Impact of Hemoglobin S Trait on Cell Surface Antibody Recognition of Plasmodium falciparum-Infected Erythrocytes in Pregnancy-Associated Malaria

Abstract

Background Sickle cell trait (HbAS) confers partial protection against malaria by reducing the adhesion of Plasmodium falciparum -infected erythrocytes to host receptors, but little is known about its potential protection against placental malaria. Methods Using flow cytometry, we assessed the recognition of HbAA and HbAS VAR2CSA-expressing infected erythrocytes, by plasma from 159 Beninese pregnant women with either HbAA (normal) or HbAS. Using multivariate linear models adjusted for gravidity, parasite infection at delivery, glucose-6-phosphate dehydrogenase deficiency, and α-thalassemia carriage, we observed significantly reduced cell surface antibody binding of HbAS-infected erythrocytes by plasma from HbAS compared with HbAA women ( P < 10 –3 ). Results The difference in cell surface antibody binding was only observed when infected erythrocytes and plasma were associated according to the same hemoglobin genotype. Similar levels of VAR2CSA-specific antibody were measured by enzyme-linked immunosorbent assay in the 2 groups, suggesting that the altered interaction between VAR2CSA and HbAS women’s antibodies could reflect abnormal display of VAR2CSA on HbAS erythrocytes. Conclusions Our data stress the need for assessments of erythrocyte disorders such as the sickle cell trait in a population group when studying immunological responses to P falciparum .

PfEMP1-Specific Immunoglobulin G Reactivity Among Beninese Pregnant Women With Sickle Cell Trait

“…Abnormal display of VAR2CSA on [ 21 , 23 ], and low antibody binding to [ 27 ], the surface of HbAS IEs have been documented previously. Whether this affects the functionality of antibodies elicited in response to these antigens has not been reported.…”

“…Previous studies reported similar IgG levels to VAR2CSA-type PfEMP1 proteins [ 27 ] and prevalence of P falciparum -IEs in the placenta [ 29 ] in HbAS and HbAA pregnant women, suggesting that both groups are equally exposed to VAR2CSA antigen, despite the protection against severe malaria enjoyed by HbAS individuals. As reported previously [ 27 ], levels of VAR2CSA-specific IgG among the Beninese women studied here did not differ significantly between HbAA and HbAS individuals ( Figure 2A and Supplementary Figure 1A ).…”

“…Previous studies reported similar IgG levels to VAR2CSA-type PfEMP1 proteins [ 27 ] and prevalence of P falciparum -IEs in the placenta [ 29 ] in HbAS and HbAA pregnant women, suggesting that both groups are equally exposed to VAR2CSA antigen, despite the protection against severe malaria enjoyed by HbAS individuals. As reported previously [ 27 ], levels of VAR2CSA-specific IgG among the Beninese women studied here did not differ significantly between HbAA and HbAS individuals ( Figure 2A and Supplementary Figure 1A ). A very high positive correlation for VAR2CSA-specific IgG levels against recombinant proteins expressed in 2 different systems was found (r s = 0.96; P < .0001) ( Supplementary Figure 1B ), documenting that the findings were not affected by the platform used to generate the recombinant full-length PfEMP1 proteins, as has previously been found in other cohorts [ 31 ].…”

“…Multiple studies in Africa have shown that HbAS provides significant protection against severe malaria (up to 90%) [ 24 ], but it does not protect against asymptomatic and low-density infection [ 25 ]. Moreover, it seems that HbAS does not protect against PM, because the prevalence of placental P falciparum infection [ 26 ] and the plasma levels of VAR2CSA-specific immunoglobulin (Ig)G [ 27 ] are similar in HbAS and HbAA women. Thus, it appears that both groups are equally exposed to IEs expressing VAR2CSA.…”

Sickle Cell Trait Modulates the Proteome and Phosphoproteome of Plasmodium falciparum-Infected Erythrocytes

“…In our proteomics works, statistical analyses were performed in order to conserve only proteins that were differentially phosphorylated or abundant in all the HbAS samples compared to all HbAA samples. Moreover, our cohort, albeit small, reflects the reality, as the co-carriage of HbS with G6PD deficiency and alpha-thalassemia are frequently found in malaria endemic areas ( Chauvet et al., 2019 ; Okafor et al., 2019 ). It is also important to note here that one of our donors, HbAS 1 , only has sickle cell trait.…”