Analysis of Antibodies to Newly Described Plasmodium falciparum Merozoite Antigens Supports MSPDBL2 as a Predicted Target of Naturally Acquired Immunity

Abstract

Prospective studies continue to identify malaria parasite genes with particular patterns of polymorphism which indicate they may be under immune selection, and the encoded proteins require investigation. Sixteen new recombinant protein reagents were designed to characterize three such polymorphic proteins expressed in Plasmodium falciparum schizonts and merozoites: MSPDBL1 (also termed MSP3.4) and MSPDBL2 (MSP3.8), which possess Duffy binding-like (DBL) domains, and SURFIN4.2, encoded by a member of the surface-associated interspersed (surf) multigene family. After testing the antigenicities of these reagents by murine immunization and parasite immunofluorescence, we analyzed naturally acquired antibody responses to the antigens in two cohorts in coastal Kenya in which the parasite was endemic (Chonyi [n = 497] and Ngerenya [n = 461]). As expected, the prevalence and levels of serum antibodies increased with age. We then investigated correlations with subsequent risk of clinical malaria among children <11 years of age during 6 months follow-up surveillance. Antibodies to the polymorphic central region of MSPDBL2 were associated with reduced risk of malaria in both cohorts, with statistical significance remaining for the 3D7 allelic type after adjustment for individuals' ages in years and antibody reactivity to whole-schizont extract (Chonyi, risk ratio, 0.51, and 95% confidence interval [CI], 0.28 to 0.93; Ngerenya, risk ratio, 0.38, and 95% CI, 0.18 to 0.82). For the MSPDBL1 Palo Alto allelic-type antigen, there was a protective association in one cohort (Ngerenya, risk ratio, 0.53, and 95% CI, 0.32 to 0.89), whereas the other antigens showed no protective associations after adjustment. These findings support the prediction that antibodies to the polymorphic region of MSPDBL2 contribute to protective immunity.

The Merozoite Surface Protein 1 Complex Is a Platform for Binding to Human Erythrocytes by Plasmodium falciparum

“…This is indicative of the important roles of the DBL domains within MSPDBL1 and -2 and is consistent with the inability to disrupt the function of both within the same parasite. Indeed, evidence is accumulating that these proteins are important targets of immunity, and increased exposure to these antigens, in particular MSPDBL2, has been associated with reduced risk of malaria (50). We have shown in this study that antibodies targeting both MSPDBL1 and MSPDBL2 had the ability to directly inhibit binding to host erythrocytes.…”

Host–parasite interactions that guide red blood cell invasion by malaria parasites

“…Lin and colleagues [16] identified a functional complex of MSP1 with MSPDBL1 and MSPDBL2, both of which were shown to bind RBCs. In P. falciparum infections in Kenya, the presence of serum antibodies to MSPDBL2 is associated with protective effects from malaria [17], supporting a study demonstrating strong selection on the gene [18]. …”

Out of Africa: origins and evolution of the human malaria parasites Plasmodium falciparum and Plasmodium vivax

“…The genome sequences of additional parasites, in particular P. praefalciparum and ape P. vivax, will provide templates for mechanistic studies and in vitro genome manipulations to compare the function of key proteins among the various ape and human Plasmodium spp. Population genomic studies of ape Laverania parasites may also inform ongoing malaria vaccine development efforts by identifying antigens that are under strong immune selection pressure in apes as well as humans (Ochola et al, 2010; Amambua-Ngwa et al, 2012; Tetteh et al, 2013). In this context, it will be important to further characterize the transmitting vectors of ape Plasmodium parasites and assess to what extent humans are exposed to these parasites through the bites of infected mosquitoes.…”

“…This suggests some form of selection that maintains divergent allelic types over very long periods of time, analogous, for example, to the trans-specific polymorphism of self-incompatibility alleles in a family of flowering plants (Solanaceae), which may date to more than 30 million years (Myr) ago (Ioerger et al, 1990). Although the mechanism(s) that maintain the dimorphic msp alleles in P. falciparum remain largely unknown (Roy and Ferreira, 2015), some genes appear to be under balancing selection (Ochola et al, 2010; Amambua-Ngwa et al, 2012) and represent targets of allele type-specific antibody responses that confer protective immunity against malaria (Polley et al, 2007; Tetteh et al, 2013). …”