PfCCp proteins of Plasmodium falciparum: Gametocyte-specific expression and role in complement-mediated inhibition of exflagellation

Scholz, Sabrina; Simon, Nina; Lavazec, Catherine; Dude, Marie-Adrienne; Templeton, Thomas J.; Pradel, Gabriele

doi:10.1016/j.ijpara.2007.08.009

Cited by 73 publications

(111 citation statements)

References 52 publications

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“…46,47 By IFA, immunoglobulin G (IgG) negative control antibody did not generate fluorescence signal in either gametocytes or ookinetes, whereas antibodies to P. falciparum chitinase (PfCHT1) and Pfs25 produced fluorescent signals in gametocytes (as previously described for Pfs25) 48 and ookinetes ( Figure 4C -H ). The fluorescence signal was observed to be stronger in ookinetes than in gametocytes, with a distinct pattern consistent with surface localization of Pfs25 notable in ookinetes but not gametocytes.…”

Section: Pfs25 and Chitinase (Pfcht1) Detection In Gametocytes And Oosupporting

confidence: 69%

In Vitro Generation of Plasmodium falciparum Ookinetes

Bounkeua¹,

Li²,

Vinetz³

2010

The American Society of Tropical Medicine and Hygiene

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Plasmodium transmission from the human host to the mosquito depends on the ability of gametocytes to differentiate into ookinetes, the invasive form of the parasite that invades and establishes infection in the mosquito midgut. The biology of P. falciparum ookinetes is poorly understood, because sufficient quantities of this stage of this parasite species have not been obtained for detailed study. This report details methods to optimize production of P. falciparum sexual stage parasites, including ookinetes. Flow cytometric sorting was used to separate diploid/tetraploid zygotes and ookinetes from haploid gametetocytes and unfertilized gametes based on DNA content. Consistent production of 106–107 P. falciparum ookinetes per 10 mL culture was observed, with ookinete transformation present in 10–40% of all parasite forms. Transmission electron micrographs of cultured parasites confirmed ookinete development.

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Section: Pfs25 and Chitinase (Pfcht1) Detection In Gametocytes And Oosupporting

confidence: 69%

In Vitro Generation of Plasmodium falciparum Ookinetes

Bounkeua¹,

Li²,

Vinetz³

2010

The American Society of Tropical Medicine and Hygiene

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“…7). Interestingly, the anti-Pfs25 antiserum in response to EM081 and EM082 showed the typical rim fluorescence in female gamete and zygote stages and showed a previously observed cytoplasmic distribution of the protein in stage V gametocytes (34). The antiPfs25 antiserum raised by alum-based adjuvants (AL007 and AL019) showed a positive signal in the gamete stages but failed to show fluorescence in the zygote stages, possibly due to low-titer/low-affinity antibodies or the differential recognition of epitopes of Pfs25.…”

Section: Figmentioning

confidence: 62%

Alga-Produced Malaria Transmission-Blocking Vaccine Candidate Pfs25 Formulated with a Human Use-Compatible Potent Adjuvant Induces High-Affinity Antibodies That Block Plasmodium falciparum Infection of Mosquitoes

