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Genetics Aug 2019Understanding the relatedness of individuals within or between populations is a common goal in biology. Increasingly, relatedness features in genetic epidemiology...
Understanding the relatedness of individuals within or between populations is a common goal in biology. Increasingly, relatedness features in genetic epidemiology studies of pathogens. These studies are relatively new compared to those in humans and other organisms, but are important for designing interventions and understanding pathogen transmission. Only recently have researchers begun to routinely apply relatedness to apicomplexan eukaryotic malaria parasites, and to date have used a range of different approaches on an basis. Therefore, it remains unclear how to compare different studies and which measures to use. Here, we systematically compare measures based on identity-by-state (IBS) and identity-by-descent (IBD) using a globally diverse data set of malaria parasites, and , and provide marker requirements for estimates based on IBD. We formally show that the informativeness of polyallelic markers for relatedness inference is maximized when alleles are equifrequent. Estimates based on IBS are sensitive to allele frequencies, which vary across populations and by experimental design. For portability across studies, we thus recommend estimates based on IBD. To generate estimates with errors below an arbitrary threshold of 0.1, we recommend ∼100 polyallelic or 200 biallelic markers. Marker requirements are immediately applicable to haploid malaria parasites and other haploid eukaryotes. C.I.s facilitate comparison when different marker sets are used. This is the first attempt to provide rigorous analysis of the reliability of, and requirements for, relatedness inference in malaria genetic epidemiology. We hope it will provide a basis for statistically informed prospective study design and surveillance strategies.
Topics: Genome, Protozoan; Models, Genetic; Pedigree; Phylogeny; Plasmodium falciparum; Plasmodium vivax; Polymorphism, Single Nucleotide
PubMed: 31209105
DOI: 10.1534/genetics.119.302120 -
Parasites & Vectors May 2011Temperature is a key determinant of environmental suitability for transmission of human malaria, modulating endemicity in some regions and preventing transmission in...
BACKGROUND
Temperature is a key determinant of environmental suitability for transmission of human malaria, modulating endemicity in some regions and preventing transmission in others. The spatial modelling of malaria endemicity has become increasingly sophisticated and is now central to the global scale planning, implementation, and monitoring of disease control and regional efforts towards elimination, but existing efforts to model the constraints of temperature on the malaria landscape at these scales have been simplistic. Here, we define an analytical framework to model these constraints appropriately at fine spatial and temporal resolutions, providing a detailed dynamic description that can enhance large scale malaria cartography as a decision-support tool in public health.
RESULTS
We defined a dynamic biological model that incorporated the principal mechanisms of temperature dependency in the malaria transmission cycle and used it with fine spatial and temporal resolution temperature data to evaluate time-series of temperature suitability for transmission of Plasmodium falciparum and P. vivax throughout an average year, quantified using an index proportional to the basic reproductive number. Time-series were calculated for all 1 km resolution land pixels globally and were summarised to create high-resolution maps for each species delineating those regions where temperature precludes transmission throughout the year. Within suitable zones we mapped for each pixel the number of days in which transmission is possible and an integrated measure of the intensity of suitability across the year. The detailed evaluation of temporal suitability dynamics provided by the model is visualised in a series of accompanying animations.
CONCLUSIONS
These modelled products, made available freely in the public domain, can support the refined delineation of populations at risk; enhance endemicity mapping by offering a detailed, dynamic, and biologically driven alternative to the ubiquitous empirical incorporation of raw temperature data in geospatial models; and provide a rich spatial and temporal platform for future biological modelling studies.
Topics: Climate; Environment; Geography; Humans; Malaria, Falciparum; Malaria, Vivax; Models, Statistical; Plasmodium falciparum; Plasmodium vivax; Seasons; Temperature
PubMed: 21615906
DOI: 10.1186/1756-3305-4-92 -
Cell Host & Microbe Mar 2018The unique relapsing nature of Plasmodium vivax infection is a major barrier to malaria eradication. Upon infection, dormant liver-stage forms, hypnozoites, linger for...
