnant women can
be found in the serum of multigravid women from malaria-endemic areas
(18). As the level of FCM-detectable plasma Abs
recognizing Ags on CSA-selected LSIE correlated with parity (Fig. 3),
we investigated whether plasma samples with high Ab levels were more
efficient in inhibiting adhesion of CSA-selected parasites to CSA than
samples with low levels of such Abs. To this end we ranked all the
third-trimester plasma samples according to their recognition of
CSA-selected LSIE by FCM. The 10 plasma samples with the highest scores
and the 10 samples with the lowest scores were then tested for their
ability to inhibit the CSA-specific adhesion of the PA/CSA isolate (as
before, these assays were always performed with coded samples). As
shown in Fig. 4, there was a very clear
relationship between the ability of a given plasma sample to score in
the FCM assay and its ability to inhibit CSA-specific parasite adhesion
in vitro.
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In a previous study third-trimester plasma from primigravid women
were found to be uniformly unable to inhibit binding of placental
LSIE to CSA in vitro (18). Nevertheless, we found that a
considerable proportion of such samples contained high levels of Abs
recognizing CSA-adhering LSIE (Fig. 3), and that high levels correlated
with inhibition of adhesion to CSA in vitro (Fig. 4). We thus
considered the possibility that the inhibitory capacity of Abs from
primigravid and multigravid women differed independently of the levels
of such Abs. To test this hypothesis, we compared the ability of
third-trimester samples from primigravid women with high and low plasma
Ab levels and those from multigravid women with high plasma Ab levels
to inhibit adhesion of LSIE to CSA. We found that the ability of plasma
to inhibit adhesion depended on the levels of Abs recognizing
CSA-adhering LSIE, but not on parity (Fig. 5A). Plasma from 10
third-trimester women without known exposure to malaria parasites and
all containing low levels of Abs recognizing CSA-adhering LSIE were
uniformly unable to affect LSIE binding to CSA (data not shown). Thus,
our data support the hypothesis that the inhibitory capacity of plasma
depends on the quantity, rather than the quality, of Abs binding to the
surface of CSA-adhering LSIE, and that the parity dependency of
protection against PAM is due to an increasing proportion of women
having high Abs against CSA-adhering parasites with increasing
parity.
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We proceeded to examine whether third-trimester plasma Abs were
capable of reversing already established binding of CSA-selected LSIE
to CSA. Addition of third-trimester plasma from malaria-exposed, but
not from nonexposed, women to CSA-selected parasites that had been
allowed to adhere to CSA caused a partial reversion of this binding
(Fig. 5B). In contrast, addition of nonimmune plasma had no
significant effect on already established adhesion.
In conclusion, plasma Abs from Ghanaian women in their third trimester of pregnancy were shown to inhibit and even reverse binding of CSA-selected parasites to CSA. Furthermore, the levels of Abs to variant-specific surface Ags on CSA-selected LSIE detected by the FCM assay correlated strongly with this inhibitory capacity, suggesting this assay as a convenient tool to evaluate the degree of Ab-mediated protection against PAM.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Receptor-specific parasite adhesion appears to be mediated primarily through parasite-derived variant Ags in the membrane of LSIE. The best characterized such Ag is P. falciparum erythrocyte membrane protein 1 (PfEMP1), which is encoded by the multigene var family (35, 36, 37). Selection of P. falciparum for adhesion to CSA in vitro results in the expression of particular PfEMP1 variants capable of binding CSA, suggesting that PfEMP1 is involved in CSA-specific parasite adhesion (38, 39). We have recently developed a flow cytometric assay that is suitable for unbiased analysis of recognition of variant LSIE surface Ags by plasma Ab (27), with PfEMP1 as a main target Ag (27, 32). The assay correlates well with assays of Ab-dependent agglutination of LSIE (5, 29).
