Targets of antibodies against Plasmodium falciparum–infected erythrocytes in malaria immunity

Abstract

Plasmodium falciparum is the major cause of malaria globally and is transmitted by mosquitoes. During parasitic development, P. falciparum-infected erythrocytes (P. falciparum-IEs) express multiple polymorphic proteins known as variant surface antigens (VSAs), including the P. falciparum erythrocyte membrane protein 1 (PfEMP1). VSA-specific antibodies are associated with protection from symptomatic and severe malaria. However, the importance of the different VSA targets of immunity to malaria remains unclear, which has impeded an understanding of malaria immunity and vaccine development. In this study, we developed assays using transgenic P. falciparum with modified PfEMP1 expression to quantify serum antibodies to VSAs among individuals exposed to malaria. We found that the majority of the human antibody response to the IE targets PfEMP1. Furthermore, our longitudinal studies showed that individuals with PfEMP1-specific antibodies had a significantly reduced risk of developing symptomatic malaria, whereas antibodies to other surface antigens were not associated with protective immunity. Using assays that measure antibody-mediated phagocytosis of IEs, an important mechanism in parasite clearance, we identified PfEMP1 as the major target of these functional antibodies. Taken together, these data demonstrate that PfEMP1 is a key target of humoral immunity. These findings advance our understanding of the targets and mediators of human immunity to malaria and have major implications for malaria vaccine development.

Critical Steps in Protein Export of Plasmodium falciparum Blood Stages

“…This is a rather mild phenotype considering that the inactivation of HSP101 inhibited the export of all classes of exported proteins, preventing a large number of effectors from reaching the host cell. The PTEX complex might therefore not seem to be the most optimal of drug targets, as specific inhibitors would require pharmacokinetic properties or treatment regimens to uphold drug levels past the 48 h. However, as many of the affected exported proteins, such as PfEMP1 and its trafficking factors, play a role in virulence [92], the in vivo effect of inhibiting export might be much more profound. Although PTEX knock down also affects gametocytes, it acts only on stages I and II, limiting the antitransmission effect for potential drugs.…”

Infectivity of Plasmodium falciparum in Malaria-Naive Individuals Is Related to Knob Expression and Cytoadherence of the Parasite

“…Antibodies to the surface of PEs predominantly recognize PfEMP1 (50). The 3D7 parasite was again used as a control.…”

The immunological balance between host and parasite in malaria

“…During maturation, the parasite exports parasite-encoded proteins to the iRBC membrane that enables the parasite to evade specific immune mechanisms (see Section 'Immune evasion mechanisms'). Abs against these parasite proteins are involved in opsonic phagocytosis of iRBCs and interfere with endothelial cytoadherence, and/or mediate rosetting (Bolad and Berzins 2000;Abdel-Latif et al 2004;Krause et al 2007;Ghumra et al 2011;Chan et al 2012). Furthermore, inhibition of parasite growth by entering of Abs inside the iRBC has been described and may be enhanced by monocytes in a process of Ab-dependent cellular inhibition mediated by Fcγ RII and TNF (Bouharoun-Tayoun et al 1995;Chimma et al 2009).…”