| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
,
*
Center for Medical Parasitology, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark;
Department of Child Health, Korle-Bu Teaching Hospital, Accra, Ghana; and
Immunology Unit, Noguchi Memorial Institute for Medical Research, Legon, Ghana
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Recent data have documented the existence of common and rare VSA in field isolates of P. falciparum parasites (7, 8). We hypothesized that the common VSA correspond to VSA that are preferred in some sense by most or all P. falciparum isolates, probably by maximizing the probability of their successful transmission to new hosts. One way that this can be achieved is if such VSA facilitate particularly efficacious adhesion of infected erythrocytes, thus interfering with splenic clearance. If so, acquisition of immunity may shape the repertoire of VSA expressed by parasites causing clinical disease by driving VSA expression away from such preferred VSA. To study this hypothesis we analyzed plasma samples from 96 healthy Ghanaian children for levels of IgG with specificity for VSA expressed by each of 68 clinical parasite isolates from 36 Ghanaian children with severe malaria (cerebral malaria and severe anemia) and 32 children with nonsevere malaria.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Patients aged 3–11 years and admitted as inpatients to the
Department of Child Health, Korle-Bu Teaching Hospital, University of
Ghana Medical School (Accra, Ghana), with a diagnosis of P.
falciparum malaria were recruited for the study. All patients were
febrile at admission (>37.5°C) and had asexual blood stage
parasitemia >10,000/µl. Only 100 patients that could be categorized
as having either severe or nonsevere malaria based on the clinical
criteria listed below were considered for the study. Patients with
severe disease included those with cerebral malaria (score 
3 on the
Blantyre coma scale (9)) and those with severe anemia
(hemoglobin, <50 g/L) in the absence of any differential diagnoses.
Patients with nonsevere malaria were all fully conscious and had
hemoglobin levels >70 g/L. Levels of parasitemia at admission and
symptom duration before admission were not statistically different
between groups (10). The study was approved by the ethics
and protocol review committee of the University of Ghana Medical School
and by the Ghanaian Ministry of Health, and malaria patients as well as
healthy children (see below) were enrolled only after signed, informed
consent from parents or guardians had been obtained.
P. falciparum isolates and parasite cultivation
A sample of parasitized erythrocytes was collected from each of the patients included in the study and snap-frozen in liquid nitrogen as previously described (11). The cryopreserved stabilates were thawed and cultured in vitro as described previously (12). The degree of clonality of the isolates (multiplicity of infection (MOI)) was estimated by PCR typing of the polymorphic regions of the gene encoding merozoite surface protein-1 (msp1), the gene encoding merozoite surface protein-2 (msp2), and the gene encoding glutamate-rich protein (glurp) as described previously (13).
Plasma samples
We used plasma samples collected from 96 Ghanaian children living in Dodowa Town, 50 km northeast of Accra, as the source of VSA Abs. The area is characterized by hyperendemic, seasonal transmission of P. falciparum parasites (14). All children were healthy at the time of blood sampling. We also used a pool of plasma from healthy, parasite-exposed adults from the village of Gomoa Onyadze, 80 km west of Accra, collected as part of an earlier study (15). Plasma samples from healthy Danish adults without a history of visits to malaria-endemic areas were included as negative controls.
