Immune Responses to the Sexual Stages of Plasmodium falciparum Parasites

Abstract

Malaria infections remain a serious global health problem in the world, particularly among children and pregnant women in Sub-Saharan Africa. Moreover, malaria control and elimination is hampered by rapid development of resistance by the parasite and the vector to commonly used antimalarial drugs and insecticides, respectively. Therefore, vaccine-based strategies are sorely needed, including those designed to interrupt disease transmission. However, a prerequisite for such a vaccine strategy is the understanding of both the human and vector immune responses to parasite developmental stages involved in parasite transmission in both man and mosquito. Here, we review the naturally acquired humoral and cellular responses to sexual stages of the parasite while in the human host and the Anopheles vector. In addition, updates on current anti-gametocyte, anti-gamete, and anti-mosquito transmission blocking vaccines are given. We conclude with our views on some important future directions of research into P. falciparum sexual stage immunity relevant to the search for the most appropriate transmission-blocking vaccine.

Keywords: Plasmodium falciparum; cellular immunity; gametocytes; humoral immunity; mosquito immunity.

Figure 1

Life cycle of P. falciparum development in the human host and mosquito vector. (1). Mosquito's bite and release sporozoites into the human host followed by migration into the liver. (2). Pre-erythrocytic schizogony: infection of hepatocytes and asexual multiplication of the parasites in the liver. (3). Erythrocytic schizogony: translocation of parasites from the liver into the bloodstream accompanied by asexual multiplication and release of merozoites upon RBC rupture. (4). Gametocyte generation: sexual commitment, sequestration of early gametocytes, maturation in tissues and release of mature gametocytes in blood (ready to be picked up by the vector). (5). Parasite development in the mosquito midgut: exflagellation of male gametocytes prior to fertilization which yields the zygote which undergoes further development into a motile ookinete. (6). Parasite development in the mosquito salivary gland: oocyst formation, sporozoite development, and release in the mosquito salivary gland (ready to be transmitted to the human host during subsequent mosquito bites).

Figure 2

Potential approaches for new vaccine candidate identification and vaccine development. This figure describes in a nutshell the life cycle of the Plasmodium species providing different stage-specific antigens and the strategies that could be used to develop more efficacious vaccine by combining potential vaccine candidates from various stages (host's and vector's). Uncharacterized and unknown antigens refer to proteins of unknown functions or proteins that have only been partially characterized such as the multigene families (var, rif, and stevor). The function of the proteins encoded by these multigene families have been tremendously studied in the asexual stages of Plasmodium but poorly exploited in their sexual counterparts. We propose that more attention should be paid to the sexual stages in terms of vaccine candidate identification and characterization. Nowadays, this could easily be done with the advent of Omics technologies. PfEMP-1, Plasmodium falciparum erythrocyte membrane protein-1; RIFINs, repetitive interspersed families of polypeptides; STEVORs, Subtelomeric variable open reading frame polypeptides; MSPs, Merozoite surface proteins; VAR2CSA, A variant of PfEMP-1 with high affinity to placental tissues; PfRHs, Plasmodium falciparum reticulocyte binding protein homologs; EBAs, Erythrocyte binding antigens; AMAs, Apical membrane antigens; CSP, Circumsporozoite protein; LSA-1, Liver-Stage Antigen; mTRAP, Merozoite thrombospondin-related anonymous protein; Pfs (230, 48/45, 25,28), Plasmodium falciparum gamete surface proteins (molecular weight in dalton); WARP, von Willebrand factor-A domain-related protein; CTRP, Circumsporozoite and TRAP-related protein; MAOP, Membrane-attack ookinete protein; SOAP, Secreted ookinete adhesive protein; CelTos, Cell-traversal protein for ookinetes and sporozoites; AnAPN1, An. Gambiae alanyl aminopeptidase; serpins, Serine protease inhibitors; saglin proteins.