As expected from previous studies, most plasma samples from adults living in an area of hyperendemic malaria transmission (coastal Ghana) contained Abs labeling erythrocytes infected with each of three P. falciparum isolates that had not been subjected to in vitro selection pressure. In marked contrast, plasma levels of Abs recognizing the CSA-selected parasite isolate PA/CSA were not significantly different from levels in the plasma of unexposed donors. This result is in line with a previous study showing that sera from parasite-exposed males were unable to agglutinate placental (presumably CSA-specific) parasites (33). Another recent study showed lower agglutination rates of parasites from pregnant than from nonpregnant donors exposed to serum from nonpregnant individuals, although the sex of the serum donors was not indicated (40). The few among our plasma samples from Gomoa Onyadze that did label PA/CSA were exclusively from women. This marked gender difference seen only with the CSA-adherent isolate points to a relation to pregnancy, although we did not know the parity or pregnancy status of these female plasma donors.
Plasma from malaria-exposed, third-trimester pregnant women generally contained much higher levels of PA/CSA-specific Abs than of Abs recognizing unselected parasites. Furthermore, there was a highly significant association between levels of PA/CSA-specific Abs and parity, whereas this was not the case for any of the unselected isolates. Among the primigravid women, more than half had low PA/CSA-specific Ab levels, whereas the remaining women had levels as high as those in women of higher parity did. In fact, the main parity-dependent change was the decreasing proportion of women with low levels of PA/CSA-specific Abs with increasing parity, whereas there was no appreciable increase in the maximum Ab level with increasing parity. It thus appears that PAM induces a strong Ab response directed against CSA-adhering parasites regardless of parity, and that the parity-dependent protection against PAM reflects an increasing likelihood of previous exposure to such parasites. In support of this idea, a very clear correlation between Ab levels in plasma samples and their capacity to inhibit CSA-specific adhesion was found between plasma levels of such Abs and the ability of plasma samples to inhibit CSA-specific adhesion. Furthermore, plasma samples from primigravid women with high plasma Ab levels were as efficient in this respect as samples from multigravid women. The fact that already established adhesion could be reversed by addition of third-trimester plasma, whereas Ab labeling of CSA-specific LSIE could not be reversed by sCSA suggests that the Ab-mediated mechanism of inhibition is steric hindrance. However, differences in the affinities of Abs and sCSA for the parasite CSA ligand may be contributory. Further studies are needed to clarify this issue.
In a study from an area of western Kenya it was reported that serum from multigravid women efficiently inhibited CSA-specific parasite adhesion, whereas serum samples from primigravidae were all completely inefficient in this respect (18). We found high levels of Abs recognizing CSA-selected parasites in a considerable proportion of plasma from primigravidae and a clear correlation between Ab levels and inhibition of adhesion regardless of parity. It thus seems that the samples from the primigravid women in the Kenyan study all had low levels of Abs specifically recognizing CSA-adherent parasites, although the endemicity there is much higher than that in our study area. This seeming paradox could be explained if Abs inhibiting CSA-specific parasite adhesion are acquired relatively late in the pregnancy, and if the samples assayed in the Kenyan study were obtained at an earlier gestational age than in our study. Parasite rates, anemia, and splenomegaly in primiparous women peak during the second trimester (2, 41). The subsequent reduction in these parameters may reflect the acquisition of inhibitory Abs, and indeed recent data showed lower agglutination rates in the sixth month of pregnancy than at delivery in first-time pregnant women from Cameroon (40). However, the fact that the serum samples used in the study from Kenya were actually obtained at term (M. Fried, personal communication) makes the above explanation of the apparent difference between the two studies less obvious. Detailed studies on the kinetics of the acquisition and decay of Abs interfering with CSA-specific parasite sequestration in areas of different endemicity are clearly needed.
In conclusion, we have shown that although levels of Abs specifically recognizing a CSA-adherent isolate of P. falciparum are generally low in an endemic population, levels are usually high in third-trimester pregnant women. Secondly, the proportion of such women with high Ab levels increases with increasing parity. Thirdly, levels of these Abs correlate with the ability of plasma to inhibit and reverse adhesion of the parasites to CSA. Taken together, our data strongly support the hypothesis that parity-dependent protection against PAM reflects acquisition of Abs interfering with CSA-specific placental sequestration of parasites. Furthermore, our study demonstrates a convenient method of measuring plasma levels of Abs recognizing the parasite Ags mediating this adhesion. These Ags constitute an obvious target for vaccination against PAM.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Lars Hviid, Department of Infectious Diseases M7641, Rigshospitalet, Tagensvej 20, 2200 Copenhagen N, Denmark.
