Abstract
Clinical immunity to malaria develops after repeated exposure to Plasmodium falciparum parasites. Broadly reactive antibodies against parasite antigens expressed on the surface of infected erythrocytes (variable surface antigens; VSAs) are candidates for anti-malaria therapeutics and vaccines. Among the VSAs, several RIFIN, STEVOR, and SURFIN family members have been demonstrated to be targets of naturally acquired immunity against malaria. For example, RIFIN family members are important ligands for opsonization of P. falciparum infected erythrocytes with specific immunoglobulins (IgG) acquiring broad protective reactivity. However, the global repertoire of human anti-VSAs IgG, its variation in children, and the key protective targets remain poorly understood. Here, we report wheat germ cell-free system-based production and serological profiling of a comprehensive library of A-RIFINs, B-RIFINs, STEVORs, and SURFINs derived from the P. falciparum 3D7 parasite strain. We observed that >98% of assayed proteins (n = 265) were immunogenic in malaria-exposed individuals in Uganda. The overall breadth of immune responses was significantly correlated with age but not with clinical malaria outcome among the study volunteers. However, children with high levels of antibodies to four RIFINs (PF3D7_0201000, PF3D7_1254500, PF3D7_1040600, PF3D7_1041100), STEVOR (PF3D7_0732000), and SURFIN 1.2 (PF3D7_0113600) had prospectively reduced the risk of developing febrile malaria, suggesting that the 5 antigens are important targets of protective immunity. Further studies on the significance of repeated exposure to malaria infection and maintenance of such high-level antibodies would contribute to a better understanding of susceptibility and naturally acquired immunity to malaria.
Highlights
Acquired clinical immunity, such as protective immunity against febrile malaria, develops progressively after repeated exposure to Plasmodium falciparum [1]
Some early models of Repetitive interspersed family (RIFIN) and subtelomeric variable open reading frame (STEVOR) structure favored a two transmembrane topology [12], but the transmembrane prediction tool TMHMM [13, 14] and recent experimental data indicate a central hydrophobic stretch that may interact with the external face of erythrocyte membrane, a single C-terminal transmembrane domain [15, 16], and an N-terminal extracellular host ligand-binding domain [17, 18]
The C-terminal variable region is found between the central hydrophobic region and the transmembrane domain for all RIFINs and STEVORs
Summary
Acquired clinical immunity, such as protective immunity against febrile malaria, develops progressively after repeated exposure to Plasmodium falciparum [1]. During cyclic intra-erythrocytic development, the parasite exports numerous proteins to the surface of infected red blood cells (iRBCs) These exported proteins are collectively referred to as variable surface antigens (VSAs) and include P. falciparum erythrocyte membrane protein 1 (PfEMP1), surface-associated interspersed gene family (SURFIN), repetitive interspersed family (RIFIN) proteins, and subtelomeric variable open reading frame (STEVOR) proteins [2,3,4,5,6]. Numerous P. falciparum proteins interact with host immunity inducing an array of potentially protective antibodies making them important targets of naturally acquired immunity [31, 32]. The global repertoire of human antibodies against the VSA SURFINs, RIFINs, and STEVORs, and their association with protective immunity against clinical malaria remains unevaluated. The study allowed us to assess immune responses to a large panel of malaria proteins to identify potential targets of protective antibodies in clinical malaria
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