Immunostaining and flow cytometry
Erythrocytes infected by late developmental stages (hemozoin-containing trophozoites and schizonts) were purified (to >75% parasitemia) from culture material by exposure to a strong magnetic field (Miltenyi Biotec, Bergish Gladbach, Germany) as previously described (16). Aliquots of 2 x 105 infected erythrocytes, labeled by ethidium bromide (Sigma-Aldrich, St. Louis, MO) to allow flow cytometric exclusion of remaining uninfected erythrocytes, were sequentially exposed to 5 µl plasma, 0.4 µl goat anti-human IgG (DAKO, Glostrup, Denmark), and 4 µl FITC-conjugated rabbit anti-goat IgG (DAKO). Samples were washed twice in PBS and 2% FCS between each Ab incubation step. Five 2-fold dilutions (1/1 to 1/16) of a plasma pool from adult, parasite-exposed Ghanaians and individual plasma samples from six Danish adults without exposure to malaria parasites were included for each parasite isolate. For each parasite/plasma combination, two-color flow cytometry data from 5000 ethidium bromide-positive erythrocytes were collected on a FACScan instrument (BD Biosciences, Franklin Lakes, NJ), and the mean FITC fluorescence was recorded. Nonspecific labeling was evaluated by analysis of uninfected (ethidium bromide-negative) erythrocytes from the same sample. All samples relating to a particular parasite isolate were processed and analyzed in a single assay.
Data scoring and analysis
To be able to compare VSA Ab levels between isolates we
calculated the mean of the FITC fluorescence values for each of the 68
isolates at each of the plasma dilutions of adult, parasite-exposed
Ghanaians. We next assigned a score to each parasite/plasma combination
according to the fluorescence relative to the calculated overall
fluorescence means. If the corrected fluorescence intensity was above
the 1/1 mean, the parasite/plasma combination was assigned a score of
5. Values between the 1/1 and 1/2 means were assigned a score of 4 and
so on, until remaining data points <1/16 mean had been assigned a
score of 0 (Fig. 1
). For each parasite,
we also calculated the sum of all scores for that parasite. A similar
sum of scores was calculated for each plasma sample.
|
2 test with
relevant post-hoc tests as required. Patterns of VSA recognition
were identified by hierarchical cluster analysis (Ward method).
Values of p < 0.05 were considered statistically
significant. |
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
To minimize the risk of unwanted changes in VSA expression due to antigenic switching after prolonged culture, only the 68/100 isolates where sufficient numbers of infected erythrocytes were available for the assays within 20 days of cultivation were used in this study. By this criterion, parasite isolates from 36 patients with severe malaria and from 32 patients with nonsevere malaria were available for analysis. Although the culture time needed to obtain sufficient parasite material varied between isolates, there was no significant correlation between time in culture, age, or category of parasite donor and recognition of the isolates by plasma Abs (data not shown). Our rate of success in adapting the clinical P. falciparum isolates to in vitro culture in this study is comparable to that obtained in similar studies (6, 7).
Similar levels of clonality in isolates from young vs old patients and from patients with severe vs nonsevere disease
Minimal MOI estimates ranged from 1–5 (mean, 2.0), based on PCR
genotyping on polymorphic regions of msp1, msp2,
and glurp (Table I and data
not shown). Contingency analysis of the relationship between MOI and
donor (patient) category did not identify any significant relationships
(p > 0.18 in all cases). Apart from a
difference of borderline significance (p =
0.04) in the proportion of RO33-positive isolates from patients with
severe and nonsevere malaria, the proportions of different
msp1 and msp2 alleles or the number of different
glurp alleles were not significantly related to donor
category (p > 0.13 in all cases; Table I and
data not shown).
|
P. falciparum-parasitized erythrocytes can be
agglutinated by Ab-mediated VSA cross-linking (17, 18, 19).
