Proteolysis of Plasmodium falciparum surface antigen, Pfs230, during gametogenesis

Brooks, S.R; Williamson, Kim C.

doi:10.1016/s0166-6851(99)00201-7

Cited by 43 publications

(29 citation statements)

References 21 publications

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“…Falcipain-1 likely also plays a role in other plasmodial life cycle stages. The processing of gametocyte (33) and sporozoite (P. Sinnis, personal communication) proteins is inhibited by cysteine protease inhibitors, and genomic (34) and proteomic (35) surveys identified falcipain-1 in sporozoites.…”

Section: Discussionmentioning

confidence: 99%

Plasmodium falciparum cysteine protease falcipain-1 is not essential in erythrocytic stage malaria parasites

Sijwali

Kato

Seydel

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

117

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Among potential new targets for antimalarial chemotherapy are Plasmodium falciparum cysteine proteases, known as falcipains. Falcipain-2 and falcipain-3 are food vacuole hemoglobinases that may have additional functions. The function of falcipain-1 remains uncertain. To better characterize the role of falcipain-1 in erythrocytic parasites, we disrupted the falcipain-1 gene and characterized recombinant parasites. Disruption of the falcipain-1 gene was confirmed with Southern blots, and loss of expression of falcipain-1 was confirmed with immunoblots and by loss of labeling with a specific protease inhibitor. Compared with wild-type parasites, falcipain-1 knockout parasites developed normally, with the same morphology, multiplication rate, and invasion efficiency, and without significant differences in sensitivity to cysteine protease inhibitors. In wild-type and knockout parasites, cysteine protease inhibitors blocked hemoglobin hydrolysis in trophozoites, with a subsequent block in rupture of erythrocytes by mature schizonts, but they did not inhibit erythrocyte invasion by merozoites. Our results indicate that although falcipain-1 is expressed by erythrocytic parasites, it is not essential for normal development during this stage or for erythrocyte invasion.

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Section: Discussionmentioning

confidence: 99%

Plasmodium falciparum cysteine protease falcipain-1 is not essential in erythrocytic stage malaria parasites

Sijwali

Kato

Seydel

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

117

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“…Pfs47 is a female-specific paralogue of Pfs48/45 located on the surfaces of female gametes following their emergence from erythrocytes, but it does not appear to be crucial for fertilization (498). Pfs230 is synthesized early in gametocyte development, similar to Pfs48/45 (233,499), and is derived from proteolytic cleavage of a 360-kDa precursor molecule into 300-and 35-kDa or 307-and 47-kDa forms (67,369,500). The 300-and 307-kDa membrane-associated Pfs230 fragments that do not contain a GPI anchor remain on the gamete surface (500, 516) as a complex with Pfs48/45 (139,232,233).…”

Section: Immune Responses Influencing Gametocyte Infectivitymentioning

confidence: 99%

Epidemiology and Infectivity of Plasmodium falciparum and Plasmodium vivax Gametocytes in Relation to Malaria Control and Elimination

2011

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SUMMARY Malaria remains a major cause of morbidity and mortality in the tropics, with Plasmodium falciparum responsible for the majority of the disease burden and P. vivax being the geographically most widely distributed cause of malaria. Gametocytes are the sexual-stage parasites that infect Anopheles mosquitoes and mediate the onward transmission of the disease. Gametocytes are poorly studied despite this crucial role, but with a recent resurgence of interest in malaria elimination, the study of gametocytes is in vogue. This review highlights the current state of knowledge with regard to the development and longevity of P. falciparum and P. vivax gametocytes in the human host and the factors influencing their distribution within endemic populations. The evidence for immune responses, antimalarial drugs, and drug resistance influencing infectiousness to mosquitoes is reviewed. We discuss how the application of molecular techniques has led to the identification of submicroscopic gametocyte carriage and to a reassessment of the human infectious reservoir. These components are drawn together to show how control measures that aim to reduce malaria transmission, such as mass drug administration and a transmission-blocking vaccine, might better be deployed.

