Acquired Antibody Responses against Plasmodium vivax Infection Vary with Host Genotype for Duffy Antigen Receptor for Chemokines (DARC)

Abstract

BackgroundPolymorphism of the Duffy Antigen Receptor for Chemokines (DARC) is associated with susceptibility to and the severity of Plasmodium vivax malaria in humans. P. vivax uses DARC to invade erythrocytes. Individuals lacking DARC are ‘resistant’ to P. vivax erythrocytic infection. However, susceptibility to P. vivax in DARC+ individuals is reported to vary between specific DARC genotypes. We hypothesized that the natural acquisition of antibodies to P. vivax blood stages may vary with the host genotype and the level of DARC expression. Furthermore, high parasitemia has been reported to effect the acquisition of immunity against pre-erythrocytic parasites. We investigated the correlation between host DARC genotypes and the frequency and magnitude of antibodies against P. vivax erythrocytic stage antigens.Methodology/FindingsWe assessed the frequencies and magnitudes of antibody responses against P. vivax and P. falciparum sporozoite and erythrocytic antigens in Colombian donors from malaria-endemic regions. The frequency and level of naturally-acquired antibodies against the P. vivax erythrocytic antigens merozoite surface protein 1 (PvMSP1) and Duffy binding protein (PvDBP) varied with the host DARC genotypes. Donors with one negative allele (FY*B/FY*Bnull and FY*A/FY*Bnull) were more likely to have anti-PvMSP1 and anti-PvDBP antibodies than those with two positive alleles (FY*B/FY*B and FY*A/FY*B). The lower IgG3 and IgG1 components of the total IgG response may account for the decreased responses to P. vivax erythrocytic antigens with FY*A/FY*B and FY*B/FY*B genotypes. No such association was detected with P. falciparum erythrocytic antigens, which does not use DARC for erythrocyte invasion.Conclusion/SignificanceIndividuals with higher DARC expression, which is associated with higher susceptibility to P. vivax infection, exhibited low frequencies and magnitudes of P. vivax blood-stage specific antibody responses. This may indicate that one of the primary mechanisms by which P. vivax evades host immunity is through DARC indirectly down-regulating humoral responses against erythrocytic invasion and development.

Platform for Plasmodium vivax vaccine discovery and development

“…In Colombia, despite the low transmission of P. vivax infection, a high prevalence of anti-DBP antibodies (40%) was observed in sera from Fy+ individuals from the Pacific coast, particularly in those > 40 years old (Michon et al 1998). This is in contrast to recent studies in the northern endemic region where only 9% of the Fy+ sera showed reactivity against a DBP recombinant protein (Maestre et al 2010). …”

“…As a result, individuals who lack Fy antigen (Fy-) are naturally protected from P. vivax blood infection (Herrera et al 2005b). This antigen has been tested with sera from PNG, the Brazilian Amazon and Colombia (Herrera et al 2005b, King et al 2008, Cole-Tobian et al 2009, Maestre et al 2010). In different populations of the Brazilian Amazon, anti-DBP antibodies were detected and shown to correlate with long-term exposure to malaria (Ceravolo et al 2009, Souza-Silva et al 2010).…”

Plasmodium vivax Pre-Erythrocytic–Stage Antigen Discovery: Exploiting Naturally Acquired Humoral Responses

“…However, if the responses to a novel vivax protein were significantly stronger in Fy+ than Fy− populations, this finding would indicate that the antigen was more likely to be expressed by P. vivax erythrocytic-stage parasites. 14,16 Pre-erythrocytic and multistage proteins. Reactivity to proteins on the array was compared using sera from 28 Fy− and 32 Fy+ individuals (Figure 3).…”

“…14 The lack of DARC on Fy− erythrocytes and the resulting prevention or reduction of blood-stage parasitemia may consequently reduce the frequency of exposure to erythrocytic parasites in the Fy− population compared with the Fy+ population. [14][15][16] Furthermore, it has been shown that, in both murine (P. yoelii) and human (P. falciparum) malaria, bloodstage infections suppress T-cell responses against liver-stage antigens. [17][18][19] Immune responses to P. vivax pre-erythrocyticstage antigens may, therefore, be stronger in Fy− than Fy+ individuals, because exposure of Fy− individuals to erythrocytic parasites in the bloodstream would be limited.…”

Anticorpos contra a proteína de ligação em Duffy (PvDBP) e proteção contra a malária vivax na Amazônia rural brasileira.

“…Além da variação alélica de PvDBP, existem evidências de que polimorfismos genéticos do hospedeiro possam afetar a resposta imune humoral contra malária vivax (KING et al, 2011;MAESTRE et al, 2010). Nesse sentido, um trabalho publicado por King et al (2011) Como já mencionado, a interação entre PvDBP-DARC é necessária para o sucesso na invasão de P. vivax, logo, a ausência desse receptor nas hemácias de indivíduos Duffy negativos confere proteção em relação a doença causada por P. vivax (MILLER et al, 1976).…”