The degree of agglutination differs between isolates, and this
diversity has been related to the severity of disease in the parasite
donor (i.e., the malaria patient) (8). To investigate
whether VSA-specific IgG recognition of parasites isolated from
patients with severe and nonsevere P. falciparum malaria
also differed, we analyzed the levels of Abs in a pool of plasma from
adult, parasite-exposed individuals that specifically recognized VSA
expressed by the 68 P. falciparum isolates (Fig. 2A). Thirty-six of the
isolates were from patients with severe malaria, while 32 were from
patients with nonsevere malaria. Ab recognition of isolates from
patients with severe malaria was consistently higher that that of
isolates from patients with nonsevere malaria at all plasma dilutions
(Fig. 2A). The difference in the associated regression lines
of parasites from the two patient categories was highly significant (by
ANCOVA, p < 0.0001), and the magnitude of the
difference indicated that Ab recognition of VSA expressed by parasites
from patients with severe disease was approximately twice that of
parasites from patients with nonsevere malaria (Fig. 2A). As
shown above, MOI estimates were similar for patients with severe and
nonsevere malaria (Table I
). Removal of the data points regarding the 8
of 36 severe malaria patients with severe anemia did not markedly
affect these results (data not shown). This shows that parasites
causing severe disease tended to express common/well-recognized VSA
compared with those expressed by parasites involved in nonsevere
P. falciparum malaria in semi-immune children.
|
In addition to the relationship to severity described above,
plasma Ab-mediated agglutination of P. falciparum parasite
isolates has also been reported to depend on the age of the malaria
patient (8). In accordance with this observation we found
that the regression line of IgG recognition of VSA expressed by
parasites from young patients (3–4 years of age; n =
26) was significantly different from that of VSA of parasites from
older patients (5–11 years of age; n = 42; by ANCOVA,
p < 0.0001; Fig. 2B). We did not detect
significant differences in VSA-specific Ab recognition of parasites
obtained from subgroups (5–6 and 7–11 years old) of children >4
years of age (data not shown). Again, Ab recognition of VSA expressed
by parasite isolates from young patients was approximately twice that
of parasites from older children (Fig. 2B), and this was not
due to differences in MOI estimates (Table I). This shows that in this
area of hyperendemic parasite transmission, the parasites obtained from
young patients tended to express common/well-recognized VSA compared
with those expressed by parasites from older children with P.
falciparum malaria.
The age dependency and severity dependency of Ab recognition of VSA occur independently of each other
The above data, together with previously published findings, show
that VSA expression by parasites infecting semi-immune children in
areas of endemic parasite transmission depends on both the age of the
malaria patient and the severity of the malaria episode. To corroborate
this finding further, we next measured levels of Abs in plasma from 96
healthy children, aged 3–8 years, with specificity for each of the 68
parasite isolates (Fig. 3). Overall, Ab
recognition of the parasite VSA differed widely among plasma donors.
While plasma samples from some children contained barely detectable
levels of Abs specific for VSA expressed by any of the isolates (e.g.,
plasma donors 15, 34, and 59; see Fig. 3), others had high levels and a
broad range of VSA-specific Ab (e.g., plasma donors 14, 41, and 84;
Fig. 3). By analyzing the parasite-specific sum of scores from the
96 x 68 recognition matrix, we found that recognition of VSA was
independently associated with both the age of the malaria patient
(3–4, 5–6, and 7–11 years; p = 0.005) and the
clinical picture (severe or nonsevere; p = 0.006, by
two-factor ANOVA). There was no significant interaction between these
two sources of variation (p = 0.26). Pairwise
multiple comparison procedures (Tukey’s post-hoc test) showed that
while the VSA sum of scores of parasites from the youngest patient
group was significantly different from that from either of the two
other age groups (p < 0.05), the latter two
were not significantly different from each other
(p 
0.05). The relationship between severity
and age of the parasite donor is illustrated in Fig. 4, A and B. These
results show that Ab recognition of parasite VSA was independently
affected by both the age and the clinical severity of the malaria
patient from whom the parasite was obtained. This is important, because
disease severity is inversely correlated with age in areas of endemic
parasite transmission, which in all likelihood reflects age-dependent
acquisition of protective immunity (reviewed in Ref. 20).
