1,721,109 research outputs found
Sub-grouping of <it>Plasmodium falciparum </it>3D7 <it>var </it>genes based on sequence analysis of coding and non-coding regions
Get PDFAbstract Background The variant surface antigen family Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP1) is an important target for protective immunity and is implicated in the pathology of malaria through its ability to adhere to host endothelial receptors. The sequence diversity and organization of the 3D7 PfEMP1 repertoire was investigated on the basis of the complete genome sequence. Methods Using two tree-building methods we analysed the coding and non-coding sequences of 3D7 var and rif genes as well as var genes of other parasite strains. Results var genes can be sub-grouped into three major groups (group A, B and C) and two intermediate groups B/A and B/C representing transitions between the three major groups. The best defined var group, group A, comprises telomeric genes transcribed towards the telomere encoding PfEMP1s with complex domain structures different from the 4-domain type dominant of groups B and C. Two sequences belonging to the var1 and var2 subfamilies formed independent groups. A rif subgroup transcribed towards the centromere was found neighbouring var genes of group A such that the rif and var 5' regions merged. This organization appeared to be unique for the group A var genes Conclusion The grouping of var genes implies that var gene recombination preferentially occurs within var gene groups and it is speculated that the groups reflect a functional diversification evolved to cope with the varying conditions of transmission and host immune response met by the parasite.</p
Cytophilic Antibodies to Plasmodium Falciparum Glutamate Rich Protein are Associated with Malaria Protection in an Area of Holoendemic Transmission.
Get PDFSeveral studies conducted in areas of medium or low malaria transmission intensity have found associations between malaria immunity and plasma antibody levels to glutamate rich protein (GLURP). This study was conducted to analyse if a similar relationship could be documented in an area of intense malaria transmission. A six month longitudinal study was conducted in an area of holoendemic malaria transmission in north-eastern Tanzania, where the incidence of febrile malaria decreased sharply by the age of three years, and anaemia constituted a significant part of the malaria disease burden. Plasma antibodies to glutamate rich protein (GLURP) were analysed and related with protection against malaria morbidity in models correcting for the effect of age. The risk of febrile malaria episodes was reduced significantly in children with measurable anti-GLURP IgG1 antibodies at enrollment [adjusted odds ratio: 0.39 (95% CI: 0.15, 0.99); P = 0.047]. Interestingly, there was an inverse relationship between the plasma anti-GLURP IgG1 and IgG3 levels and the levels of parasitaemia at enrollment. However, anti-GLURP IgG2 and IgG4 levels were not associated with reduction in parasite density. Similarly, antibody levels were not associated with haemoglobin levels or anaemia risk. Cytophilic IgG1 and IgG3 antibodies against R0-GLURP may contribute to the control of parasite multiplication and reduction in febrile malaria incidence in children living in an area of intense malaria transmission
Antibody levels to multiple malaria vaccine candidate antigens in relation to clinical malaria episodes in children in the Kasena-Nankana district of Northern Ghana.
