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The humoral response to Plasmodium falciparum VarO rosetting variant and its association with protection against malaria in Beninese children.

Vigan-Womas I, Lokossou A, Guillotte M, Juillerat A, Bentley G, Garcia A, Mercereau-Puijalon O, Migot-Nabias F - Malar. J. (2010)

Bottom Line: Antibody responses were compared in the clinical groups.They were essentially stable, although levels tended to decrease with time.The mechanism of such protection seems independent of rosette-disruption, suggesting that the cytophilic properties of antibodies come into play.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institut Pasteur, Unité d'Immunologie Moléculaire des Parasites, F-75015 Paris, France.

ABSTRACT

Background: The capacity of Plasmodium falciparum-infected erythrocytes to bind uninfected erythrocytes (rosetting) is associated with severe malaria in African children. Rosetting is mediated by a subset of the variant surface antigens PfEMP1 targeted by protective antibody responses. Analysis of the response to rosette-forming parasites and their PfEMP1 adhesive domains is essential for understanding the acquisition of protection against severe malaria. To this end, the antibody response to a rosetting variant was analysed in children recruited with severe or uncomplicated malaria or asymptomatic P. falciparum infection.

Methods: Serum was collected from Beninese children with severe malaria, uncomplicated malaria or P. falciparum asymptomatic infection (N = 65, 37 and 52, respectively) and from immune adults (N = 30) living in the area. Infected erythrocyte surface-reactive IgG, rosette disrupting antibodies and IgG to the parasite crude extract were analysed using the single variant Palo Alto VarO-infected line. IgG, IgG1 and IgG3 to PfEMP1-varO-derived NTS-DBL1α1, CIDRγ and DBL2βC2 recombinant domains were analysed by ELISA. Antibody responses were compared in the clinical groups. Stability of the response was studied using a blood sampling collected 14 months later from asymptomatic children.

Results: Seroprevalence of erythrocyte surface-reactive IgG was high in adults (100%) and asymptomatic children (92.3%) but low in children with severe or uncomplicated malaria (26.1% and 37.8%, respectively). The IgG, IgG1 and IgG3 antibody responses to the varO-derived PfEMP1 domains were significantly higher in asymptomatic children than in children with clinical malaria in a multivariate analysis correcting for age and parasite density at enrolment. They were essentially stable, although levels tended to decrease with time. VarO-surface reactivity correlated positively with IgG reactivity to the rosetting domain varO-NTS-DBL1α1. None of the children sera, including those with surface-reactive antibodies possessed anti-VarO-rosetting activity, and few adults had rosette-disrupting antibodies.

Conclusions: Children with severe and uncomplicated malaria had similar responses. The higher prevalence and level of VarO-reactive antibodies in asymptomatic children compared to children with malaria is consistent with a protective role for anti-VarO antibodies against clinical falciparum malaria. The mechanism of such protection seems independent of rosette-disruption, suggesting that the cytophilic properties of antibodies come into play.

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Surface-reactive antibodies to single-variant culture of VarO-IE. Plasma samples were obtained from healthy adults (HA, n = 30) and children with asymptomatic P. falciparum infection (AP, n = 52), uncomplicated (UM, n = 37) or severe (SM, n = 65) malaria. For each child, antibodies (total IgG) reacting with the surface of live VarO-IE were analyzed by S-IFA and flow cytometry. Results are expressed in arbitrary units (AU, see Materials and Methods). (A) Prevalence (95% CI) of surface-reactive antibodies to VarO parasites in the four groups of individuals: HA, AP, UM or SM. (B) Surface reactivity levels in HA, AP, UM or SM children. Box-whisker plots illustrate medians with 25th and 75th percentiles, and whiskers for 10th and 90th percentiles. The outlying dots indicate values exceeding the 90th and 10th percentiles. The P values were estimated using the χ2 test (A) and the nonparametric Man-Whitney U-test (B). ***, P < 0.0001.
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Figure 1: Surface-reactive antibodies to single-variant culture of VarO-IE. Plasma samples were obtained from healthy adults (HA, n = 30) and children with asymptomatic P. falciparum infection (AP, n = 52), uncomplicated (UM, n = 37) or severe (SM, n = 65) malaria. For each child, antibodies (total IgG) reacting with the surface of live VarO-IE were analyzed by S-IFA and flow cytometry. Results are expressed in arbitrary units (AU, see Materials and Methods). (A) Prevalence (95% CI) of surface-reactive antibodies to VarO parasites in the four groups of individuals: HA, AP, UM or SM. (B) Surface reactivity levels in HA, AP, UM or SM children. Box-whisker plots illustrate medians with 25th and 75th percentiles, and whiskers for 10th and 90th percentiles. The outlying dots indicate values exceeding the 90th and 10th percentiles. The P values were estimated using the χ2 test (A) and the nonparametric Man-Whitney U-test (B). ***, P < 0.0001.

Mentions: Antibodies (total IgG) reacting with the VarO-IE surface were studied using a single-variant parasite culture with more than 95% IE at mature stages expressing the PfEMP1-varO adhesin. All healthy, immune adults reacted against the VarO-IE surface. Seroprevalence rate was higher in AP children (92.3%, 95% confidence interval [CI], 85.1 to 99.6) than in UM and SM children (37.8% [95% CI, 22.2 to 53.5] and 26.2% [95% CI, 15.5 to 37.8], respectively) (Figure 1A). This difference between AP children and children with clinical malaria was highly significant (χ2 test, P < 0001), but there was no statistical difference between UM and SM children as well as between UM and the CM sub-group of SM children.


