Polymorphism in the gene encoding the apical membrane antigen-1 (AMA-1) of Plasmodium falciparum. X. Asembo Bay Cohort Project

Escalante, Ananías A.; Grebert, Heather M.; Chaiyaroj, Sansanee C.; Magris, Magda; Biswas, Subrata; Nahlen, Bernard L.; Lal, Altaf A.

doi:10.1016/s0166-6851(01)00229-8

Cited by 113 publications

(117 citation statements)

References 31 publications

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“…For example, antibodies to strain 3D7 AMA1 were noninhibitory for strain W2mef, and this was shown to be due to the AMA1 sequence differences of these two strains (20). This result is consistent with analyses of AMA1 sequences which indicate that the ama1 gene is under diversifying selection (21)(22)(23). The recent demonstration that anti-AMA1 antibodies in humans are associated with protection from malaria (24) provides support for the view that AMA1 polymorphisms are being selected in response to naturally acquired protective immune responses of humans.…”

supporting

confidence: 68%

“…A set of 129 nonredundant P. falciparum AMA1 sequences was compiled from several studies (21)(22)(23)41). The lowest coverage was at the N terminus of the crystallized region (34 sequences).…”

Section: Analysis Of Polymorphismsmentioning

confidence: 99%

“…Both are bound by inhibitory antibodies in vitro, and the clustering of polymorphisms suggests that they are both targets of protective antibody responses in humans (21,(26)(27)(28)(29). Domain I is conserved among Plasmodium species and in other apicomplexan parasites.…”

mentioning

confidence: 99%

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Structure of AMA1 from Plasmodium falciparum reveals a clustering of polymorphisms that surround a conserved hydrophobic pocket

Bai

Becker

Gupta

et al. 2005

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

190

267

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Apical membrane antigen 1 (AMA1) is a leading malaria vaccine candidate that possesses polymorphisms that may pose a problem for a vaccine based on this antigen. Knowledge of the distribution of the polymorphic sites on the surface of AMA1 is necessary to obtain a detailed understanding of their significance for vaccine development. For this reason we have sought to determine the three-dimensional structure of AMA1 using x-ray crystallography. The central two-thirds of AMA1 is relatively conserved among Plasmodium species as well as more distantly related apicomplexan parasites, and contains two clusters of disulfide-bonded cysteines termed domains I and II. The crystal structure of this fragment of AMA1 reported here reveals that domains I؉II consists of two intimately associated PAN domains. PAN domain I contains many long loops that extend from the domain core and form a scaffold for numerous polymorphic residues. This extreme adaptation of a PAN domain reveals how malaria parasites have introduced significant flexibility and variation into AMA1 to evade protective human antibody responses. The polymorphisms on the AMA1 surface are exclusively located on one side of the molecule, presumably because this region of AMA1 is most accessible to antibodies reacting with the parasite surface. Moreover, the most highly polymorphic residues surround a conserved hydrophobic trough that is ringed by domain I and domain II loops. Precedents set by viral receptor proteins would suggest that this is likely to be the AMA1 receptor binding pocket.

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supporting

confidence: 68%

Section: Analysis Of Polymorphismsmentioning

confidence: 99%

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Structure of AMA1 from Plasmodium falciparum reveals a clustering of polymorphisms that surround a conserved hydrophobic pocket

Bai

Becker

Gupta

et al. 2005

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

190

267

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“…21,22 The sequencing of the highly variable AMA1 gene 23,24 in some samples further increased the power to identify different strains of P. falciparum. It is remarkable that only a single P. falciparum strain was detected in all tested samples.…”

Section: Discussionmentioning

confidence: 99%

The population structure of Plasmodium falciparum and Plasmodium vivax during an epidemic of malaria in the Eastern Highlands of Papua New Guinea.

Müeller¹,

Kaiok²,

Reeder³

et al. 2002

The American Journal of Tropical Medicine and Hygiene

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Abstract. Although most of the Papua New Guinea highlands are too high for stable malaria transmission, local epidemics are a regular feature of the region. Few detailed descriptions of such epidemics are available, however. We describe the investigation of a malaria epidemic in the Obura Valley, Eastern Highlands Province, Papua New Guinea. Of the 244 samples examined by microscopy, 6.6% were positive for Plasmodium falciparum only, 9.4% were positive for Plasmodium vivax only, and 1.2% were mixed infections. MSP2 and MSP3␣ genotyping and AMA1 sequencing were used to determine the genetic variation present in a sample of P. falciparum and P. vivax infections. The P. vivax infections were found to be genetically highly diverse. In contrast, all P. falciparum samples were of a single genotype. This striking difference in genetic diversity suggests endemic, low-level local transmission for P. vivax but an outside introduction of P. falciparum as the most likely source of the epidemic.