Protective immunity appears to involve acquisition of Ab responses to a
broad range of VSA (5), and consistent with this
observation we found that VSA Ab levels correlated with the age of the
healthy plasma donors (Fig. 4, C and D). The
authenticity of our finding of independent effects of patient age and
disease severity is supported by the fact that the age distributions of
children with severe and nonsevere disease were similar (by
t test, p = 0.5) in the present study
(5.6 ± 0.4 and 6.0 ± 0.5 years, respectively; mean ±
SD), due to the exclusion of children <3 years of age.
|
|
To further substantiate our findings and to investigate whether
parasites from patients with severe P. falciparum malaria
expressed particular VSA, we used the 96 x 68 recognition matrix
(Fig. 3) to search for patterns of similarity in the VSA Ab recognition
of the parasite isolates. Hierarchical cluster analysis identified
three main clusters (data not shown). In one of these (cluster I), all
but one (90%) of the isolates were from severe cases, whereas this was
the case for only 5 of 20 (25%) in cluster II. The third and largest
cluster (III) showed an intermediate pattern, with 21 of 38 (55%)
isolates from patients with severe malaria. The proportion of isolates
from severe patients in the three clusters was thus quite different (by
2 test, p = 0.009). When we
analyzed the age distribution of the patients donating the parasites
within the clusters, cluster I was composed of parasites from young
patients, whereas the other two clusters contained parasites from older
patients (Fig. 5A). The
cluster-specific differences in patient age composition did not quite
reach conventional statistical significance (by Kruskal-Wallis test,
p = 0.06). The distribution of the parasite-specific
sum of scores among the clusters showed that cluster I was composed
entirely of parasites expressing very well-recognized VSA, whereas the
opposite was true for cluster II. Again, cluster III formed an
intermediate group (Fig. 5B). The distribution of sum of
scores was significantly different among the three clusters (by
Kruskal-Wallis test, p < 0.001), with all pairwise
differences being significant (by Dunn’s post-hoc test,
p < 0.01 in all cases).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The repertoire of antigenically distinct VSA is unknown, but is presumably large, and it has been speculated that the slow acquisition of protective immunity to malaria reflects the necessity to build up a broad repertoire of VSA-specific Abs. Several lines of evidence support this scenario. Thus, P. falciparum parasites causing clinical disease in semi-immune children tend to express VSA that are not well recognized by preexisting plasma Abs, and clinical episodes cause a marked increase only in VSA Abs specific for the infecting parasite isolate (5, 6). Arguably the most striking evidence in favor of a major protective role of VSA-specific Abs is the marked malaria susceptibility in otherwise clinically immune women in endemic areas during their first pregnancy and its subsequent parity-dependent reduction (23, 27, 28, 29, 30). If clinical protection against P. falciparum malaria is indeed mediated at least in part by VSA-specific Ab, it can be expected that the VSA repertoire expressed by P. falciparum parasites causing disease in semi-immune individuals is shaped by the necessity to avoid preexisting VSA-specific immunity in the host. Recent reports of an association among VSA Ab-mediated agglutination, host age, and disease severity indicate that such modulation actually occurs (7, 8).
In this study we have used flow cytometry to measure VSA-specific IgG
to provide evidence of modulation of VSA expression by acquired
immunity. Our method is particularly suited to this type of analysis,
as it allows unbiased and quantitative analysis of large
matrixes of VSA and corresponding Abs of specified isotype. We
found that the level of plasma IgG recognition of VSA expressed by
P. falciparum isolates obtained from patients with severe
malaria was approximately twice that of VSA from nonsevere isolates
(Fig. 2A). In a similar way we found that VSA Ab recognition
of isolates from young patients (3–4 years of age) was 
2-fold that
of isolates from older patients (5–11 years of age; Fig. 2B). In neither case was this due to differences in MOI
estimates between patient categories. As such, our data suggest that
the earlier findings have general validity and for the first time
provide quantitative information regarding immune-mediated modulation
of VSA expression by parasites causing malaria in semi-immune
children.