The humoral response to Plasmodium falciparum VarO rosetting variant and its association with protection against malaria in Beninese children.

Vigan-Womas I, Lokossou A, Guillotte M, Juillerat A, Bentley G, Garcia A, Mercereau-Puijalon O, Migot-Nabias F - Malar. J. (2010)

Surface-reactive antibodies to single-variant culture of VarO-IE. Plasma samples were obtained from healthy adults (HA, n = 30) and children with asymptomatic P. falciparum infection (AP, n = 52), uncomplicated (UM, n = 37) or severe (SM, n = 65) malaria. For each child, antibodies (total IgG) reacting with the surface of live VarO-IE were analyzed by S-IFA and flow cytometry. Results are expressed in arbitrary units (AU, see Materials and Methods). (A) Prevalence (95% CI) of surface-reactive antibodies to VarO parasites in the four groups of individuals: HA, AP, UM or SM. (B) Surface reactivity levels in HA, AP, UM or SM children. Box-whisker plots illustrate medians with 25th and 75th percentiles, and whiskers for 10th and 90th percentiles. The outlying dots indicate values exceeding the 90th and 10th percentiles. The P values were estimated using the χ2 test (A) and the nonparametric Man-Whitney U-test (B). ***, P < 0.0001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2959068&req=5

Figure 1: Surface-reactive antibodies to single-variant culture of VarO-IE. Plasma samples were obtained from healthy adults (HA, n = 30) and children with asymptomatic P. falciparum infection (AP, n = 52), uncomplicated (UM, n = 37) or severe (SM, n = 65) malaria. For each child, antibodies (total IgG) reacting with the surface of live VarO-IE were analyzed by S-IFA and flow cytometry. Results are expressed in arbitrary units (AU, see Materials and Methods). (A) Prevalence (95% CI) of surface-reactive antibodies to VarO parasites in the four groups of individuals: HA, AP, UM or SM. (B) Surface reactivity levels in HA, AP, UM or SM children. Box-whisker plots illustrate medians with 25th and 75th percentiles, and whiskers for 10th and 90th percentiles. The outlying dots indicate values exceeding the 90th and 10th percentiles. The P values were estimated using the χ2 test (A) and the nonparametric Man-Whitney U-test (B). ***, P < 0.0001.
Mentions: Antibodies (total IgG) reacting with the VarO-IE surface were studied using a single-variant parasite culture with more than 95% IE at mature stages expressing the PfEMP1-varO adhesin. All healthy, immune adults reacted against the VarO-IE surface. Seroprevalence rate was higher in AP children (92.3%, 95% confidence interval [CI], 85.1 to 99.6) than in UM and SM children (37.8% [95% CI, 22.2 to 53.5] and 26.2% [95% CI, 15.5 to 37.8], respectively) (Figure 1A). This difference between AP children and children with clinical malaria was highly significant (χ2 test, P < 0001), but there was no statistical difference between UM and SM children as well as between UM and the CM sub-group of SM children.

Bottom Line: Antibody responses were compared in the clinical groups.They were essentially stable, although levels tended to decrease with time.The mechanism of such protection seems independent of rosette-disruption, suggesting that the cytophilic properties of antibodies come into play.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institut Pasteur, Unité d'Immunologie Moléculaire des Parasites, F-75015 Paris, France.

ABSTRACT

Background: The capacity of Plasmodium falciparum-infected erythrocytes to bind uninfected erythrocytes (rosetting) is associated with severe malaria in African children. Rosetting is mediated by a subset of the variant surface antigens PfEMP1 targeted by protective antibody responses. Analysis of the response to rosette-forming parasites and their PfEMP1 adhesive domains is essential for understanding the acquisition of protection against severe malaria. To this end, the antibody response to a rosetting variant was analysed in children recruited with severe or uncomplicated malaria or asymptomatic P. falciparum infection.

Methods: Serum was collected from Beninese children with severe malaria, uncomplicated malaria or P. falciparum asymptomatic infection (N = 65, 37 and 52, respectively) and from immune adults (N = 30) living in the area. Infected erythrocyte surface-reactive IgG, rosette disrupting antibodies and IgG to the parasite crude extract were analysed using the single variant Palo Alto VarO-infected line. IgG, IgG1 and IgG3 to PfEMP1-varO-derived NTS-DBL1α1, CIDRγ and DBL2βC2 recombinant domains were analysed by ELISA. Antibody responses were compared in the clinical groups. Stability of the response was studied using a blood sampling collected 14 months later from asymptomatic children.

Results: Seroprevalence of erythrocyte surface-reactive IgG was high in adults (100%) and asymptomatic children (92.3%) but low in children with severe or uncomplicated malaria (26.1% and 37.8%, respectively). The IgG, IgG1 and IgG3 antibody responses to the varO-derived PfEMP1 domains were significantly higher in asymptomatic children than in children with clinical malaria in a multivariate analysis correcting for age and parasite density at enrolment. They were essentially stable, although levels tended to decrease with time. VarO-surface reactivity correlated positively with IgG reactivity to the rosetting domain varO-NTS-DBL1α1. None of the children sera, including those with surface-reactive antibodies possessed anti-VarO-rosetting activity, and few adults had rosette-disrupting antibodies.

Conclusions: Children with severe and uncomplicated malaria had similar responses. The higher prevalence and level of VarO-reactive antibodies in asymptomatic children compared to children with malaria is consistent with a protective role for anti-VarO antibodies against clinical falciparum malaria. The mechanism of such protection seems independent of rosette-disruption, suggesting that the cytophilic properties of antibodies come into play.

Show MeSH
Related in: MedlinePlus