The unique relapsing nature of Plasmodium vivax infection is a major barrier to malaria eradication. Upon infection, dormant liver-stage forms, hypnozoites, linger for weeks to months and then relapse to cause recurrent blood-stage infection. Very little is known about hypnozoite biology; definitive biomarkers are lacking and in vitro platforms that support phenotypic studies are needed. Here, we recapitulate the entire liver stage of P. vivax in vitro, using a multiwell format that incorporates micropatterned primary human hepatocyte co-cultures (MPCCs). MPCCs feature key aspects of P. vivax biology, including establishment of persistent small forms and growing schizonts, merosome release, and subsequent infection of reticulocytes. We find that the small forms exhibit previously described hallmarks of hypnozoites, and we pilot MPCCs as a tool for testing candidate anti-hypnozoite drugs. Finally, we employ a hybrid capture strategy and RNA sequencing to describe the hypnozoite transcriptome and gain insight into its biology.
Topics: Animals; Antimalarials; Biomarkers; Cell Culture Techniques; Cell Line; Coculture Techniques; Fibroblasts; Hepatocytes; Humans; In Vitro Techniques; Kinetics; Liver; Malaria, Vivax; Mice; Parasitic Sensitivity Tests; Plasmodium vivax; Sequence Analysis, RNA; Sporozoites; Transcriptome
PubMed: 29478773
DOI: 10.1016/j.chom.2018.01.002 -
Malaria Journal Apr 2010Plasmodium vivax and Plasmodium falciparum are the major causative agents of malaria. While knowledge of the genetic structure of malaria parasites is useful for...
BACKGROUND
Plasmodium vivax and Plasmodium falciparum are the major causative agents of malaria. While knowledge of the genetic structure of malaria parasites is useful for understanding the evolution of parasite virulence, designing anti-malarial vaccines and assessing the impact of malaria control measures, there is a paucity of information on genetic diversity of these two malaria parasites in Pakistan. This study sought to shed some light on the genetic structure of P. vivax and P. falciparum in this understudied region.
METHODS
The genetic diversities of P. vivax and P. falciparum populations from the densely populated, malaria-endemic Bannu district of Pakistan were evaluated by analysis of their merozoite surface protein (msp) genes by PCR-RFLP. Specifically, the Pvmsp-3alpha and Pvmsp-3beta genes of P. vivax and the Pfmsp-1 and Pfmsp-2 genes of P. falciparum were analysed.
RESULTS
In P. vivax, genotyping of Pvmsp-3alpha and Pvmsp-3beta genes showed a high level of diversity at these loci. Four distinct allele groups: A (1.9 kb), B (1.5 kb), C (1.2 kb), and D (0.3 kb) were detected for Pvmsp-3alpha, type A being the most prevalent (82%). Conversely, amplification of the P. vivax msp-3beta locus produced two allele groups: A (1.7-2.2 kb, 62%) and B (1.4-1.5 kb, 33%), with 5% mixed-strain infections. Restriction analysis of Pvmsp-3alpha and Pvmsp-3beta yielded 12 and 8 distinct alleles, respectively, with a combined mixed genotype prevalence of 20%. In P. falciparum, all three known genotypes of Pfmsp-1 and two of Pfmsp-2 were observed, with MAD20 occurring in 67% and 3D7/IC in 65% of the isolates, respectively. Overall, 24% P. falciparum samples exhibited mixed-strain infections.
CONCLUSION
These results indicate that both P. vivax and P. falciparum populations in Pakistan are highly diverse.
Topics: Antigens, Protozoan; Genetic Structures; Genetic Variation; Genotype; Humans; Merozoite Surface Protein 1; Pakistan; Plasmodium falciparum; Plasmodium vivax; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Protozoan Proteins; Sequence Analysis, DNA
PubMed: 20416089
DOI: 10.1186/1475-2875-9-112 -
Memorias Do Instituto Oswaldo Cruz Aug 2011It is generally accepted that Plasmodium vivax, the most widely distributed human malaria parasite, causes mild disease and that this species does not sequester in the... (Review)
Review
It is generally accepted that Plasmodium vivax, the most widely distributed human malaria parasite, causes mild disease and that this species does not sequester in the deep capillaries of internal organs. Recent evidence, however, has demonstrated that there is severe disease, sometimes resulting in death, exclusively associated with P. vivax and that P. vivax-infected reticulocytes are able to cytoadhere in vitro to different endothelial cells and placental cryosections. Here, we review the scarce and preliminary data on cytoadherence in P. vivax, reinforcing the importance of this phenomenon in this species and highlighting the avenues that it opens for our understanding of the pathology of this neglected human malaria parasite.
