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

Müeller, Ivo; Kaiok, Japalis; Reeder, John C.; Cortés, Alfred

doi:10.4269/ajtmh.2002.67.459

Cited by 52 publications

(47 citation statements)

References 22 publications

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“…The simplicity of this picture is remarkable; the mutations that contribute to pyrimethamine resistance appear to be the same worldwide, synonymous substitutions are very rarely observed, and only one insertion has ever been reported (7). These patterns support the idea that the present P. falciparum populations have evolved recently from a few founders and spread virtually worldwide from these foci, probably influenced by the strong selection pressure of drug treatment (6,42,51,67).Limited studies to date have demonstrated that there is a far higher level of overall genetic diversity in the P. vivax population than one observes in the P. falciparum population (9,16,29,41). This difference is likely to be important to the evolution of drug resistance.…”

supporting

confidence: 73%

Novel Plasmodium vivax dhfr Alleles from the Indonesian Archipelago and Papua New Guinea: Association with Pyrimethamine Resistance Determined by a Saccharomyces cerevisiae Expression System

Hastings

Maguire

Bangs

et al. 2005

Antimicrob Agents Chemother

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In plasmodia, the dihydrofolate reductase (DHFR) enzyme is the target of the pyrimethamine component of sulfadoxine-pyrimethamine (S/P). Plasmodium vivax infections are not treated intentionally with antifolates. However, outside Africa, coinfections with Plasmodium falciparum and P. vivax are common, and P. vivax infections are often exposed to S/P. Cloning of the P. vivax dhfr gene has allowed molecular comparisons of dhfr alleles from different regions. Examination of the dhfr locus from a few locations has identified a very diverse set of alleles and showed that mutant alleles of the vivax dhfr gene are prevalent in Southeast Asia where S/P has been used extensively. We have surveyed patient isolates from six locations in Indonesia and two locations in Papua New Guinea. We sequenced P. vivax dhfr alleles from 114 patient samples and identified 24 different alleles that differed from the wild type by synonymous and nonsynonymous point mutations, insertions, or deletions. Most importantly, five alleles that carried four or more nonsynonymous mutations were identified. Only one of these highly mutant alleles had been previously observed, and all carried the 57L and 117T mutations. P. vivax cannot be cultured continuously, so we used a yeast assay system to determine in vitro sensitivity to pyrimethamine for a subset of the alleles. Alleles with four nonsynonymous mutations conferred very high levels of resistance to pyrimethamine. This study expands significantly the total number of novel dhfr alleles now identified from P. vivax and provides a foundation for understanding how antifolate resistance arises and spreads in natural P. vivax populations.Plasmodium vivax causes a severe and debilitating febrile illness. This mosquito-borne parasite infects an estimated 80 million people each year and is a prevalent cause of malaria outside sub-Saharan Africa (39). Unfortunately, P. vivax cannot be maintained in continuous culture, so despite its prevalence, the study of vivax has lagged markedly behind that of Plasmodium falciparum. This difference is particularly true with respect to the genetics and epidemiology of drug resistance in P. vivax. Chloroquine has been the first-line antimalarial treatment in most areas of endemicity, but resistance to this drug has virtually eliminated its usefulness against P. falciparum (61, 63, 65) and chloroquine resistance has now been observed with P. vivax as well (1,21,34,45,52,55,58,59). Fansidar, a fixed combination of sulfadoxine and pyrimethamine (S/P), is most often the alternative chosen when chloroquine-resistant P. falciparum parasites render chloroquine ineffective (4). However, S/P has not been recommended for primary therapy of vivax malaria due to the poor clinical efficacy reported when the drug was introduced in the 1950s (13,14,26,49,64,68).In both P. falciparum and P. vivax, the dihydrofolate reductase (DHFR, E.C. 1.5.1.3) enzyme is the therapeutic target of the pyrimethamine component of S/P (12,18,23,26,27,43,44,60). A combination of in vitro analysis of cultu...

