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Biomedical subjects

John C Reeder

Publications and source records attributed to John C Reeder.

At least 37 records · Page 2Linked to original sources
PubMed2003

A human complement receptor 1 polymorphism that reduces Plasmodium falciparum rosetting confers protection against severe malaria.

Parasitized red blood cells (RBCs) from children suffering from severe malaria often adhere to complement receptor 1 (CR1) on uninfected RBCs to form clumps of cells known as "rosettes." Despite a well documented association between rosetting and severe malaria, it is controversial whether rosetting is a cause or a correlate of parasite virulence. CR1-deficient RBC show greatly reduced rosetting; therefore, we hypothesized that, if rosetting is a direct cause of malaria pathology, CR1-deficient individuals should be protected against severe disease. In this study, we show that RBC CR1 deficiency occurs in up to 80% of healthy individuals from the malaria-endemic regions of Papua New Guinea. This RBC CR1 deficiency is associated with polymorphisms in the CR1 gene and, unexpectedly, with alpha-thalassemia, a common genetic disorder in Melanesian populations. Analysis of a case-control study demonstrated that the CR1 polymorphisms and alpha-thalassemia independently confer protection against severe malaria. We have therefore identified CR1 as a new malaria resistance gene and provided compelling evidence that rosetting is an important parasite virulence phenotype that should be a target for drug and vaccine development.

Adult↗
PubMed2003

Regulation of antigenic variation in Plasmodium falciparum: censoring freedom of expression?

Plasmodium falciparum employs a strategy of clonal antigenic variation to evade the host immune response during the intraerythrocytic stage of its life cycle. The major variant parasite molecule is the P. falciparum erythrocyte membrane protein (PfEMP)1, which is encoded by the var multigene family. The parasite switches between different PfEMP1 molecules through regulation of var transcription. Recent studies have shed considerable light on this process, but much remains unknown. However, striking parallels between transcriptional control of var and genes in other organisms provide direction for future studies.

Animals↗
PubMed2003

Health research in Papua New Guinea.

The Papua New Guinea Institute of Medical Research (PNGIMR) is one of the most respected health research institutions in the developing world, and its studies of the local health problems of PNG have consistently had international relevance. This article examines the structural and philosophical factors that have enabled the success of the PNGIMR, and presents the PNGIMR approach to research as a potential model for other disease-endemic countries. An overview of PNGIMR research into malaria and filariasis is given with selected examples as an introduction to a Trends in Parasitology series on health research in Papua New Guinea.

Animals↗
PubMed2003

Engaging the community in research: lessons learned from the malaria vaccine trial.

When staff of the Papua New Guinea Institute of Medical Research first went into Wosera in 1979, to try and interest the community into participating in malaria research, the traditional warning sign of crossed bamboo sticks constantly blocked their path as they tried to enter the villages. In 2003, the site is a thriving research centre, with many projects under its belt, a successfully executed malaria vaccine trial to its credit, and approximately 13000 people from 29 villages currently participating in demographic surveillance and various research projects. It has been a long road from community suspicion to sustainable community participation, and the field workers have learned many important lessons along the way that can be applicable to research programs in other disease-endemic areas.

Clinical Trials as Topic↗
PubMed2003

The malaria vaccine development program in Papua New Guinea.

Through a collaborative project led by the Papua New Guinea Institute of Medical Research (PNGIMR), Papua New Guinea has a significant role in the global effort to develop a malaria vaccine, ensuring that the malaria patterns in Asia and the Pacific region are considered in vaccine development strategies. Some of the major perspectives and achievements of the program are discussed here, one of the most successful being the trial of Combination B, a vaccine comprising three asexual blood-stage proteins [merozoite surface protein (MSP)1, MSP2 and ring-infected erythrocyte surface antigen (RESA)], which led to a considerable reduction of parasite density in the immunized children.

Animals↗
PubMed2003

Geographical structure of diversity and differences between symptomatic and asymptomatic infections for Plasmodium falciparum vaccine candidate AMA1.

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.

Amino Acid Sequence↗
PubMed2003

New haplotypes of the Plasmodium falciparum chloroquine resistance transporter (pfcrt) gene among chloroquine-resistant parasite isolates.

Mutations in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) gene were examined to assess their associations with chloroquine resistance in clinical samples from Armopa (Papua) and Papua New Guinea. In Papua, two of the five pfcrt haplotypes found were new: SVIET from Armopa and CVIKT from an isolate in Timika. There was also a strong association (P < 0.0001) between the pfcrt 76T allele and chloroquine resistance in 50 samples. In Papua New Guinea, mutations in the pfcrt gene were observed in 15 isolates with chloroquine minimum inhibitory concentrations (MICs) of 16-64 pmol, while the remaining six isolates, which had a wild-type pfcrt gene at codon 76, had MICs of 2-8 pmol. These observations confirm that mutations at codon 76 in the pfcrt gene are present in both in vivo and in vitro cases of chloroquine resistance, and that detection of the pfcrt 76T allele could predict potential chloroquine treatment failures.