Get PDFBACKGROUND: Considering the natural history of malaria of continued susceptibility to infection and episodes of illness that decline in frequency and severity over time, studies which attempt to relate immune response to protection must be longitudinal and have clearly specified definitions of immune status. Putative vaccines are expected to protect against infection, mild or severe disease or reduce transmission, but so far it has not been easy to clearly establish what constitutes protective immunity or how this develops naturally, especially among the affected target groups. The present study was done in under six year old children to identify malaria antigens which induce antibodies that correlate with protection from Plasmodium falciparum malaria. METHODS: In this longitudinal study, the multiplex assay was used to measure IgG antibody levels to 10 malaria antigens (GLURP R0, GLURP R2, MSP3 FVO, AMA1 FVO, AMA1 LR32, AMA1 3D7, MSP1 3D7, MSP1 FVO, LSA-1and EBA175RII) in 325 children aged 1 to 6 years in the Kassena Nankana district of northern Ghana. The antigen specific antibody levels were then related to the risk of clinical malaria over the ensuing year using a negative binomial regression model. RESULTS: IgG levels generally increased with age. The risk of clinical malaria decreased with increasing antibody levels. Except for FMPOII-LSA, (p = 0.05), higher IgG levels were associated with reduced risk of clinical malaria (defined as axillary temperature ≥37.5°C and parasitaemia of ≥5000 parasites/ul blood) in a univariate analysis, upon correcting for the confounding effect of age. However, in a combined multiple regression analysis, only IgG levels to MSP1-3D7 (Incidence rate ratio = 0.84, [95% C.I.= 0.73, 0.97, P = 0.02]) and AMA1 3D7 (IRR = 0.84 [95% C.I.= 0.74, 0.96, P = 0.01]) were associated with a reduced risk of clinical malaria over one year of morbidity surveillance. CONCLUSION: The data from this study support the view that a multivalent vaccine involving different antigens is most likely to be more effective than a monovalent one. Functional assays, like the parasite growth inhibition assay will be necessary to confirm if these associations reflect functional roles of antibodies to MSP1-3D7 and AMA1-3D7 in this population
Cohort study of the association of antibody levels to AMA1, MSP119, MSP3 and GLURP with protection from clinical malaria in Ghanaian children.
Get PDFBACKGROUND: Antigen-specific antibody-mediated immune responses play an important role in natural protection against clinical malaria, but conflicting estimates of this association have emerged from immuno-epidemiological studies in different geographical settings. This study was aimed at assessing in a standardized manner the relationship between the antibody responses to four malaria vaccine candidate antigens and protection from clinical malaria, in a cohort of Ghanaian children. METHODS: Standardized ELISA protocols were used to measure isotype and IgG subclass levels to Apical Membrane Antigen 1 (AMA1), Merozoite Surface Protein 1-19 (MSP119), Merozoite Surface Protein 3 (MSP3) and Glutamate Rich Protein (GLURP) antigens in plasma samples from 352 Ghanaian children, aged three to 10 years with subsequent malaria surveillance for nine months. This is one of a series of studies in different epidemiological settings using the same standardized ELISA protocols to permit comparisons of results from different laboratories. RESULTS: The incidence rate of malaria was 0.35 episodes per child per year. Isotype and IgG subclasses for all antigens investigated increased with age, while the risk of malaria decreased with age. After adjusting for age, higher levels of IgG to GLURP, MSP119, MSP3 and IgM to MSP119, MSP3 and AMA1 were associated with decreased malaria incidence. Of the IgG subclasses, only IgG1 to MSP119 was associated with reduced incidence of clinical malaria. A previous study in the same location failed to find an association of antibodies to MSP119 with clinical malaria. The disagreement may be due to differences in reagents, ELISA and analytical procedures used in the two studies. When IgG, IgM and IgG subclass levels for all four antigens were included in a combined model, only IgG1 [(0.80 (0.67-0.97), p = 0.018)] and IgM [(0.48 (0.32-0.72), p < 0.001)] to MSP119 were independently associated with protection from malaria. CONCLUSION: Using standardized procedures, the study has confirmed the importance of antibodies to MSP119 in reducing the risk of clinical malaria in Ghanaian children, thus substantiating its potential as a malaria vaccine candidate
Spatial and temporal variation in malaria transmission in a low endemicity area in northern Tanzania.
Get PDFBACKGROUND: Spatial and longitudinal monitoring of transmission intensity will allow better targeting of malaria interventions. In this study, data on meteorological, demographic, entomological and parasitological data over the course of a year was collected to describe malaria epidemiology in a single village of low transmission intensity. METHODS: Entomological monitoring of malaria vectors was performed by weekly light trap catches in 10 houses. Each house in the village of Msitu wa Tembo, Lower Moshi, was mapped and censused. Malaria cases identified through passive case detection at the local health centre were mapped by residence using GIS software and the incidence of cases by season and distance to the main breeding site was calculated. RESULTS: The principle vector was Anopheles arabiensis and peak mosquito numbers followed peaks in recent rainfall. The entomological inoculation rate estimated was 3.4 (95% CI 0.7-9.9) infectious bites per person per year. The majority of malaria cases (85/130) occurred during the rainy season (chi2 = 62,3, p < 0.001). Living further away from the river (OR 0.96, CI 0.92-0.998, p = 0.04 every 50 m) and use of anti-insect window screens (OR 0.65, CI 0.44-0.94, p = 0.023) were independent protective factors for the risk of malaria infection. Children aged 1-5 years and 5-15 years were at greater risk of clinical episodes (OR 2.36, CI 1.41-3.97, p = 0.001 and OR 3.68, CI 2.42-5.61, p < 0.001 respectively). CONCLUSION: These data show that local malaria transmission is restricted to the rainy season and strongly associated with proximity to the river. Transmission reducing interventions should, therefore, be timed before the rain-associated increase in mosquito numbers and target households located near the river
The epidemiology of malaria in adults in a rural area of southern Mozambique.
