Characterisation of the rif and stevor Multigene Families in Plasmodium falciparum Isolates Sampled From Natural Infections

Parasite-derived variant surface antigens (VSA) expressed on the infected erythrocyte surface are important targets of naturally acquired protective immune responses against malaria. The three major VSA-encoding multigene families of Plasmodium falciparum, var, rif and stevor, exhibit high inter- and intra-strain genomic variability. The VSA component encoded by the var gene family, PfEMP1, comprises the major cytoadhesive ligand and the major antigenic target of protective antibodies. However, other VSA families, including those encoded by the rif and stevor multigene families, may also play important roles in malaria pathogenesis and immunity. However, the biological relevance of non-PfEMP1 VSA remains largely unknown. This thesis represents the first extensive analysis of sequence diversity and expression patterns of rif and stevor variant gene families in African field isolates of P. falciparum. The work details the characterization of rif and stevor gene repertoires of P. falciparum parasites from diverse geographical locations and identification of conserved genes in both P. falciparum and the related chimpanzee malaria parasite P. reichenowi. Both capillary sequencing and clone-free, 454 deep sequencing methods have been used to study changes in variant gene expression during asexual development of wild and culture-adapted isolates. Isolate- and stage-specific transcription patterns of rif and stevor genes were observed, and the major sets of transcripts in multiple isolates, including parasites that have been selected for different cytoadhesive phenotypes (resetting and adhesion to human brain endothelial cell lines) identified. The role of RIFIN antigens in the natural acquisition of antibodies to malaria was tested using a strain transcendent variant PF3D7_1253700 (PFL2585c). The hypervariable region of this RIFIN, expressed as a recombinant protein was used to purify naturally acquired human antibodies from sera from malaria-immune African adults. These antibodies recognized native RIFIN antigen on the surface of intact trophozoites showing that RIFINs for additional targets of naturally acquired antibodies that recognize the surface of parasite-infected red blood cells

Revisiting gametocyte biology in malaria parasites

Gametocytes are the only form of the malaria parasite that is transmissible to the mosquito vector. They are present at low levels in blood circulation and significant knowledge gaps exist in their biology. Recent reductions in the global malaria burden have brought the possibility of elimination and eradication, with renewed focus on malaria transmission biology as a basis for interventions. This review discusses recent insights into gametocyte biology in the major human malaria parasite, Plasmodium falciparum and related species

Plasmodium gametocytes display homing and vascular transmigration in the host bone marrow

Transmission of Plasmodium parasites to the mosquito requires the formation and development of gametocytes. Studies in infected humans have shown that only the most mature forms of Plasmodium falciparum gametocytes are present in circulation, whereas immature forms accumulate in the hematopoietic environment of the bone marrow. We used the rodent model Plasmodium berghei to study gametocyte behavior through time under physiological conditions. Intravital microscopy demonstrated preferential homing of early gametocyte forms across the intact vascular barrier of the bone marrow and the spleen early during infection and subsequent development in the extravascular environment. During the acute phase of infection, we observed vascular leakage resulting in further parasite accumulation in this environment. Mature gametocytes showed high deformability and were found entering and exiting the intact vascular barrier. We suggest that extravascular gametocyte localization and mobility are essential for gametocytogenesis and transmission of Plasmodium to the mosquito

Editorial: advances on the gametocyte biology, host immunity and vector stages to interrupt the transmission of malaria

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Naturally acquired immunity against immature Plasmodium falciparum gametocytes

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The acquisition of humoral immune responses targeting Plasmodium falciparum sexual stages in controlled human malaria infections

Individuals infected with P. falciparum develop antibody responses to intra-erythrocytic gametocyte proteins and exported gametocyte proteins present on the surface of infected erythrocytes. However, there is currently limited knowledge on the immunogenicity of gametocyte antigens and the specificity of gametocyte-induced antibody responses. In this study, we assessed antibody responses in participants of two controlled human malaria infection (CHMI) studies by ELISA, multiplexed bead-based antibody assays and protein microarray. By comparing antibody responses in participants with and without gametocyte exposure, we aimed to disentangle the antibody response induced by asexual and sexual stage parasites. We showed that after a single malaria infection, a significant anti-sexual stage humoral response is induced in malaria-naïve individuals, even after exposure to relatively low gametocyte densities (up to ~1,600 gametocytes/mL). In contrast to antibody responses to well-characterised asexual blood stage antigens that were detectable by day 21 after infection, responses to sexual stage antigens (including transmission blocking vaccine candidates Pfs48/45 and Pfs230) were only apparent at 51 days after infection. We found antigens previously associated with early gametocyte or anti-gamete immunity were highly represented among responses linked with gametocyte exposure. Our data provide detailed insights on the induction and kinetics of antibody responses to gametocytes and identify novel antigens that elicit antibody responses exclusively in individuals with gametocyte exposure. Our findings provide target identification for serological assays for surveillance of the malaria infectious reservoir, and support vaccine development by describing the antibody response to leading vaccine antigens after primary infection

Naturally acquired immunity against immature Plasmodium falciparum gametocytes

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