Animals↗
PubMed2002

Plasmodium falciparum erythrocyte invasion through glycophorin C and selection for Gerbich negativity in human populations.

Geographic overlap between malaria and the occurrence of mutant hemoglobin and erythrocyte surface proteins has indicated that polymorphisms in human genes have been selected by severe malaria. Deletion of exon 3 in the glycophorin C gene (called GYPCDeltaex3 here) has been found in Melanesians; this alteration changes the serologic phenotype of the Gerbich (Ge) blood group system, resulting in Ge negativity. The GYPCDeltaex3 allele reaches a high frequency (46.5%) in coastal areas of Papua New Guinea where malaria is hyperendemic. The Plasmodium falciparum erythrocyte-binding antigen 140 (EBA140, also known as BAEBL) binds with high affinity to the surface of human erythrocytes. Here we show that the receptor for EBA140 is glycophorin C (GYPC) and that this interaction mediates a principal P. falciparum invasion pathway into human erythrocytes. EBA140 does not bind to GYPC in Ge-negative erythrocytes, nor can P. falciparum invade such cells using this invasion pathway. This provides compelling evidence that Ge negativity has arisen in Melanesian populations through natural selection by severe malaria.

Animals↗
PubMed2002

Restricted polymorphisms of the mannose-binding lectin gene in a population of Papua New Guinea.

The human mannose-binding lectin (MBL) is an important protein of the innate immune system. MBL is able to eliminate potential pathogens by activating the complement cascade or by opsonisation. We investigated the gene and promoter region of MBL in a population from Papua New Guinea infected with Plasmodium falciparum parasites and measured the appropriate serum concentrations of these individuals. Their serum levels of MBL, detected by ELISA, showed a wide range with concentrations between 632 and 7325 microg/l MBL. A known polymorphism in exon 1 at codon 54 causing an amino acid exchange from Gly to Asp occurred with a low frequency of 3%. Additional to the previously reported polymorphisms in the gene and promoter region of MBL, two novel polymorphic sites were found in the promoter region. One site was in the untranslated region of the MBL gene at position +1 (G-->A, termed R/S), and the second was located upstream of the gene at position -4 (G-->A, termed T/U).

5' Untranslated Regions↗
PubMed2002

Transcription of multiple var genes by individual, trophozoite-stage Plasmodium falciparum cells expressing a chondroitin sulphate A binding phenotype.

In this study, we detected multiple var gene transcripts within single, mature trophozoite-infected red blood cells (iRBCs) bound to chondroitin sulphate A (CSA). Several of the var detected had previously been demonstrated to encode Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP-1) variants with domains that mediated iRBC adhesion to receptors other than CSA. Parasites expressing the CSA-adherent phenotype transcribed far more of one var than of all others, but this gene was different from the two other var previously purported to encode adhesion to CSA. Previous work suggesting that only single var are transcribed by mature trophozoites needs re-examination in the light of these data from single, infected cells.

Animals↗
PubMed2002

Increasing genetic diversity of Salmonella enterica serovar typhi isolates from papua new guinea over the period from 1992 to 1999.

Pulsed-field gel electrophoresis (PFGE) of XbaI-digested chromosomal DNA was performed on 133 strains of Salmonella enterica serovar Typhi obtained from Papua New Guinea, with the objective of assessing the temporal variation of these strains. Fifty-two strains that were isolated in 1992 and 1994 were of one phage type, D2, and only two predominant PFGE profiles, X1 and X2, were present. Another 81 strains isolated between 1997 and 1999 have shown divergence, with four new phage types, UVS I (n = 63), UVS (n = 5), VNS (n = 4), and D1 (n = 9), and more genetic variability as evidenced by the multiple and new PFGE XbaI profiles (21 profiles; Dice coefficient, F = 0.71 to 0.97). The two profiles X1 and X2 have remained the stable, dominant subtypes since 1992. Cluster analysis based on the unweighted pair group method using arithmetic averages algorithm identifies two main clusters (at 87% similarity), indicating that the divergence of the PFGE subtypes was probably derived from some genomic mutations of the X1 and X2 subtypes. The majority of isolates were from patients with mild and moderate typhoid fever and had various XbaI profiles. A single isolate from a patient with fatal typhoid fever had a unique X11 profile, while four of six isolates from patients with severe typhoid fever had the X1 pattern. In addition, 12 paired serovar Typhi isolates recovered from the blood and fecal swabs of individual patients exhibited similar PFGE patterns, while in another 11 individuals paired isolates exhibited different PFGE patterns. Three pairs of isolates recovered from three individuals had different phage types and PFGE patterns, indicating infection with multiple strains. The study reiterates the usefulness of PFGE in assessing the genetic diversity of S. enterica serovar Typhi for both long-term epidemiology and in vivo stability and instability within an individual patient.