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“…Membrane-permeant E64d has also been shown to inhibit the processing of the 360-kDa P. falciparum gametocyte surface antigen Pfs230 to 35-kDa and 300-kDa fragments during gametogenesis, while the production of the 47-kDa and the 307-kDa fragments is not affected. When the parasite emerges from the red blood cell (RBC) as a gamete in the mosquito midgut, 35-kDa and 47-kDa sections of the first 555 amino acids (aa) of Pfs230, which includes the immunodominant glutamate-rich repeat domains, are released as soluble fragments (3,24). In contrast, the 300-kDa and 307-kDa fragments remain associated with the gamete surface and are the targets of malaria parasite transmission-blocking monoclonal antibodies (3, 38).…”

mentioning

confidence: 99%

“…When the parasite emerges from the red blood cell (RBC) as a gamete in the mosquito midgut, 35-kDa and 47-kDa sections of the first 555 amino acids (aa) of Pfs230, which includes the immunodominant glutamate-rich repeat domains, are released as soluble fragments (3,24). In contrast, the 300-kDa and 307-kDa fragments remain associated with the gamete surface and are the targets of malaria parasite transmission-blocking monoclonal antibodies (3,38). Four papain-like cysteine proteases have been identified in the P. falciparum genome and have been named falcipains 1, 2A, 2B, and 3 (18,27).…”

mentioning

confidence: 99%

Inhibition of Plasmodium falciparum Oocyst Production by Membrane-Permeant Cysteine Protease Inhibitor E64d

Ekşi

Czesny

Gemert³

et al. 2007

Antimicrob Agents Chemother

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During asexual intraerythrocytic growth, Plasmodium falciparum utilizes hemoglobin obtained from the host red blood cell (RBC) as a nutrient source. Papain-like cysteine proteases, falcipains 2 and 3, have been reported to be involved in hemoglobin digestion and are targets of current antimalarial drug development efforts. However, their expression during gametocytogenesis, which is required for malaria parasite transmission, has not been studied. Many of the available antimalarials do not inhibit development of sexual stage parasites, and therefore, the persistence of gametocytes after drug treatment allows continued transmission of the disease. In the work reported here, incubation of stage V gametocytes with membrane-permeant cysteine protease inhibitor E64d significantly inhibited oocyst production (80 to 100%). The same conditions inhibited processing of gametocyte-surface antigen Pfs230 during gametogenesis but did not alter the morphology of the food vacuole in gametocytes, inhibit emergence, or block male exflagellation. E64d reduced the level of oocyst production more effectively than that reported previously for falcipain 1-knockout parasites, suggesting that falcipains 2 and 3 may also be involved in malaria parasite transmission. However, in this study only falcipain 3 and not falcipain 2 was found to be expressed in stage V gametocytes. Interestingly, during gametocytogenesis falcipain 3 was transported into the red blood cell and by stage V was localized in vesicles along the RBC surface, consistent with a role during gamete emergence. The ability of a membrane-permeant cysteine protease inhibitor to significantly reduce malaria parasite transmission suggests that future drug design should include evaluation of gametogenesis and sporogonic development.The clinical symptoms of malaria are caused by asexually replicating parasites, but malaria parasite transmission requires that a subpopulation of parasites undergo sexual differentiation. In the species of parasite responsible for the most virulent form of malaria, Plasmodium falciparum, complete maturation into mature stage V gametocytes takes 10 to 12 days in the human host. Once stage V gametocytes are taken up by a mosquito, gametogenesis is stimulated and, after fertilization, the zygote differentiates into an ookinete. The ookinete then migrates to the basal surface of the midgut and forms an oocyst, where tens of thousands of infectious sporozoites are produced.Both asexual and sexual stage parasites are present concurrently in an infected individual and therefore would both be exposed to antimalarial drugs. However, gametocytes have been found to be resistant to many of the commonly used antimalarials, such as the 4-aminoquinolines; and sulfadoxinepyrimethamine has been reported to increase the production of gametocytes, which could enhance transmission (2, 12, 21, 36). Consequently, even after successful treatment for clinical symptoms, an individual can still transmit the malaria parasite for at least a week. Therefore, it is important to d...

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Proteolysis of Plasmodium falciparum surface antigen, Pfs230, during gametogenesis

Cited by 43 publications

References 21 publications

Plasmodium falciparum cysteine protease falcipain-1 is not essential in erythrocytic stage malaria parasites

Plasmodium falciparum cysteine protease falcipain-1 is not essential in erythrocytic stage malaria parasites

Epidemiology and Infectivity of Plasmodium falciparum and Plasmodium vivax Gametocytes in Relation to Malaria Control and Elimination

Inhibition of Plasmodium falciparum Oocyst Production by Membrane-Permeant Cysteine Protease Inhibitor E64d

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