Topics: Cell Adhesion; Erythrocytes; Humans; Malaria, Vivax; Plasmodium vivax
PubMed: 21881760
DOI: 10.1590/s0074-02762011000900010 -
PLoS Biology May 2020Plasmodium vivax and P. falciparum, the parasites responsible for most human malaria worldwide, exhibit striking biological differences, which have important clinical...
Plasmodium vivax and P. falciparum, the parasites responsible for most human malaria worldwide, exhibit striking biological differences, which have important clinical consequences. Unfortunately, P. vivax, unlike P. falciparum, cannot be cultivated continuously in vitro, which limits our understanding of its biology and, consequently, our ability to effectively control vivax malaria. Here, we describe single-cell gene expression profiles of 9,215 P. vivax parasites from bloodstream infections of Aotus and Saimiri monkeys. Our results show that transcription of most P. vivax genes occurs during short periods of the intraerythrocytic cycle and that this pattern of gene expression is conserved in other Plasmodium species. However, we also identify a strikingly high proportion of species-specific transcripts in late schizonts, possibly associated with the specificity of erythrocyte invasion. Our findings provide new and robust markers of blood-stage parasites, including some that are specific to the elusive P. vivax male gametocytes, and will be useful for analyzing gene expression data from laboratory and field samples.
Topics: Animals; Aotidae; Chloroquine; Female; Gene Expression; Male; Multigene Family; Plasmodium vivax; Saimiri; Schizonts; Sequence Analysis, RNA; Single-Cell Analysis; Species Specificity; Transcriptome
PubMed: 32365102
DOI: 10.1371/journal.pbio.3000711 -
Current Opinion in Infectious Diseases Dec 2011For over 50 years, the treatment of Plasmodium vivax has relied on a combination of chloroquine and primaquine, but this strategy is under threat. Chloroquine efficacy... (Review)
Review
PURPOSE OF REVIEW
For over 50 years, the treatment of Plasmodium vivax has relied on a combination of chloroquine and primaquine, but this strategy is under threat. Chloroquine efficacy is now compromised across much of the vivax endemic world and there are significant operational difficulties in deploying primaquine. We review the recent advances in P. vivax chemotherapy that may influence the future management of this neglected pathogen.
RECENT FINDINGS
New-generation artemisinin combination therapies (ACTs) have shown potent efficacy against the erythrocytic stages of both drug-resistant P. vivax and Plasmodium falciparum. Antimalarial regimens containing slowly eliminated drugs provide a measure of protection against the first, and possibly second, relapse of tropical strains of P. vivax, but reliable radical cure is needed to prevent future relapses. Primaquine is currently the only licensed hypnozoitocidal treatment, but requires long treatment courses and its effectiveness in different endemic settings remains largely unknown.
SUMMARY
In regions coendemic for P. vivax and P. falciparum, a unified treatment policy for malaria of any parasitological cause is likely to confer the greatest individual and public health benefit. Optimizing the safety and effectiveness of primaquine through the development of rapid diagnostic tests for glucose-6-phosphate dehydrogenase deficiency and improving drug adherence will be crucial endeavors in the fight against vivax malaria.
Topics: Antimalarials; Artemisinins; Drug Therapy, Combination; Humans; Malaria, Vivax; Plasmodium vivax
PubMed: 21986614
DOI: 10.1097/QCO.0b013e32834c61e3 -
Emerging Infectious Diseases Jan 2005We report 11 cases of severe Plasmodium vivax malaria in Bikaner (western India). Patients exhibited cerebral malaria, renal failure, circulatory collapse, severe...
We report 11 cases of severe Plasmodium vivax malaria in Bikaner (western India). Patients exhibited cerebral malaria, renal failure, circulatory collapse, severe anemia, hemoglobinurea, abnormal bleeding, acute respiratory distress syndrome, and jaundice. Peripheral blood microscopy, parasite antigen-based assays, and parasite 18s rRNA gene-based polymerase chain reaction showed the presence of P. vivax and absence of P. falciparum.