3 Abbreviations used in this paper: PAM, pregnancy-associated malaria; CSA, chondroitin sulfate A; FCM, flow cytometry; LSIE, late-stage-infected erythrocytes; PfEMP1, Plasmodium falciparum erythrocyte membrane protein 1; sCSA, soluble CSA.
Received for publication January 18, 2000. Accepted for publication June 28, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and TNF-
associated with pregnancy outcomes. J. Immunol. 160:2523.This article has been cited by other articles:
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R. N. Haase, R. Megnekou, M. Lundquist, M. F. Ofori, L. Hviid, and T. Staalsoe Plasmodium falciparum Parasites Expressing Pregnancy-Specific Variant Surface Antigens Adhere Strongly to the Choriocarcinoma Cell Line BeWo. Infect. Immun., May 1, 2006; 74(5): 3035 - 3038. [Abstract] [Full Text] [PDF]
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K. Brustoski, M. Kramer, U. Moller, P. G. Kremsner, and A. J. F. Luty Neonatal and Maternal Immunological Responses to Conserved Epitopes within the DBL-{gamma}3 Chondroitin Sulfate A-Binding Domain of Plasmodium falciparum Erythrocyte Membrane Protein 1 Infect. Immun., December 1, 2005; 73(12): 7988 - 7995. [Abstract] [Full Text] [PDF]
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S. R. Elliott, A. K. Brennan, J. G. Beeson, E. Tadesse, M. E. Molyneux, G. V. Brown, and S. J. Rogerson Placental Malaria Induces Variant-Specific Antibodies of the Cytophilic Subtypes Immunoglobulin G1 (IgG1) and IgG3 That Correlate with Adhesion Inhibitory Activity Infect. Immun., September 1, 2005; 73(9): 5903 - 5907. [Abstract] [Full Text] [PDF]
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R. Megnekou, T. Staalsoe, D. W Taylor, R. Leke, and L. Hviid Effects of Pregnancy and Intensity of Plasmodium falciparum Transmission on Immunoglobulin G Subclass Responses to Variant Surface Antigens Infect. Immun., July 1, 2005; 73(7): 4112 - 4118. [Abstract] [Full Text] [PDF]
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S. Chaisavaneeyakorn, N. Lucchi, C. Abramowsky, C. Othoro, S. C. Chaiyaroj, Y. P. Shi, B. L. Nahlen, D. S. Peterson, J. M. Moore, and V. Udhayakumar Immunohistological Characterization of Macrophage Migration Inhibitory Factor Expression in Plasmodium falciparum-Infected Placentas Infect. Immun., June 1, 2005; 73(6): 3287 - 3293. [Abstract] [Full Text] [PDF]
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S. E. Cox, T. Staalsoe, P. Arthur, J. N. Bulmer, L. Hviid, K. Yeboah-Antwi, B. R. Kirkwood, and E. M. Riley Rapid Acquisition of Isolate-Specific Antibodies to Chondroitin Sulfate A-Adherent Plasmodium falciparum Isolates in Ghanaian Primigravidae Infect. Immun., May 1, 2005; 73(5): 2841 - 2847. [Abstract] [Full Text] [PDF]
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S. R. Elliott, M. F. Duffy, T. J. Byrne, J. G. Beeson, E. J. Mann, D. W. Wilson, S. J. Rogerson, and G. V. Brown Cross-Reactive Surface Epitopes on Chondroitin Sulfate A-Adherent Plasmodium falciparum-Infected Erythrocytes Are Associated with Transcription of var2csa Infect. Immun., May 1, 2005; 73(5): 2848 - 2856. [Abstract] [Full Text] [PDF]
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 K. Brustoski, U. Moller, M. Kramer, A. Petelski, S. Brenner, D. R. Palmer, M. Bongartz, P. G. Kremsner, A. J. F. Luty, and U. Krzych IFN-{gamma} and IL-10 Mediate Parasite-Specific Immune Responses of Cord Blood Cells Induced by Pregnancy-Associated Plasmodium falciparum Malaria J. Immunol., February 1, 2005; 174(3): 1738 - 1745. [Abstract] [Full Text] [PDF]
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 J. D. Smith and K. W. Deitsch Pregnancy-associated Malaria and the Prospects for Syndrome-specific Antimalaria Vaccines J. Exp. Med., November 1, 2004; 200(9): 1093 - 1097. [Abstract] [Full Text] [PDF]
