Plasmodium vivaxspleen-dependent genes encode antigens associated with cytoadhesion and clinical protection

Abstract

Plasmodium vivax, the most widely distributed human malaria parasite, causes severe clinical syndromes despite low peripheral blood parasitemia. This conundrum is further complicated as cytoadherence in the microvasculature is still a matter of investigations. Previous reports inPlasmodium knowlesi, another parasite species shown to infect humans, demonstrated that variant genes involved in cytoadherence were dependent on the spleen for their expression. Hence, using a global transcriptional analysis of parasites obtained from spleen-intact and splenectomized monkeys, we identified 67P. vivaxgenes whose expression was spleen dependent. To determine their role in cytoadherence, twoPlasmodium falciparumtransgenic lines expressing two variant proteins pertaining to VIR and Pv-FAM-D multigene families were used. Cytoadherence assays demonstrated specific binding to human spleen but not lung fibroblasts of the transgenic line expressing the VIR14 protein. To gain more insights, we expressed fiveP. vivaxspleen-dependent genes as recombinant proteins, including members of three different multigene families (VIR, Pv-FAM-A, Pv-FAM-D), one membrane transporter (SECY), and one hypothetical protein (HYP1), and determined their immunogenicity and association with clinical protection in a prospective study of 383 children in Papua New Guinea. Results demonstrated that spleen-dependent antigens are immunogenic in natural infections and that antibodies to HYP1 are associated with clinical protection. These results suggest that the spleen plays a major role in expression of parasite proteins involved in cytoadherence and can reveal antigens associated with clinical protection, thus prompting a paradigm shift inP. vivaxbiology toward deeper studies of the spleen during infections.

From Circulation to Cultivation: Plasmodium In Vivo versus In Vitro

“…The density of PfEMP1 knobs on the RBC surface ( Figure 1B), which mediate sequestration in P. falciparum to avoid physical filtration by the spleen, was reduced fivefold upon adaptation of ex vivo isolates to in vitro culture [31]. Transcription of many P. vivax cytoadherence genes was reduced in vivo in splenectomized Aotus monkeys relative to spleen-intact monkeys, demonstrating that Plasmodium cytoadherence is likely regulated by many factors, including serum lipoproteins [16], rheology [32], and splenic pressure [33].…”

Alternative Invasion Mechanisms and Host Immune Response to Plasmodium vivax Malaria: Trends and Future Directions

“…On the other hand, members of the TRAg gene family that were highly expressed in non-DARC Saimiri -infected P. vivax have also shown to induce antibody response in people from vivax-endemic regions. A recent study of 383 children in Papua New Guinea showed that antibodies against PvFAM-D2 were significantly more common in children with active P. vivax infections [ 159 ]. The coexpression of PvFAM-A2 and PvFAM-D2 proteins in infected reticulocytes is spleen-dependent, based on the Aotus monkey model [ 160 ].…”

“…Moreover, PVX_108770 (VIR14) of the multi-gene VIR family largely located at the subtelomeric regions also presented high sero-positivity, despite the role of its conserved globular domains in eliciting cross-reacting antibodies being unclear [ 162 , 163 ]. Other proteins, such as HYP, which is 100% conserved among P. vivax isolates from Mauritania, North Korea, India, and Brazil, and had antibodies significantly associated with protection against clinical P. vivax episodes in children [ 159 ], are a potential target of blood-stage vaccine. Taken together, it is possible that individuals with low-to-no DARC expression have lower susceptibility to infection than individuals having high DARC expression by eliciting high frequency and magnitude of anti-DBP, anti-MSP, anti-RBP, and anti-FAM antibody response against P. vivax during the blood stage.…”

Alternative Invasion Mechanisms and Host Immune Response to Plasmodium vivax Malaria: Trends and Future Directions

“…vivax infections [156]. The coexpression of PvFAM-A2 and PvFAM-D2 proteins in infected reticulocytes is spleen-dependent based on the Aotus monkey model [157].…”

“…Besides, PVX_108770 (VIR14) of the multi-gene VIR family largely located at the subtelomeric regions also presented high seropositivity, despite the role of its conserved globular domains in eliciting cross-reacting antibodies is unclear [159,160]. Other proteins such as HYP that is 100% conserved among P. vivax isolates from Mauritania, North Korea, India, and Brazil, and had antibodies significantly associated with protection against clinical P. vivax episodes in children [156], a potential target of blood-stage vaccine.…”