Merozoite surface coat precursor protein completely protects Aotus monkeys against Plasmodium falciparum malaria.

Siddiqui, Wasim A.; Tam, Leslie Q.; Kramer, Kenton J.; Hui, George; Case, S. E.; Yamaga, Karen; Chang, Sandra P.; Chan, Eugene B. T.; Kan, Siu-Chow

doi:10.1073/pnas.84.9.3014

Cited by 249 publications

(147 citation statements)

References 35 publications

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“…Strong diversifying selections on microneme proteins have been detected (e.g., AMA-1 and EBA-175), suggesting that polymorphism of these proteins has been maintained to evade host immunity in parasite populations [17,18]. Antibodies against the PfRhopH complex partially inhibit the growth of P. falciparum in vitro and in vivo, consistent with its potential as a vaccine target [19][20][21]. Although the RhopH complex has been shown to induce host protective immunity and is likely to be under host immune pressure, the genetic diversity and immunologic characteristics of this complex are not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Diversity and evolution of the rhoph1/clag multigene family of Plasmodium falciparum

Iriko

Kaneko

Otsuki

et al. 2008

Molecular and Biochemical Parasitology

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A complex of high molecular mass proteins (PfRhopH) of the human malaria parasite Plasmodium falciparum induces host protective immunity and therefore is a candidate for vaccine development. Understanding the level of polymorphism and the evolutionary processes is important for advancements in both vaccine design and knowledge of the evolution of cell invasion in this parasite. In the present study, we sequenced the entire open reading frames of seven genes encoding the proteins of the PfRhopH complex (rhoph2, rhoph3, and five rhoph1/clag gene paralogs). We found that four rhoph1/clag genes (clag2, 3.1, 3.2, and 8) were highly polymorphic. Amino acid substitutions and indels are predominantly clustered around amino acid positions 1000-1200 of these four rhoph1/clag genes. An excess of nonsynonymous substitutions over synonymous substitutions was detected for clag8 and 9, indicating positive selection. The McDonald-Kreitman test with a Plasmodium reichenowi orthologous sequence also supports positive selection on clag8. Based on the ratio of interspecific genetic distance to intraspecific distance, the time to the most recent common ancestor of the clag2 and 8 polymorphisms was estimated to be 1.89 and 0.87 million years ago, respectively, assuming divergence of P. falciparum and P. reichenowi 6 million years ago. In addition to a copy number polymorphism, gene conversion events were detected for the rhoph1/clag genes on chromosome 3, which likely play a role in increasing the diversity of each locus. Our results indicate that a high diversity of the PfRhopH1/Clag multigene family is maintained by diversifying selection forces over a considerably long period.

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Section: Introductionmentioning

confidence: 99%

Diversity and evolution of the rhoph1/clag multigene family of Plasmodium falciparum

Iriko

Kaneko

Otsuki

et al. 2008

Molecular and Biochemical Parasitology

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“…It is a potential vaccine candidate because it is directly exposed and interacts with the host milieu during RBC invasion. The MSP1 precursor protein, which has been shown to induce complete protection against Plasmodium falciparum in monkeys (5), is processed by proteases into a number of fragments. The primary processing at schizont rupture cleaves the precursor protein into major fragments of ϳ83 (MSP1 83 ), 30 (MSP1 30 ), 38 (MSP1 38 ), and 42 (MSP1 42 ) kDa.…”

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confidence: 99%

Identification of T Cell Epitopes on the 33-kDa Fragment of Plasmodium yoelii Merozoite Surface Protein 1 and Their Antibody-Independent Protective Role in Immunity to Blood Stage Malaria

Wipasa

Hirunpetcharat

Mahakunkijcharoen

et al. 2002

The Journal of Immunology

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Merozoite surface protein 1 (MSP1) of malaria parasites undergoes proteolytic processing at least twice before invasion into a new RBC. The 42-kDa fragment, a product of primary processing, is cleaved by proteolytic enzymes giving rise to MSP133, which is shed from the merozoite surface, and MSP119, which is the only fragment carried into a new RBC. In this study, we have identified T cell epitopes on MSP133 of Plasmodium yoelii and have examined their function in immunity to blood stage malaria. Peptides 20 aa in length, spanning the length of MSP133 and overlapping each other by 10 aa, were analyzed for their ability to induce T cell proliferation in immunized BALB/c and C57BL/6 mice. Multiple epitopes were recognized by these two strains of mice. Effector functions of the dominant epitopes were then investigated. Peptides Cm15 and Cm21 were of particular interest as they were able to induce effector T cells capable of delaying growth of lethal P. yoelii YM following adoptive transfer into immunodeficient mice without inducing detectable Ab responses. Homologs of these epitopes could be candidates for inclusion in a subunit vaccine.