Topics: Adolescent; Adult; Animals; DNA, Protozoan; DNA, Ribosomal; Female; Humans; India; Malaria, Cerebral; Malaria, Vivax; Male; Middle Aged; Parasitemia; Plasmodium vivax; Polymerase Chain Reaction; RNA, Ribosomal, 18S; Severity of Illness Index
PubMed: 15705338
DOI: 10.3201/eid1101.040519 -
Proceedings of the National Academy of... Oct 2005Plasmodium vivax causes the most geographically widespread human malaria, accounting annually for 70-80 million clinical cases throughout the tropical and subtropical...
Plasmodium vivax causes the most geographically widespread human malaria, accounting annually for 70-80 million clinical cases throughout the tropical and subtropical regions of the world's continents. We have analyzed the DNA sequences of the Csp (circumsporozoite protein) gene in 24 geographically representative strains of P. vivax and 2 of P. simium, which parasitizes several species of New World monkeys. The Csp sequences are of two types, VK210 and VK247, which differ by three diagnostic amino acid replacements, one in each of the 5' and 3' terminal regions [5' nonrepeat (NR) and 3' NR] of the gene and in an insertion sequence that precedes the 3' NR region. The central region of the gene consists of approximately 38 repetitive "motifs," which are alternatively four and five amino acids long, which also are diagnostically different between the VK210 and VK247 types. There are very few synonymous substitutions within and between the two types of strains, which we hypothesize reflects that the worldwide spread of P. vivax is very recent. The two P. simium Csp sequences belong one to each of the two VK types and are genetically indistinguishable from the corresponding P. vivax strains, suggesting that at least two host transfers have occurred between humans and New World monkeys. We exclude as unlikely the possibility that the two types of sequences could have independently arisen in humans and platyrrhines by natural selection. There are reasons favoring each of the two possible directions of host transfer between humans and monkeys.
Topics: Animals; Haplorhini; Humans; Plasmodium; Plasmodium vivax; Polymorphism, Genetic; Protozoan Proteins; Sequence Analysis, DNA
PubMed: 16227436
DOI: 10.1073/pnas.0507413102 -
MBio Jan 2018parasites have a unique dormant stage that can cause relapses weeks or months after the initial infection. These dormant parasites are among the main challenges of...
parasites have a unique dormant stage that can cause relapses weeks or months after the initial infection. These dormant parasites are among the main challenges of vivax malaria control as they constitute a reservoir that is difficult to eliminate. Since field studies are confounded by reinfections and possible recrudescence of drug-resistant parasites, most analyses of relapses have focused on travelers returning from regions of malaria endemicity. However, it is not clear whether these individuals accurately recapitulate the relapse patterns of repeatedly infected individuals residing in areas of endemicity. Here, we present analyses of vivax malaria patients enrolled in a tightly controlled field study in Cambodia. After antimalarial drug treatment was administered, we relocated 20 individuals to a nontransmission area and followed them for 60 days, with blood collection performed every second day. Our analyses reveal that 60% of the patients relapsed during the monitoring period. Using whole-genome sequencing and high-throughput genotyping, we showed that relapses in Cambodia are often polyclonal and that the relapsing parasites harbor various degrees of relatedness to the parasites present in the initial infection. Our analyses also showed that clone populations differed dynamically, with new clones emerging during the course of the relapsing infections. Overall, our study data show that it is possible to investigate the patterns, dynamics, and diversity of relapses of individuals living in a region of malaria endemicity and reveal that relapses are much more pervasive and complex than previously considered. (This study has been registered at ClinicalTrials.gov under registration no. NCT02118090) parasites can remain dormant in the liver and relapse weeks or months after the initial infection, greatly complicating malaria control and elimination efforts. The few investigations of this dormant stage have relied on travelers and military personnel returning from areas of malaria endemicity. However, it is not clear whether these individuals, exposed to a limited number of infections, accurately represent the patterns of relapses of individuals living in areas of endemicity, who are repeatedly infected by parasites. Our study combined tightly controlled fieldwork with comprehensive genomic analyses, and our report provides a first opportunity to investigate the patterns, dynamics, and diversity of relapses directly with individuals living in areas of endemicity.
Topics: Cambodia; Female; Genetic Variation; Genotype; Genotyping Techniques; Humans; Malaria, Vivax; Male; Plasmodium vivax; Recurrence; Whole Genome Sequencing
PubMed: 29362233
DOI: 10.1128/mBio.01888-17