Although the incidence of severe P. falciparum malaria
generally declines with increasing age in areas of endemic parasite
transmission (20), our analysis of VSA Abs in plasma
samples from 96 healthy children and with specificity for each of 68
parasite isolates enabled us to demonstrate independent effects of both
age and severity on VSA expression (Figs. 3 and 4, A and
B). In addition, our cluster analysis of VSA Ab recognition
showed that parasites expressing common or well-recognized VSA grouped
together, and that the cluster thus formed was composed of parasites
from young children and from children with severe disease. A similar
cluster composed of rare parasites from older patients and patients
with nonsevere disease could also be identified (Fig. 5).
Our findings and the earlier studies all support the "hole in the Ab
repertoire" hypothesis of susceptibility to P. falciparum
malaria (5, 6). According to this hypothesis, parasites
causing clinical disease in semi-immune patients express VSA that
correspond to holes in the VSA Ab repertoire. Thus, only parasites
expressing VSA to which there is no preexisting acquired immunity can
multiply in a substantial way, leading to clinical disease. Following
this argument, acquisition of protective immunity involves a sequential
closure of these holes. Thus, young children with limited immunity are
susceptible to infection by parasites expressing the majority of VSA,
while only parasites expressing rarer VSA are capable of establishing
infection in older, and more immune, children (7). Apart
from this age effect, experimental and theoretical data indicate that
immunity to severe disease is acquired more rapidly than immunity to
infection per se, pointing to a nonrandom VSA expression sequence and
thus a nonrandom closure of the corresponding holes (8, 31, 32, 33). Our finding that VSA Ab recognition of parasites from
severe patients was broader and more intense than recognition of VSA
expressed by parasites from other malaria patients (Figs. 3 and 4),
independently of the age of the patient, supports these
observations.
Taken together, our data suggest that acquisition of VSA-specific Ab responses gradually restricts the repertoire of VSA that are compatible with parasite survival in the semi-immune host. Furthermore, it appears to limit the risk of severe disease by preventing the expression of VSA likely to cause life-threatening complications, such as cerebral malaria and severe anemia.
It should be emphasized that our data suggest that VSA associated with severe disease are common and somehow preferred by parasites infecting a nonimmune host, suggesting that the sequence of appearance of VSA in P. falciparum is nonrandom, as has been observed in malaria parasites in nonhuman primates (34, 35, 36). This conclusion is at variance with the widely accepted hypothesis based on mathematical modeling that severe disease, and, in particular, cerebral malaria, is likely to be caused by rare and highly virulent parasite variants (37). Although more data on the mechanism driving VSA switching in vivo and the molecular identity of common or preferred VSA are clearly needed, all these findings hold the promise that development of morbidity-reducing vaccines targeting a limited subset of common and particularly virulent VSA may be a realistic goal.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Morten A. Nielsen, Department of Infectious Diseases M7641, Center for Medical Parasitology, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen 0, Denmark. E-mail address: mncmp{at}rh.dk
3 Abbreviations used in this paper: VSA, variant surface Ag; ANCOVA, analysis of covariance; glurp, gene encoding glutamate-rich protein; MOI, multiplicity of infection; msp, gene encoding merozoite surface protein; PfEMP1, Plasmodium falciparum erythrocyte membrane protein 1.
