Functional and Immunological Characterization of a Duffy Binding-Like Alpha Domain from Plasmodium falciparum Erythrocyte Membrane Protein 1 That Mediates Rosetting

Abstract

The Duffy binding-like (DBL) domains are common adhesion modules present in Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) variants, which are responsible for immune evasion and cytoadherence. Knowledge about how immune responses are acquired against polymorphic DBL domains of PfEMP1 can aid in the development of vaccines for malaria. A recombinant DBL␣ domain, encoded by R29 var1, which binds complement receptor 1 to mediate rosetting by the P. falciparum laboratory strain R29, was expressed in Escherichia coli, renatured by oxidative refolding to its native form, and purified to homogeneity. Antibody levels in 704 plasmas obtained from residents of areas of different levels of malaria endemicity in Orissa (India) and Manhiça (Mozambique) were assessed by enzyme-linked immunosorbent assay. The refolded DBL␣ domain was pure, homogeneous, and functional in that it bound human erythrocytes with specificity and was capable of inhibiting rosetting. The proportion of individuals who had measurable anti-DBL␣ immunoglobulin G responses was low in areas of low malaria endemicity in Orissa (6.7%) but high in areas of high endemicity in Orissa (87.5%) and Manhiça (74.5%). Seroprevalence and antibody levels against the recombinant protein increased with the age of inhabitants from areas with high transmission rates (P < 0.001). Half of the children in these areas had seroconverted by the age of 5 years. These findings suggest that in spite of the extreme polymorphism of PfEMP1 DBL␣ domains, the acquisition of specific antibodies is rapid and age related and reflects the reduced risk of malaria in areas with high transmission rates. Further studies are required to elucidate the role of these antibodies in protection from malaria.

IgG Antibodies to Endothelial Protein C Receptor-Binding Cysteine-Rich Interdomain Region Domains of Plasmodium falciparum Erythrocyte Membrane Protein 1 Are Acquired Early in Life in Individuals Exposed to Malaria

“…The present study confirms earlier findings (48,52) that the level of malaria endemicity in the area of habitation has a profound effect on the pace by which the anti-PfEMP1 antibody repertoire is developed (Fig. 5).…”

Cytokine Profiling in Immigrants with Clinical Malaria after Extended Periods of Interrupted Exposure to Plasmodium falciparum

“…Non-pregnant women and men patients attending the Manhiça District Hospital with a diagnosis of P. falciparum clinical malaria in 2006 were enrolled into the study [24]. Clinical malaria was defined as the presence of asexual P.…”

High Antibody Responses against Plasmodium falciparum in Immigrants after Extended Periods of Interrupted Exposure to Malaria

“…Fifty semi-immune adults with P. falciparum clinical malaria were recruited at the Manhiça District Hospital in the context of a hospital-based study conducted at the Centro de Investigação em Saúde de Manhiça in 2006 [13]. Clinical malaria was defined as the presence of asexual P.…”

“…The P. falciparum erythrocyte membrane protein 1 ( Pf EMP-1) is the major antigen of this VSA family, containing several domains that mediate cytoadherence to host cells, like the Duffy binding-like alpha (DBL-α) domain that is involved in rosetting [13]. …”