Get PDFBACKGROUND: Epidemiological studies of malaria in adults who live in malaria endemic areas are scarce. More attention to the natural history of malaria affecting adults is needed to understand the dynamics of malaria infection and its interaction with the immune system. The present study was undertaken to investigate the clinical, parasitological and haematological status of adults exposed to malaria, and to characterize parasites in these individuals who progressively acquire protective immunity. METHODS: A cross-sectional survey of 249 adults was conducted in a malaria endemic area of Mozambique. Clinical, parasitological and haematological status of the study population was recorded. Sub-microscopic infections and multiplicity of infections were investigated using polymerase chain reaction (PCR) and restriction fragment length polymorphism of Plasmodium falciparum merozoite surface protein 2 (msp2). RESULTS: Prevalence of P. falciparum infection by microscopy (14%) and PCR (42%) decreased progressively during adulthood, in parallel with an increase in the prevalence of sub-microscopic infections. Anaemia was only related to parasitaemia as detected by PCR. Multiplicity of infection decreased with age and was higher in subjects with high P. falciparum densities, highlighting density-dependent constraints upon the PCR technique. CONCLUSION: Adults of Manhiça progressively develop non-sterile, protective immunity against P. falciparum malaria. The method of parasite detection has a significant effect on the observed natural history of malaria infections. A more sensitive definition of malaria in adults should be formulated, considering symptoms such as diarrhoea, shivering and headache, combined with the presence of parasitaemia
Factors determining the occurrence of submicroscopic malaria infections and their relevance for control.
Get PDFMalaria parasite prevalence in endemic populations is an essential indicator for monitoring the progress of malaria control, and has traditionally been assessed by microscopy. However, surveys increasingly use sensitive molecular methods that detect higher numbers of infected individuals, questioning our understanding of the true infection burden and resources required to reduce it. Here we analyse a series of data sets to characterize the distribution and epidemiological factors associated with low-density, submicroscopic infections. We show that submicroscopic parasite carriage is common in adults, in low-endemic settings and in chronic infections. We find a strong, non-linear relationship between microscopy and PCR prevalence in population surveys (n=106), and provide a tool to relate these measures. When transmission reaches very low levels, submicroscopic carriers are estimated to be the source of 20-50% of all human-to-mosquito transmissions. Our findings challenge the idea that individuals with little previous malaria exposure have insufficient immunity to control parasitaemia and suggest a role for molecular screening
Genetic diversity of expressed Plasmodium falciparum var genes from Tanzanian children with severe malaria
Get PDFBACKGROUND: Severe malaria has been attributed to the expression of a restricted subset of the var multi-gene family, which encodes for Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). PfEMP1 mediates cytoadherence and sequestration of infected erythrocytes into the post-capillary venules of vital organs such as the brain, lung or placenta. var genes are highly diverse and can be classified in three major groups (ups A, B and C) and two intermediate groups (B/A and B/C) based on the genomic location, gene orientation and upstream sequences. The genetic diversity of expressed var genes in relation to severity of disease in Tanzanian children was analysed. METHODS: Children with defined severe (SM) and asymptomatic malaria (AM) were recruited. Full-length var mRNA was isolated and reversed transcribed into var cDNA. Subsequently, the DBL and N-terminal domains, and up-stream sequences were PCR amplified, cloned and sequenced. Sequences derived from SM and AM isolates were compared and analysed. RESULTS: The analysis confirmed that the var family is highly diverse in natural Plasmodium falciparum populations. Sequence diversity of amplified var DBL-1α and upstream regions showed minimal overlap among isolates, implying that the var gene repertoire is vast and most probably indefinite in endemic areas. var DBL-1α sequences from AM isolates were more diverse with more singletons found (p<0.05) than those from SM infections. Furthermore, few var DBL-1α sequences from SM patients were rare and restricted suggesting that certain PfEMP1 variants might induce severe disease. CONCLUSIONS: The genetic sequence diversity of var genes of P. falciparum isolates from Tanzanian children is large and its relationship to disease severity has been studied. Observed differences suggest that different var genes might have fundamentally different roles in the host-parasite interaction. Further research is required to examine clear disease-associations of var gene subsets in different geographical settings. The importance of very strict clinical definitions and appropriate large control groups needs to be emphasized for future studies on disease associations of PfEMP1
Modelling the impact of intermittent preventive treatment for malaria on selection pressure for drug resistance.