Received for publication October 30, 2001. Accepted for publication January 22, 2002.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
|
|
 |
|
  I. Vigan-Womas, M. Guillotte, C. Le Scanf, S. Igonet, S. Petres, A. Juillerat, C. Badaut, F. Nato, A. Schneider, A. Lavergne, et al. An In Vivo and In Vitro Model of Plasmodium falciparum Rosetting and Autoagglutination Mediated by varO, a Group A var Gene Encoding a Frequent Serotype Infect. Immun., December 1, 2008; 76(12): 5565 - 5580. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. S. Vestergaard, J. P. Lusingu, M. A. Nielsen, B. P. Mmbando, D. Dodoo, B. D. Akanmori, M. Alifrangis, I. C. Bygbjerg, M. M. Lemnge, T. Staalsoe, et al. Differences in Human Antibody Reactivity to Plasmodium falciparum Variant Surface Antigens Are Dependent on Age and Malaria Transmission Intensity in Northeastern Tanzania Infect. Immun., June 1, 2008; 76(6): 2706 - 2714. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Kyes, S. M. Kraemer, and J. D. Smith Antigenic Variation in Plasmodium falciparum: Gene Organization and Regulation of the var Multigene Family Eukaryot. Cell, September 1, 2007; 6(9): 1511 - 1520. [Full Text] [PDF]
|
|
|
|
 |
|
 F. S. Toure, O. Ouwe-Missi-Oukem-Boyer, J. Mezui-Me-Ndong, G. R. Ndong-Atome, U. Bisvigou, D. Mazier, and S. Bisser Cytoadherence and Genotype of Plasmodium falciparum Strains from Symptomatic Children in Franceville, Southeastern Gabon Clin. Med. Res., June 1, 2007; 5(2): 106 - 113. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. A. Magistrado, J. Lusingu, L. S. Vestergaard, M. Lemnge, T. Lavstsen, L. Turner, L. Hviid, A. T. R. Jensen, and T. G. Theander Immunoglobulin G Antibody Reactivity to a Group A Plasmodium falciparum Erythrocyte Membrane Protein 1 and Protection from P. falciparum Malaria Infect. Immun., May 1, 2007; 75(5): 2415 - 2420. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Conway Molecular Epidemiology of Malaria Clin. Microbiol. Rev., January 1, 2007; 20(1): 188 - 204. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Moll, F. Pettersson, A. M. Vogt, C. Jonsson, N. Rasti, S. Ahuja, M. Spangberg, O. Mercereau-Puijalon, D. E. Arnot, M. Wahlgren, et al. Generation of Cross-Protective Antibodies against Plasmodium falciparum Sequestration by Immunization with an Erythrocyte Membrane Protein 1-Duffy Binding-Like 1{alpha} Domain Infect. Immun., January 1, 2007; 75(1): 211 - 219. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Joergensen, L. S. Vestergaard, L. Turner, P. Magistrado, J. P. Lusingu, M. Lemnge, T. G. Theander, and A. T. R. Jensen 3D7-Derived Plasmodium falciparum Erythrocyte Membrane Protein 1 Is a Frequent Target of Naturally Acquired Antibodies Recognizing Protein Domains in a Particular Pattern Independent of Malaria Transmission Intensity J. Immunol., January 1, 2007; 178(1): 428 - 435. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Joergensen, L. Turner, P. Magistrado, M. A. Dahlback, L. S. Vestergaard, J. P. Lusingu, M. Lemnge, A. Salanti, T. G. Theander, and A. T. R. Jensen Limited Cross-Reactivity among Domains of the Plasmodium falciparum Clone 3D7 Erythrocyte Membrane Protein 1 Family Infect. Immun., December 1, 2006; 74(12): 6778 - 6784. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Rottmann, T. Lavstsen, J. P. Mugasa, M. Kaestli, A. T. R. Jensen, D. Muller, T. Theander, and H.-P. Beck Differential Expression of var Gene Groups Is Associated with Morbidity Caused by Plasmodium falciparum Infection in Tanzanian Children Infect. Immun., July 1, 2006; 74(7): 3904 - 3911. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. A. Lusingu, A. T. R. Jensen, L. S. Vestergaard, D. T. Minja, M. B. Dalgaard, S. Gesase, B. P. Mmbando, A. Y. Kitua, M. M. Lemnge, D. Cavanagh, et al. Levels of Plasma Immunoglobulin G with Specificity against the Cysteine-Rich Interdomain Regions of a Semiconserved Plasmodium falciparum Erythrocyte Membrane Protein 1, VAR4, Predict Protection against Malarial Anemia and Febrile Episodes. Infect. Immun., May 1, 2006; 74(5): 2867 - 2875. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