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supporting

confidence: 73%

Novel Plasmodium vivax dhfr Alleles from the Indonesian Archipelago and Papua New Guinea: Association with Pyrimethamine Resistance Determined by a Saccharomyces cerevisiae Expression System

Hastings

Maguire

Bangs

et al. 2005

Antimicrob Agents Chemother

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“…These data suggest that this mutation has arisen recently, and although it has had time to spread among the Papua New Guinea and Western Papua populations to relatively high frequencies, apparently there has not been time for recombination or point mutations at other positions to generate new alleles bearing this mutation. A parallel situation occurs with the T 590 mutation, which has also been detected in the Papua New Guinea Highlands (34).…”

Section: Discussionmentioning

confidence: 66%

Geographical Structure of Diversity and Differences between Symptomatic and Asymptomatic Infections for Plasmodium falciparum Vaccine Candidate AMA1

et al. 2003

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Plasmodium falciparum apical membrane antigen 1 (AMA1) is a prime malaria vaccine candidate. Antigenic diversity within parasite populations is one of the main factors potentially limiting the efficacy of any asexual-stage vaccine, including one based on AMA1. The DNA coding for the most variable region of this antigen, domain I, was sequenced in 168 samples from the Wosera region of Papua New Guinea, including samples from symptomatic and asymptomatic infections. Neutrality tests applied to these sequences provided strong evidence of selective pressure operating on the sequence of ama1 domain I, consistent with AMA1 being a target of protective immunity. Similarly, a peculiar pattern of geographical diversity and the particular substitutions found were suggestive of strong constraints acting on the evolution of AMA1 at the population level, probably as a result of immune pressure. In addition, a strong imbalance between symptomatic and asymptomatic infections was detected in the frequency of particular residues at certain polymorphic positions, pointing to AMA1 as being one of the determinants of the morbidity associated with a particular strain. The information yielded by this study has implications for the design and assessment of AMA1-based vaccines and provides additional data supporting the importance of AMA1 as a malaria vaccine candidate.

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“…A focal outbreak of P. falciparum malaria caused by a clonal parasite line was documented on Santiago Island, Cape Verde (32), and among Amazonian Yanomami Amerindians (45). A previous study conducted during a malaria epidemic in the eastern highlands of Papua New Guinea showed that all P. falciparum infections shared a single genotype, suggesting external introduction as the epidemic source, while the P. vivax infections were highly diverse, suggesting endemic transmission (46). To our knowledge, the 2002 Aneityum outbreak is the first documented outbreak of P. vivax malaria caused by a semiclonal parasite line.…”

Section: Discussionmentioning

confidence: 99%

Characteristic Age Distribution of Plasmodium vivax Infections after Malaria Elimination on Aneityum Island, Vanuatu

et al. 2014

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mResurgence is a major concern after malaria elimination. After the initiation of the elimination program on Aneityum Island in 1991, microscopy showed that Plasmodium falciparum disappeared immediately, whereas P. vivax disappeared from 1996 onward, until P. vivax cases were reported in January 2002. By conducting malariometric surveys of the entire population of Aneityum, we investigated the age distribution of individuals with parasites during this epidemic in the context of antimalarial antibody levels and parasite antigen diversity. In July 2002, P. vivax infections were detected by microscopy in 22/759 individuals: 20/298 born after the beginning of the elimination program in 1991, 2/126 born between 1982 and 1991, and none of 335 born before 1982. PCR increased the number of infections detected to 77, distributed among all age groups. Prevalences were 12.1%, 16.7%, and 6.0%, respectively (P < 0.001). In November, a similar age pattern was found, but with fewer infections: 6/746 and 39/741 individuals were found to be infected by microscopy and PCR, respectively. The frequencies of antibody responses to P. vivax were significantly higher in individuals born before 1991 than in younger age groups and were similar to those on Malakula Island, an area of endemicity. Remarkably low antigen diversity (h, 0.15) of P. vivax infections was observed on Aneityum compared with the other islands (h, 0.89 to 1.0). A P. vivax resurgence was observed among children and teenagers on Aneityum, an age distribution similar to those before elimination and on islands where P. vivax is endemic, suggesting that in the absence of significant exposure, immunity may persist, limiting infection levels in adults. The limited parasite gene pool on islands may contribute to this protection.

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

Cited by 52 publications

References 22 publications

Novel Plasmodium vivax dhfr Alleles from the Indonesian Archipelago and Papua New Guinea: Association with Pyrimethamine Resistance Determined by a Saccharomyces cerevisiae Expression System

Novel Plasmodium vivax dhfr Alleles from the Indonesian Archipelago and Papua New Guinea: Association with Pyrimethamine Resistance Determined by a Saccharomyces cerevisiae Expression System

Geographical Structure of Diversity and Differences between Symptomatic and Asymptomatic Infections for Plasmodium falciparum Vaccine Candidate AMA1

Characteristic Age Distribution of Plasmodium vivax Infections after Malaria Elimination on Aneityum Island, Vanuatu

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