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“…Although PfAMA1 is less polymorphic than other merozoite surface proteins that are also vaccine candidates, such as merozoite surface proteins 1 and 2 (MSP1 and MSP2) (14,35), there is evidence that the AMA1 polymorphisms are under balancing selection, especially domains I and III (8,13,38,39,46). It has been assumed that selective pressure by the host immune system is responsible for maintenance of these polymorphisms.…”

mentioning

confidence: 99%

In Immunization with Plasmodium falciparum Apical Membrane Antigen 1, the Specificity of Antibodies Depends on the Species Immunized

et al. 2007

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At least a million people, mainly African children under 5 years old, still die yearly from malaria, and the burden of disease and death has increased. Plasmodium falciparum apical membrane antigen 1 (PfAMA1) is one of the most promising blood-stage malarial vaccine candidates. However, the allelic polymorphism observed in this protein is a potential stumbling block for vaccine development. To overcome the polymorphismand strain-specific growth inhibition in vitro, we previously showed in a rabbit model that vaccination with a mixture of two allelic forms of PfAMA1 induced parasite growth-inhibitory antisera against both strains of P. falciparum parasites in vitro. In the present study, we have established that, in contrast to a single-allele protein, the antigen mixture elicits primarily antibodies recognizing antigenic determinants common to the two antigens, as judged by an antigen reversal growth inhibition assay (GIA). We also show that a similar reactivity pattern occurs after immunization of mice. By contrast, sera from rhesus monkeys do not distinguish the two alleles when tested by an enzyme-linked immunosorbent assay or by GIA, regardless of whether the immunogen is a single AMA1 protein or the mixture. This is the first report that a malarial vaccine candidate induced different specificities of functional antibodies depending on the animal species immunized. These observations, as well as data available on human immune responses in areas of endemicity, suggest that polymorphism in the AMA1 protein may not be as formidable a problem for vaccine development as anticipated from studies with rabbits and mice.The malarial parasite remains a scourge on human civilization, and recent data suggest that previous estimates of malaria morbidity and mortality may have significantly underestimated the worldwide burden of this disease. Snow and colleagues estimate that there may be 300 to 500 million clinical cases of malaria annually, a rate approximately twice as high as previous estimates (42). To compound the human toll of this disease, recent macroeconomic analysis by the WHO Commission on Macroeconomics and Health has found that malaria reduces economic growth in sub-Saharan Africa by over 1% per year, with major long-term consequences for the gross national products of the afflicted countries (41). As the burden of disease and death due directly and indirectly to malaria has increased, the need for an effective vaccine has also assumed greater importance (4, 29).Of the major vaccine candidates directed against bloodstage malaria parasites which are responsible for the pathology associated with this disease, Plasmodium falciparum apical membrane antigen 1 (PfAMA1) is one of the best studied (36).Expressed late in the erythrocytic replication cycle, this 83-kDa membrane protein is initially found in apical organelles called micronemes in the invasive form of the blood-stage parasite known as the merozoite (2, 18). AMA1 is subsequently processed to a 66-kDa form by removal of an N-terminal prosequence and is tr...

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Polymorphism in the gene encoding the apical membrane antigen-1 (AMA-1) of Plasmodium falciparum. X. Asembo Bay Cohort Project

Cited by 113 publications

References 31 publications

Structure of AMA1 from Plasmodium falciparum reveals a clustering of polymorphisms that surround a conserved hydrophobic pocket

Structure of AMA1 from Plasmodium falciparum reveals a clustering of polymorphisms that surround a conserved hydrophobic pocket

The population structure of Plasmodium falciparum and Plasmodium vivax during an epidemic of malaria in the Eastern Highlands of Papua New Guinea.

In Immunization with Plasmodium falciparum Apical Membrane Antigen 1, the Specificity of Antibodies Depends on the Species Immunized

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