C. L. R. P. Yone, P. G. Kremsner, and A. J. F. Luty Immunoglobulin G Isotype Responses to Erythrocyte Surface-Expressed Variant Antigens of Plasmodium falciparum Predict Protection from Malaria in African Children Infect. Immun., April 1, 2005; 73(4): 2281 - 2287. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. C. Bonner, Z. Zhou, L. B. Mirel, J. G. Ayisi, Y. P. Shi, A. M. van Eijk, J. A. Otieno, B. L. Nahlen, R. W. Steketee, and V. Udhayakumar Placental Malaria Diminishes Development of Antibody Responses to Plasmodium falciparum Epitopes in Infants Residing in an Area of Western Kenya Where P. falciparum Is Endemic Clin. Vaccine Immunol., March 1, 2005; 12(3): 375 - 379. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S. ABDEL-LATIF, G. CABRERA, C. KOHLER, P. G. KREMSNER, and A. J. F. LUTY ANTIBODIES TO RIFIN: A COMPONENT OF NATURALLY ACQUIRED RESPONSES TO PLASMODIUM FALCIPARUM VARIANT SURFACE ANTIGENS ON INFECTED ERYTHROCYTES Am J Trop Med Hyg, August 1, 2004; 71(2): 179 - 186. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Muthusamy, R. N. Achur, M. Valiyaveettil, S. V. Madhunapantula, I. Kakizaki, V. P. Bhavanandan, and C. D. Gowda Structural characterization of the bovine tracheal chondroitin sulfate chains and binding of Plasmodium falciparum-infected erythrocytes Glycobiology, July 1, 2004; 14(7): 635 - 645. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Nielsen, L. S. Vestergaard, J. Lusingu, J. A. L. Kurtzhals, H. A. Giha, B. Grevstad, B. Q. Goka, M. M. Lemnge, J. B. Jensen, B. D. Akanmori, et al. Geographical and Temporal Conservation of Antibody Recognition of Plasmodium falciparum Variant Surface Antigens Infect. Immun., June 1, 2004; 72(6): 3531 - 3535. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. T.R. Jensen, P. Magistrado, S. Sharp, L. Joergensen, T. Lavstsen, A. Chiucchiuini, A. Salanti, L. S. Vestergaard, J. P. Lusingu, R. Hermsen, et al. Plasmodium falciparum Associated with Severe Childhood Malaria Preferentially Expresses PfEMP1 Encoded by Group A var Genes J. Exp. Med., May 3, 2004; 199(9): 1179 - 1190. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Cabrera, C. Yone, A. E. Tebo, J. van Aaken, B. Lell, P. G. Kremsner, and A. J. F. Luty Immunoglobulin G Isotype Responses to Variant Surface Antigens of Plasmodium falciparum in Healthy Gabonese Adults and Children during and after Successive Malaria Attacks Infect. Immun., January 1, 2004; 72(1): 284 - 294. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Garred, M. A. Nielsen, J. A.L. Kurtzhals, R. Malhotra, H. O. Madsen, B. Q. Goka, B. D. Akanmori, R. B. Sim, and L. Hviid Mannose-Binding Lectin Is a Disease Modifier in Clinical Malaria and May Function as Opsonin for Plasmodium falciparum- Infected Erythrocytes Infect. Immun., September 1, 2003; 71(9): 5245 - 5253. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Hviid, T. Staalsoe, M. A. Nielsen, and T. G. Theander Specificity and Cross-Reactivity of Plasmodium falciparum Variant Surface Antigen-Specific Antibody Responses Infect. Immun., April 1, 2003; 71(4): 2296 - 2296. [Full Text]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
D. J. Roberts Understanding Naturally Acquired Immunity to Plasmodium falciparum Malaria Infect. Immun., February 1, 2003; 71(2): 589 - 590. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
) P. falciparum malaria.
B, Ab recognition of isolates according to their origin
from young (•; 3–4 years of age) or older (