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A. Salanti, M. Dahlback, L. Turner, M. A. Nielsen, L. Barfod, P. Magistrado, A. T.R. Jensen, T. Lavstsen, M. F. Ofori, K. Marsh, et al. Evidence for the Involvement of VAR2CSA in Pregnancy-associated Malaria J. Exp. Med., November 1, 2004; 200(9): 1197 - 1203. [Abstract] [Full Text] [PDF]
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T. Staalsoe, C. E Shulman, E. K. Dorman, K. Kawuondo, K. Marsh, and L. Hviid Intermittent Preventive Sulfadoxine-Pyrimethamine Treatment of Primigravidae Reduces Levels of Plasma Immunoglobulin G, Which Protects against Pregnancy-Associated Plasmodium falciparum Malaria Infect. Immun., September 1, 2004; 72(9): 5027 - 5030. [Abstract] [Full Text] [PDF]
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A. Muthusamy, R. N. Achur, V. P. Bhavanandan, G. G. Fouda, D. W. Taylor, and D. C. Gowda Plasmodium falciparum-Infected Erythrocytes Adhere Both in the Intervillous Space and on the Villous Surface of Human Placenta by Binding to the Low-Sulfated Chondroitin Sulfate Proteoglycan Receptor Am. J. Pathol., June 1, 2004; 164(6): 2013 - 2025. [Abstract] [Full Text] [PDF]
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D. W. Taylor, A. Zhou, L. E. Marsillio, L. W. Thuita, E. B. Leke, O. Branch, D. C. Gowda, C. Long, and R. F. G. Leke Antibodies That Inhibit Binding of Plasmodium falciparum-Infected Erythrocytes to Chondroitin Sulfate A and to the C Terminus of Merozoite Surface Protein 1 Correlate with Reduced Placental Malaria in Cameroonian Women Infect. Immun., March 1, 2004; 72(3): 1603 - 1607. [Abstract] [Full Text] [PDF]
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P. E. Duffy and M. Fried Antibodies That Inhibit Plasmodium falciparum Adhesion to Chondroitin Sulfate A Are Associated with Increased Birth Weight and the Gestational Age of Newborns Infect. Immun., November 1, 2003; 71(11): 6620 - 6623. [Abstract] [Full Text] [PDF]
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D. I. Baruch, B. Gamain, and L. H. Miller DNA Immunization with the Cysteine-Rich Interdomain Region 1 of the Plasmodium falciparum Variant Antigen Elicits Limited Cross-Reactive Antibody Responses Infect. Immun., August 1, 2003; 71(8): 4536 - 4543. [Abstract] [Full Text] [PDF]
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A. M. Creasey, T. Staalsoe, A. Raza, D. E. Arnot, and J. A. Rowe Nonspecific Immunoglobulin M Binding and Chondroitin Sulfate A Binding Are Linked Phenotypes of Plasmodium falciparum Isolates Implicated in Malaria during Pregnancy Infect. Immun., August 1, 2003; 71(8): 4767 - 4771. [Abstract] [Full Text] [PDF]
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A. T. R. Jensen, H. D. Zornig, C. Buhmann, A. Salanti, K. A. Koram, E. M. Riley, T. G. Theander, L. Hviid, and T. Staalsoe Lack of Gender-Specific Antibody Recognition of Products from Domains of a var Gene Implicated in Pregnancy-Associated Plasmodium falciparum Malaria Infect. Immun., July 1, 2003; 71(7): 4193 - 4196. [Abstract] [Full Text] [PDF]
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S. T. Agbor-Enoh, R. N. Achur, M. Valiyaveettil, R. Leke, D. W. Taylor, and D. C. Gowda Chondroitin Sulfate Proteoglycan Expression and Binding of Plasmodium falciparum-Infected Erythrocytes in the Human Placenta during Pregnancy Infect. Immun., May 1, 2003; 71(5): 2455 - 2461. [Abstract] [Full Text] [PDF]
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 R. N. Achur, M. Valiyaveettil, and D. C. Gowda The Low Sulfated Chondroitin Sulfate Proteoglycans of Human Placenta Have Sulfate Group-clustered Domains That Can Efficiently Bind Plasmodium falciparum-infected Erythrocytes J. Biol. Chem., March 21, 2003; 278(13): 11705 - 11713. [Abstract] [Full Text] [PDF]
