Adhesion protein complexes of malaria gametocytes assemble following parasite transmission to the mosquito

Simon, Nina; Kuehn, Andrea; Williamson, Kim C.; Pradel, Gabriele

doi:10.1016/j.parint.2015.09.007

Cited by 35 publications

(60 citation statements)

References 21 publications

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“…This is the first report showing that a Pfs230-specific mAb with an IgG1 isotype, which does not activate complement by the classical pathway (33) may block transmission in the presence or absence of human complement (Table 1). This result suggests that the biological function of Pfs230 may be disrupted directly by the formation of an antigen-antibody complex or possibly interfere with the formation of Pfs230 protein complexes (34).…”

Section: Discussionmentioning

confidence: 99%

Structural and Immunological Characterization of Recombinant 6-Cysteine Domains of the Plasmodium falciparum Sexual Stage Protein Pfs230

MacDonald

Nguyen

Shimp

et al. 2016

Journal of Biological Chemistry

122

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Development of a Plasmodium falciparum (Pf) transmission blocking vaccine (TBV) has the potential to significantly impact malaria control. Antibodies elicited against sexual stage proteins in the human bloodstream are taken up with the blood meal of the mosquitoes and inactivate parasite development in the mosquito. In a phase 1 trial, a leading TBV identified as Pfs25-EPA/Alhydrogel appeared safe and immunogenic, however, the level of Pfs25-specific antibodies were likely too low for an effective vaccine. Pfs230, a 230-kDa sexual stage protein expressed in gametocytes is an alternative vaccine candidate. A unique 6-cysteine-rich domain structure within Pfs230 have thwarted its recombinant expression and characterization for clinical evaluation for nearly a quarter of a century. Here, we report on the identification, biochemical, biophysical, and immunological characterization of recombinant Pfs230 domains. Rabbit antibodies generated against recombinant Pfs230 domains blocked mosquito transmission of a laboratory strain and two field isolates using an ex vivo assay. A planned clinical trial of the Pfs230 vaccine is a significant step toward the potential development of a transmission blocking vaccine to eliminate malaria.Development of a malaria vaccine that effectively protects against parasite infection of both the natural host, Anopheles mosquitoes, and its secondary host, man, would effectively disrupt transmission and clinical disease. The most well known investigational vaccine against Plasmodium falciparum malaria that recently received a positive scientific opinion from the Committee for Medicinal Products for Human Use of the European Medicines Agency in July 2015, is identified as RTS,S (Mosquirix TM ). This vaccine targets the circumsporozoite protein that is present on the surface of the sporozoite, the parasite stage that infects man (1). RTS,S, a virus like-particle-based vaccine, is protective against clinical disease in about 30% of the young children who participated in a phase 3 trial (1, 2).Efforts toward development of a vaccine to disrupt parasite infection of the mosquito host, also identified as a transmission blocking vaccine have to date only been able to evaluate a sexual stage-specific protein, Pfs25, 2 which is a 25-kDa protein expressed on the zygote and ookinete surfaces. A phase 1 study demonstrated that human antibodies raised against a recombinant Pfs25 (Pfs25H) protein formulated in Montanide ISA 51, a water-in-oil adjuvant formulation, were biologically active in an ex vivo feeding assay (3), however, this formulation was not deemed suitable for a public health vaccine. More recently, in preclinical studies, Pfs25H has been shown to have enhanced immunogenic properties when chemically conjugated to a carrier molecule such as Neisseria meningitis outer membrane protein complex (4), or Pseudomonas aeruginosa ExoProtein A (EPA) (5, 6). In particular, the chemically conjugated Pfs25-EPA has the biophysical features of a nanoparticle with a diameter of about 25 m in solution, simil...