Get PDFBACKGROUND\ud
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Intermittent preventive treatment (IPT) is a promising intervention for malaria control, although there are concerns about its impact on drug resistance.\ud
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METHODS\ud
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The key model inputs are age-specific values for a) baseline anti-malarial dosing rate, b) parasite prevalence, and c) proportion of those treated with anti-malarials (outside IPT) who are infected. These are used to estimate the immediate effect of IPT on the genetic coefficient of selection (s). The scenarios modelled were year round IPT to infants in rural southern Tanzania, and three doses at monthly intervals of seasonal IPT in Senegal.\ud
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RESULTS\ud
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In the simulated Tanzanian setting, the model suggests a high selection pressure for drug resistance, but that IPTi would only increase this by a small amount (4.4%). The percent change in s is larger if parasites are more concentrated in infants, or if baseline drug dosing is less common or less specific. If children aged up to five years are included in the Tanzanian scenario then the predicted increase in s rises to 31%. The Senegalese seasonal IPT scenario, in children up to five years, results in a predicted increase in s of 16%.\ud
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CONCLUSION\ud
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There is a risk that the useful life of drugs will be shortened if IPT is implemented over a wide childhood age range. On the other hand, IPT delivered only to infants is unlikely to appreciably shorten the useful life of the drug used
Low density parasitaemia, red blood cell polymorphisms and Plasmodium falciparum specific immune responses in a low endemic area in northern Tanzania.
Get PDFBACKGROUND: Low density Plasmodium falciparum infections, below the microscopic detection limit, may play an important role in maintaining malaria transmission in low endemic areas as well as contribute to the maintenance of acquired immunity. Little is known about factors influencing the occurrence of sub-microscopic parasitaemia or the relation with immune responses.We investigated possible associations between the occurrence of sub-microscopic P. falciparum parasite carriage and antibody responses to the asexual stage antigens, G6PD deficiency and alpha+-thalassaemia in 464 subjects from a low endemic area in northern Tanzania. METHODS: We used samples collected from two cross sectional surveys conducted during dry and wet season in 2005. Submicroscopic parasitaemia was detected by using quantitative nucleic acid sequence based amplification (QT-NASBA). Genotyping for G6PD and alpha+-thalassaemia were performed by high throughput PCR; the prevalence and level of total IgG antibodies against MSP-1, MSP-2 and AMA-1 were determined by ELISA. RESULTS: Compared to parasite free individuals, individuals carrying sub-microscopic densities of P. falciparum parasites had significantly higher median antibody levels to MSP-1 (p = 0.042) and MSP-2 (p = 0.034) but not to AMA-1 (p = 0.14) while no clear relation between sub-microscopic parasite carriage and G6PD deficiency or alpha+-thalassaemia was observed. CONCLUSION: Our data suggest a role for sub-microscopic parasite densities in eliciting or maintaining humoral immune responses without evidence for a modulating effect of G6PD deficiency or alpha+-thalassaemia
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