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M. F. Ofori, T. Staalsoe, V. Bam, M. Lundquist, K. P. David, E. N. L. Browne, B. D. Akanmori, and L. Hviid Expression of Variant Surface Antigens by Plasmodium falciparum Parasites in the Peripheral Blood of Clinically Immune Pregnant Women Indicates Ongoing Placental Infection Infect. Immun., March 1, 2003; 71(3): 1584 - 1586. [Abstract] [Full Text] [PDF]
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 M. Cot, J. Y. Le Hesran, T. Staalsoe, N. Fievet, L. Hviid, and P. Deloron Maternally Transmitted Antibodies to Pregnancy-Associated Variant Antigens on the Surface of ErythrocytesInfected with Plasmodium falciparum: Relation to Child Susceptibility to Malaria Am. J. Epidemiol., February 1, 2003; 157(3): 203 - 209. [Abstract] [Full Text] [PDF]
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B. Gamain, S. Gratepanche, L. H. Miller, and D. I. Baruch Molecular basis for the dichotomy in Plasmodium falciparum adhesion to CD36 and chondroitin sulfate A PNAS, July 23, 2002; 99(15): 10020 - 10024. [Abstract] [Full Text] [PDF]
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M. F. Ofori, D. Dodoo, T. Staalsoe, J. A. L. Kurtzhals, K. Koram, T. G. Theander, B. D. Akanmori, and L. Hviid Malaria-Induced Acquisition of Antibodies to Plasmodium falciparum Variant Surface Antigens Infect. Immun., June 1, 2002; 70(6): 2982 - 2988. [Abstract] [Full Text] [PDF]
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M. A. Nielsen, T. Staalsoe, J. A. L. Kurtzhals, B. Q. Goka, D. Dodoo, M. Alifrangis, T. G. Theander, B. D. Akanmori, and L. Hviid Plasmodium falciparum Variant Surface Antigen Expression Varies Between Isolates Causing Severe and Nonsevere Malaria and Is Modified by Acquired Immunity J. Immunol., April 1, 2002; 168(7): 3444 - 3450. [Abstract] [Full Text] [PDF]
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I. O'Neil-Dunne, R. N. Achur, S. T. Agbor-Enoh, M. Valiyaveettil, R. S. Naik, C. F. Ockenhouse, A. Zhou, R. Megnekou, R. Leke, D. W. Taylor, et al. Gravidity-Dependent Production of Antibodies That Inhibit Binding of Plasmodium falciparum-Infected Erythrocytes to Placental Chondroitin Sulfate Proteoglycan during Pregnancy Infect. Immun., December 1, 2001; 69(12): 7487 - 7492. [Abstract] [Full Text] [PDF]
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D. Dodoo, T. Staalsoe, H. Giha, J. A. L. Kurtzhals, B. D. Akanmori, K. Koram, S. Dunyo, F. K. Nkrumah, L. Hviid, and T. G. Theander Antibodies to Variant Antigens on the Surfaces of Infected Erythrocytes Are Associated with Protection from Malaria in Ghanaian Children Infect. Immun., June 1, 2001; 69(6): 3713 - 3718. [Abstract] [Full Text] [PDF]
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
, NIP), pooled plasma from Ghanaian adults selected for high titers
of plasma Abs to variant surface Ags (•, HIPP), 20 men (
), and 20
women (
) living in an area of hyperendemic malaria transmission
(Gomoa Onyadze, Ghana). Data obtained with one unselected parasite
isolate (E2039, A) and one CSA-selected isolate (PA/CSA,
B) are shown. Statistically significant differences are
indicated (Dunn’s test following Kruskal-Wallis one-way ANOVA on
ranks).
) and high (
) titers of PA/CSA-specific Abs detected by
FCM. Data are presented as the percent adhesion to CSA alone (positive
control, 
). Adhesion to BSA alone (background, ) and to CSA in
the presence of soluble CSA (10 and 100 µg/ml,
) are shown for
comparison. Asterisks indicate medians that were not significantly
different from median adhesion to BSA alone (Kruskal-Wallis test
followed by Dunn’s test). Inset, Absolute relationship between plasma
Ab levels (