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Section: Discussionmentioning

confidence: 99%

Structural and Immunological Characterization of Recombinant 6-Cysteine Domains of the Plasmodium falciparum Sexual Stage Protein Pfs230

MacDonald

Nguyen

Shimp

et al. 2016

Journal of Biological Chemistry

122

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“…Several proteins have been linked to microgamete attachment to macrogametes, including the LCCL‐domain proteins (termed CCp proteins in P . falciparum ) and the six‐cys motif proteins Ps47, Ps48/45 and Ps230 (van Dijk et al ., 2001; Pradel et al ., 2004; van Schaijk et al ., 2006; Simon et al ., 2009, 2016). The latter two are considered as promising candidates for transmission blocking vaccines (reviewed in Pradel, 2007).…”

Section: The Formation Of Gametesmentioning

confidence: 99%

“…It has recently been shown that in P . falciparum Ps230, Ps48/45 and the six CCp proteins assemble to multi‐protein complexes, which are linked via P25 to the macrogamete surface (Simon et al ., 2009, 2016; reviewed in Kuehn et al ., 2010). …”

Section: The Formation Of Gametesmentioning

confidence: 99%

The development of malaria parasites in the mosquito midgut

Bennink

Kiesow

Pradel

2016

Cellular Microbiology

Self Cite

163

155

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SummaryThe mosquito midgut stages of malaria parasites are crucial for establishing an infection in the insect vector and to thus ensure further spread of the pathogen. Parasite development in the midgut starts with the activation of the intraerythrocytic gametocytes immediately after take‐up and ends with traversal of the midgut epithelium by the invasive ookinetes less than 24 h later. During this time period, the plasmodia undergo two processes of stage conversion, from gametocytes to gametes and from zygotes to ookinetes, both accompanied by dramatic morphological changes. Further, gamete formation requires parasite egress from the enveloping erythrocytes, rendering them vulnerable to the aggressive factors of the insect gut, like components of the human blood meal. The mosquito midgut stages of malaria parasites are unprecedented objects to study a variety of cell biological aspects, including signal perception, cell conversion, parasite/host co‐adaptation and immune evasion. This review highlights recent insights into the molecules involved in gametocyte activation and gamete formation as well as in zygote‐to‐ookinete conversion and ookinete midgut exit; it further discusses factors that can harm the extracellular midgut stages as well as the measures of the parasites to protect themselves from any damage.

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“…1B), all with roles in parasite sexual reproduction and development in the mosquito (Tomas et al, 2001; Pradel et al, 2004; Scholz et al, 2008; Simon et al, 2009, 2016). Thus far, this is the only report of s48/45 proteins as part of a larger complex.…”

Section: 6-cys Proteins In the Sexual Stagesmentioning

confidence: 99%

“…Following gametocyte activation, Pfs230 also establishes an interaction with the other PfCCp proteins stabilizing the complex on the membrane. Absence of Pfs230 or inhibition of its proteolytic cleavage results in degradation of PfCCp proteins (Simon et al, 2016). A different study also reports the interaction of Pfs230 with PfWL1, a newly identified WD40-repeat protein that might also be part of the PfCCp complex (von Bohl et al, 2015).…”

Section: 6-cys Proteins In the Sexual Stagesmentioning

confidence: 99%

The s48/45 six-cysteine proteins: mediators of interaction throughout the Plasmodium life cycle

Arredondo

Kappe

2017

International Journal for Parasitology

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During their life cycle Plasmodium parasites rely upon an arsenal of proteins that establish key interactions with the host or vector, and between the parasite sexual stages, with the purpose of ensuring infection, reproduction and proliferation. Among these is a group of secreted or membrane-anchored proteins known as the six-cysteine (6-cys) family. This is a small but important family with only 14 members thus far identified, each stage-specifically expressed during the parasite life cycle. 6-cys proteins often localize at the parasite surface or interface with the host and are conserved in different Plasmodium species. The unifying feature of the family is the s48/45 domain, presumably involved in adhesion and structurally related to Ephrins, the ligands of Eph receptors. The most prominent s48/45 members are currently under functional investigation and are being pursued as vaccine candidates. In this review, we examine what is known about the 6-cys family, their structure and function, and discuss future research directions.

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Adhesion protein complexes of malaria gametocytes assemble following parasite transmission to the mosquito

Cited by 35 publications

References 21 publications

Structural and Immunological Characterization of Recombinant 6-Cysteine Domains of the Plasmodium falciparum Sexual Stage Protein Pfs230

Structural and Immunological Characterization of Recombinant 6-Cysteine Domains of the Plasmodium falciparum Sexual Stage Protein Pfs230

The development of malaria parasites in the mosquito midgut

The s48/45 six-cysteine proteins: mediators of interaction throughout the Plasmodium life cycle

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