Integral membrane protein located in the apical complex of Plasmodium falciparum.

Peterson, M G; Marshall, Vikki M.; Smythe, Jason A.; Crewther, Pauline E.; Lew, Andrew M.; Silva, A; Anders, Robin F.; Kemp, David J.

doi:10.1128/mcb.9.7.3151

Cited by 234 publications

(198 citation statements)

References 28 publications

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“…The parasite then, in a process mainly mediated by apical merozoite antigen-1 (AMA-1) protein, 11 orientates its apical pole to bring it into direct contact with the RBC. Parasite entry and invasion follows proteins being released from intracytoplasmic organelles (named micronemes and rhoptrias) [Fig-ure 1B], a process taking place in less than 40 s. Some of these membrane and microneme merozoite proteins are anchored to the surface by a glycosyl phosphatidyl inositol (GPI) tail or a transmembrane domain, establishing a strong interaction with RBC and aiding formation of the parasitophorous vacuole (PV) in which the merozoite multiplies.…”

Section: Rationale For Multiantigenic Multistage Vaccine Developmentmentioning

confidence: 99%

Emerging Rules for Subunit-Based, Multiantigenic, Multistage Chemically Synthesized Vaccines

2008

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S eventeen million people die of transmittable diseases and 2/3 of the world's population suffer them annually. Malaria, tuberculosis, AIDS, hepatitis, and reemerging and new diseases are a great threat to humankind. A logical and rational approach for vaccine development is thus desperately needed.Protein chemistry provides the best tools for tackling these problems. The tremendous complexity of microbes, the different pathways they use for invading host cells, and the immune responses they induce can only be resolved by using the minimum subunit-based (chemically produced ∼20-mer peptides), multiantigenic (most proteins involved in invasion), multistage (different invasion mechanisms) vaccine development approach.The most lethal form of malaria caused by Plasmodium falciparum (killing 3 million and affecting 500 million people worldwide annually) was used as target disease since many of its proteins, its invasion pathways, and its genome have been described recently. A New World primate (the Aotus monkey) is highly susceptibly to human malaria; its immune system molecules are 80 -100% identical to those of its human counterpart, making it an excellent model for vaccine development.Chemically synthesized ∼20-mer peptides, covering all the P. falciparum malaria proteins involved in red blood cell (RBC) invasion were synthesized by the classical t-Boc technology (based on synthetic SPf66 antimalarial vaccine information for identifying targets) and assayed in a highly sensitive, specific, and robust test for detecting receptor-ligand interactions between high-activity binding peptides (HABPs) and RBCs. HABPs were identified, some in which the molecule displays genetic variability (to be discarded due to their tremendous complexity) and elicits a strain-specific immune response and others that are conserved (no amino acid sequence variation).Conserved HABPs were synthesized in a polymeric form by adding cysteines at their N-and C-terminal ends to be used for monkey immunization. They became nonimmunogenic (no antibodies were induced) nonprotection inducers (monkeys were not protected against P. falciparum malaria challenge with a highly infective strain) suggesting a code of immunological silence or nonresponsiveness for these conserved HABPs.A large number of monkey trials involving a considerable number of Aotus monkeys were performed to break this code of immunological silence by replacing critical residues (determined by glycine peptide analogue scanning) to find that the following amino acid changes had to be made to render them antibody and protection inducing: FTR; WTY; LTH; ITN; MTK; PTD; QTE; CTT.The three-dimensional (3D) structure of >100 of these native modified HABPs (determined by 1 H NMR) revealed that the following structural changes had all to be achieved to allow a better fit into the major histocompatibility complex class II (MHC II)-peptide-TCR complex to properly activate the immune system: R-helix shortening, modifying their -turn, adopting segmental R-helix configuration, changing residue or...

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Section: Rationale For Multiantigenic Multistage Vaccine Developmentmentioning

confidence: 99%

Emerging Rules for Subunit-Based, Multiantigenic, Multistage Chemically Synthesized Vaccines

2008

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“…Two of these, TRAP (thrombospondin-related anonymous protein; [64]) and AMA-1 (apical membrane antigen 1; [65]), have been characterized in some detail and several lines of evidence support a role for these proteins in hepatocyte invasion.…”

Section: Sporozoite and Hepatocyte Proteins Involved In The Invasion mentioning

confidence: 99%

A long and winding road: The Plasmodium sporozoite's journey in the mammalian host

Sinnis

Coppi

2007

Parasitology International

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“…Included in this category are genes encoding secretory proteins such as apical membrane antigen 1 (AMA-1) that is found in P. falciparum, T. gondii, and E. tenella. AMA-1 is present on the parasite cell surface and has been implicated in host cell invasion by P. falciparum (Peterson et al 1989;Waters et al 1990) and T. gondii (Donahue et al 2000;Hehl et al 2000). Also included are other microneme proteins, likely involved in cell recognition (Soldati et al 2001), the major surface antigens (SAGs; Boothroyd et al 1997), and a number of proteins characterized from sporozoites or oocysts.…”

Section: Identification Of Genes Restricted To the Apicomplexamentioning

confidence: 99%

Gene Discovery in the Apicomplexa as Revealed by EST Sequencing and Assembly of a Comparative Gene Database

Li¹,

Brunk²,

Kissinger³

et al. 2003

Genome Res.

133

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Large-scale EST sequencing projects for several important parasites within the phylum Apicomplexa were undertaken for the purpose of gene discovery. Included were several parasites of medical importance (Plasmodium falciparum, Toxoplasma gondii) and others of veterinary importance (Eimeria tenella, Sarcocystis neurona, and Neospora caninum). A total of 55,192 ESTs, deposited into dbEST/GenBank, were included in the analyses. The resulting sequences have been clustered into nonredundant gene assemblies and deposited into a relational database that supports a variety of sequence and text searches. This database has been used to compare the gene assemblies using BLAST similarity comparisons to the public protein databases to identify putative genes. Of these new entries, ∼15%-20% represent putative homologs with a conservative cutoff of p < 10 −9 , thus identifying many conserved genes that are likely to share common functions with other well-studied organisms. Gene assemblies were also used to identify strain polymorphisms, examine stage-specific expression, and identify gene families. An interesting class of genes that are confined to members of this phylum and not shared by plants, animals, or fungi, was identified. These genes likely mediate the novel biological features of members of the Apicomplexa and hence offer great potential for biological investigation and as possible therapeutic targets.

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Integral membrane protein located in the apical complex of Plasmodium falciparum.

Cited by 234 publications

References 28 publications

Emerging Rules for Subunit-Based, Multiantigenic, Multistage Chemically Synthesized Vaccines

Emerging Rules for Subunit-Based, Multiantigenic, Multistage Chemically Synthesized Vaccines

A long and winding road: The Plasmodium sporozoite's journey in the mammalian host

Gene Discovery in the Apicomplexa as Revealed by EST Sequencing and Assembly of a Comparative Gene Database

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