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“…A major focus has been on synthetic peptides or recombinant proteins of cell surface antigens (2)(3)(4)(5)(6). However, this approach has not been highly effective, although immunization with native cell surface proteins purified from the erythrocytic stage parasite is known to confer significant protective immunity (7)(8)(9)(10). It is plausible that post-translational modifications play an important role in antigenicity.…”

mentioning

confidence: 99%

Glycosylphosphatidylinositol Anchors Represent the Major Carbohydrate Modification in Proteins of Intraerythrocytic Stage Plasmodium falciparum

Gowda

Gupta

Davidson

1997

Journal of Biological Chemistry

135

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The nature and extent of carbohydrate modification in intraerythrocytic stage Plasmodium falciparum proteins have been controversial. This study describes the characterization of the carbohydrates in intraerythrocytic P. falciparum proteins and provides an overall picture of the nature of carbohydrate modification in the parasite proteins. P. falciparum strains were metabolically labeled with radioactive sugar precursors and ethanolamine at different developmental stages. The individual parasite proteins separated on SDS-polyacrylamide gels and whole parasite cell lysates were analyzed for the carbohydrate moieties. The results established the following: 1) glycosylphosphatidylinositol (GPI) anchors represent the major carbohydrate modification in the intraerythrocytic stage P. falciparum proteins; 2) in contrast to previous reports, O-linked carbohydrates are either absent or present only at very low levels in the parasite; and 3) P. falciparum contains low levels of N-glycosylation capability. The amount of N-linked carbohydrates in whole parasite proteins is ϳ6% compared with the GPI anchors attached to proteins based on radioactive GlcN incorporated into the proteins.The glycan cores of multiple parasite protein GPI anchors are all similar, consisting of protein-ethanolamine-phosphate-(Man␣1-2)6Man␣1-2Man␣1-6Man␣1-4GlcN. The fourth Man residues distal to GlcN of the GPI anchor glycan cores contain unidentified substituents that are susceptible to conditions of nitrous acid deamination. This unusual structural feature may contribute to the reported pathogenic properties of the P. falciparum GPI anchors.Malaria, a life-threatening disease caused by parasitic protozoa of the genus Plasmodium, is a major health problem throughout the tropical and subtropical regions of the world. Among the four species that infect humans, Plasmodium falciparum is the most virulent. New approaches such as vaccine development and novel therapeutic agents are urgently needed due to the emergence of parasite strains resistant to chloroquine and other commonly used drugs (1).Vaccines based on antigens of the blood stage parasite are under intensive study. A major focus has been on synthetic peptides or recombinant proteins of cell surface antigens (2-6). However, this approach has not been highly effective, although immunization with native cell surface proteins purified from the erythrocytic stage parasite is known to confer significant protective immunity (7-10). It is plausible that post-translational modifications play an important role in antigenicity. Accordingly, a basic understanding of such modifications may assist in the development of effective vaccines.Glycosylation is an often extensive post-translational modification of eukaryotic proteins. Carbohydrate moieties of glycoproteins perform a variety of functions including modulation of immunological properties, receptor-ligand interactions, sorting and localization of proteins, cell adhesion, and cell-cell communication (11). In addition, they contribute to protein conform...

show abstract

Merozoite surface coat precursor protein completely protects Aotus monkeys against Plasmodium falciparum malaria.

Cited by 249 publications

References 35 publications

Diversity and evolution of the rhoph1/clag multigene family of Plasmodium falciparum

Diversity and evolution of the rhoph1/clag multigene family of Plasmodium falciparum

Identification of T Cell Epitopes on the 33-kDa Fragment of Plasmodium yoelii Merozoite Surface Protein 1 and Their Antibody-Independent Protective Role in Immunity to Blood Stage Malaria

Glycosylphosphatidylinositol Anchors Represent the Major Carbohydrate Modification in Proteins of Intraerythrocytic Stage Plasmodium falciparum

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