Molecular characterization of Plasmodium falciparum PHISTb proteins as potential targets of naturally-acquired immunity against malaria [version 2; peer review: 3 approved with reservations]

Background: Plasmodium falciparum causes the deadliest form of malaria in humans. Upon infection, the host’s infected red blood cells (iRBCs) are remodelled by exported parasite proteins in order to provide a niche for parasite development and maturation.Methods: Here we analysed the role of three PHISTb proteins Pf3D7_0532400, Pf3D7_1401600, and Pf3D7_1102500 by expressing recombinant proteins and evaluated antibody responses against these proteins using immune sera from malaria-exposed individuals from Kenya and The Gambia in Africa. Results: Our findings show that children and adults from malaria-endemic regions recognized the three PHISTb proteins. Responses against the PHISTb proteins varied with malaria transmission intensity in three different geographical sites in Kenya (Siaya and Takaungu) and The Gambia (Sukuta). Antibody responses against PHISTb antigens Pf3D7_1102500 and Pf3D7_1401600 were higher in Sukuta, a low transmission region in the Gambia, as compared to Siaya, a high transmission region in western Kenya, unlike Pf3D7_0532400. Anti-PHIST responses show a negative correlation between antibody levels and malaria transmission intensity for two PHIST antigens, Pf3D7_1102500 and Pf3D7_1401600. However, we report a correlation in antibody responses between schizont extract and Pf3D7_0532400 (p=0.00582). Acquisition of anti-PHIST antibodies was correlated with exposure to malaria for PHISTb protein Pf3D7_0532400 (p=0.009) but not the other PHIST antigens Pf3D7_1102500 and Pf3D7_1401600 (p=0.507 and p=0.15, respectively, CI=95%). Children aged below 2 years had the lowest antibody levels, but the responses do not correlate with age differences.Conclusions: Collectively, these findings provide evidence of natural immunity against PHISTb antigens that varies with level of malaria exposure and underscore potential for these parasite antigens as possible serological markers to P. falciparum infection aimed at contributing to malaria control through vaccine development.