Bacteriophage Typing↗
PubMed2002

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

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 MSP3alpha 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.

Adolescent↗
PubMed2002

Alterations in Plasmodium falciparum genotypes during sequential infections suggest the presence of strain specific immunity.

Many of the asexual stage Plasmodium falciparum proteins that are the targets of host protective responses are markedly polymorphic. The full repertoire of diversity is not defined for any antigen. Most studies have focused on the genes encoding merozoite surface proteins 1 and 2 (MSP1, MSP2). We explored the extent of diversity of some of the less studied merozoite surface antigens and analyzed the degree of complexity of malaria field isolates by deriving nucleotide sequences of several antigens. We have determined the genotype of apical membrane antigen 1 (AMA1) in a group of 30 field samples, collected over 29 months, from individuals living in an area of intense malaria transmission in Irian Jaya, identifying 14 different alleles. AMA1 genotyping was combined with previously determined MSP2 typing. AMA1 had the greatest power in distinguishing between isolates but methodological problems, especially when mixed infections are present, suggest it is not an ideal typing target. MSP1, MSP3, and glutamate-rich protein genotypes were also determined from a smaller group of samples, and all results were combined to derive an extended antigenic haplotype. Within this subset of 10 patients, nine different genotypes could be discerned; however, five patients were all infected with the same strain. This strain was present in individuals from two separate villages and was still present 12 months later. This strain was predominant at the first time point but had disappeared at the fourth time point. This significant change in malaria genotypes could be due to strain-specific immunity developing in this population.

Alleles↗
PubMedDate not supplied

Plasmodium falciparum: distribution of msp2 genotypes among symptomatic and asymptomatic individuals from the Wosera region of Papua New Guinea.

The merozoite surface protein 2 (MSP2) is a leading asexual-stage malaria vaccine candidate that has already proven to have an effect in phase I/IIb vaccine trials, where it was tested in combination with other antigens. Alleles of msp2 fall within two major allelic families, 3D7 and FC27. We analyzed the msp2 genotype in 306 asymptomatic and 63 symptomatic infections from the Wosera region of Papua New Guinea. The multiplicity of infection and the distribution of msp2 alleles was similar to that found in previous studies in the region, but there was no association found between FC27-type or 3D7-type forms of MSP2 and clinical malaria.

Adolescent↗
PubMedDate not supplied

Complex patterns of malaria epidemiology in the highlands region of Papua New Guinea.

A cross-sectional malaria survey of the Pabrabuk area in the Western Highlands Province found that all 4 human malaria species were present in a single village, with an overall parasite prevalence rate of 27%. Plasmodium falciparum was the most frequently detected infection (14%) followed by P. vivax (11%), P. malariae (5%) and P. ovale (3%). 10 of the 51 infections were mixed. Anopheles punctulatus was the most frequent vector species in the area, but both An. farauti no. 6 and An. karwari were also present in low numbers. This diversity in both parasite and vector populations indicates that complex malaria patterns are found in Papua New Guinea even at the moderate transmission levels found in low-lying inter-montane valleys.

Humans↗
PubMedDate not supplied

The epidemiology of malaria in the Papua New Guinea highlands: 1. Western Highlands Province.

Despite a resurgence of malaria in many Papua New Guinea highlands and highlands fringe areas after the cessation of control activities in the early 1980s the malaria situation in these areas has received little attention. A series of cross-sectional surveys were therefore carried out to provide accurate and up-to-date information on the prevalence of malaria and the risk of epidemics and to propose adequate malaria control strategies. Studies in 24 villages in Western Highlands Province found the prevalence of malarial infections to be strongly correlated with altitude, ranging from 1.6% at altitudes of 1500-1800 m to over 30% in villages below 900 m. Malaria outbreaks were observed at the end of the rainy season. All four human malaria species were present with P. falciparum infections clearly dominating. The relative importance of P. vivax increased with altitude, while both P. malariae and P. ovale were rare. Many infections were of low density. While malaria is an important source of febrile illness in endemic areas below 1500 m altitude, only few observed or reported fevers are due to malarial infections in higher, nonendemic areas. Rates of enlarged spleens, mean haemoglobin levels and the prevalence of anaemia (Hb <7.5 g/dl) were strongly linked to the level of malaria found in each community and were associated with both altitude and concurrent malarial infection. Based on the survey results, areas of different malaria epidemiology are delineated and options for control in each area are discussed.

Adolescent↗