Patra

Carter

et al. 2015

Infect Immun

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A vaccine to prevent the transmission of malaria parasites from infected humans to mosquitoes is an important component for the elimination of malaria in the 21st century, yet it remains neglected as a priority of malaria vaccine development. The lead candidate for Plasmodium falciparum transmission-blocking vaccine development, Pfs25, is a sexual stage surface protein that has been produced for vaccine testing in a variety of heterologous expression systems. Any realistic malaria vaccine will need to optimize proper folding balanced against cost of production, yield, and potentially reactogenic contaminants. Here Chlamydomonas reinhardtii microalga-produced recombinant Pfs25 protein was formulated with four different human-compatible adjuvants (alum, Toll-like receptor 4 [TLR-4] agonist glucopyranosal lipid A [GLA] plus alum, squalene-oil-in-water emulsion, and GLA plus squalene-oil-in-water emulsion) and compared for their ability to induce malaria transmission-blocking antibodies. Alga-produced recombinant Pfs25 plus GLA plus squalene-oil-in-water adjuvant induced the highest titer and avidity in IgG antibodies, measured using alga-produced recombinant Pfs25 as the enzyme-linked immunosorbent assay (ELISA) antigen. These antibodies specifically reacted with the surface of P. falciparum macrogametes and zygotes and effectively prevented parasites from developing within the mosquito vector in standard membrane feeding assays. Alga-produced Pfs25 in combination with a human-compatible adjuvant composed of a TLR-4 agonist in a squalene-oil-in-water emulsion is an attractive new vaccine candidate that merits head-to-head comparison with other modalities of vaccine production and administration.A vaccine to prevent gametocytemic humans from infecting mosquitoes by inducing antibodies against sexual stage Plasmodium antigens, termed a transmission-blocking vaccine (TBV), was first demonstrated experimentally as proof of principle using a chicken model of Plasmodium gallinaceum more than 30 years ago (1, 2). TBV development has been stated to be a key priority toward achieving the global goals of malaria control and elimination (3, 4), yet it lags behind other malaria vaccine development despite candidate proteins such as Pfs25 being deeply studied as a TBV. Pfs25, the first molecularly cloned Plasmodium sexual stage protein, was identified more than 25 years ago and remains a lead TBV candidate (5, 6). Parasite-produced Pfs25 contains 4 epidermal growth factor (EGF)-like domains and is not glycosylated, which makes it biotechnologically challenging to produce the properly folded, conformationally correct recombinant protein(s) required for the induction of effective transmission-blocking antibodies (7-9). Heterologous expression systems used to produce Pfs25 as a recombinant subunit immunogen include Escherichia coli (10), Saccharomyces cerevisiae (11), Pichia pastoris (7, 12), baculovirus (13), Nicotiana benthamiana (14), Triticum vulgare (wheat germ) extract (6,15,16), and most recently, the chloroplast of the mic...

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“…Recombinant proteins were expressed in BL21(DE3) RIL cells according to the manufacturer's protocol (Stratagene). Inclusion bodies containing recombinant proteins were purified from bacterial extracts as described previously (44). Specific immune sera were generated by immunizing 6-week-old female NMRI mice (Charles River Laboratories) with 100 g recombinant protein emulsified in Freund's incomplete adjuvant (SigmaAldrich), followed by a second immunization after 4 weeks.…”

Section: Vol 55 2011 Thiostrepton Derivatives Target the Malaria Prmentioning

confidence: 99%

Thiostrepton and Derivatives Exhibit Antimalarial and Gametocytocidal Activity by Dually Targeting Parasite Proteasome and Apicoplast

Aminake

Schoof

Sologub

et al. 2011

Antimicrob Agents Chemother

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113

111

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Ribosome-targeting antibiotics exert their antimalarial activity on the apicoplast of the malaria parasite, an organelle of prokaryote origin having essential metabolic functions. These antibiotics typically cause a delayeddeath phenotype, which manifests in parasite killing during the second replication cycle following administration. As an exception, treatment with the antibiotic thiostrepton results in an immediate killing. We recently demonstrated that thiostrepton and its derivatives interfere with the eukaryotic proteasome, a multimeric protease complex that is important for the degradation of ubiquitinated proteins. Here, we report that the thiostrepton-based compounds are active against chloroquine-sensitive and -resistant Plasmodium falciparum, where they rapidly eliminate parasites before DNA replication. The minor parasite fraction that escapes the fast killing of the first replication cycle is arrested in the schizont stage of the following cycle, displaying a delayed-death phenotype. Thiostrepton further exhibits gametocytocidal activity by eliminating gametocytes, the sexual precursor cells that are crucial for parasite transmission to the mosquito. Compound treatment results in an accumulation of ubiquitinated proteins in the blood stages, indicating an effect on the parasite proteasome. In accordance with these findings, expression profiling revealed that the proteasome is present in the nucleus and cytoplasm of trophozoites, schizonts, and gametocytes. In conclusion, thiostrepton derivatives represent promising candidates for malaria therapy by dually acting on two independent targets, the parasite proteasome and the apicoplast, with the capacity to eliminate both intraerythrocytic asexual and transmission stages of the parasite.

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PfCCp proteins of Plasmodium falciparum: Gametocyte-specific expression and role in complement-mediated inhibition of exflagellation

Cited by 73 publications

References 52 publications

In Vitro Generation of Plasmodium falciparum Ookinetes

In Vitro Generation of Plasmodium falciparum Ookinetes

Alga-Produced Malaria Transmission-Blocking Vaccine Candidate Pfs25 Formulated with a Human Use-Compatible Potent Adjuvant Induces High-Affinity Antibodies That Block Plasmodium falciparum Infection of Mosquitoes

Thiostrepton and Derivatives Exhibit Antimalarial and Gametocytocidal Activity by Dually Targeting Parasite Proteasome and Apicoplast

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