Fitness components and natural selection: why are there different patterns on the emergence of drug resistance in Plasmodium falciparum and Plasmodium vivax?

BACKGROUND: Considering the distinct biological characteristics of Plasmodium species is crucial for control and elimination efforts, in particular when facing the spread of drug resistance. Whereas the evolutionary fitness of all malarial species could be approximated by the probability of being taken by a mosquito and then infecting a new host, the actual steps in the malaria life cycle leading to a successful transmission event show differences among Plasmodium species. These “steps” are called fitness components. Differences in terms of fitness components may affect how selection imposed by interventions, e.g. drug treatments, differentially acts on each Plasmodium species. Thus, a successful malaria control or elimination programme should understand how differences in fitness components among different malaria species could affect adaptive evolution (e.g. the emergence of drug resistance). In this investigation, the interactions between some fitness components and natural selection are explored. METHODS: A population-genetic model is formulated that qualitatively explains how different fitness components (in particular gametocytogenesis and longevity of gametocytes) affect selection acting on merozoites during the erythrocytic cycle. By comparing Plasmodium falciparum and Plasmodium vivax, the interplay of parasitaemia and gametocytaemia dynamics in determining fitness is modelled under circumstances that allow contrasting solely the differences between these two parasites in terms of their fitness components. RESULTS: By simulating fitness components, it is shown that selection acting on merozoites (e.g., on drug resistant mutations or malaria antigens) is more efficient in P. falciparum than in P. vivax. These results could explain, at least in part, why resistance against drugs, such as chloroquine (CQ) is highly prevalent in P. falciparum worldwide, while CQ is still a successful treatment for P. vivax despite its massive use. Furthermore, these analyses are used to explore the importance of understanding the dynamic of gametocytaemia to ascertain the spreading of drug resistance. CONCLUSIONS: The strength of natural selection on mutations that express their advantage at the merozoite stage is different in P. vivax and P. falciparum. Species-specific differences in gametocytogenesis and longevity of gametocytes need to be accounted for when designing effective malaria control and elimination programmes. There is a need for reliable data on gametocytogenesis from field studies

Plasmodium vivax populations revisited: mitochondrial genomes of temperate strains in Asia suggest ancient population expansion

<p>Abstract</p> <p>Background</p> <p><it>Plasmodium vivax </it>is the most widely distributed human malaria parasite outside of Africa, and its range extends well into the temperate zones. Previous studies provided evidence for vivax population differentiation, but temperate vivax parasites were not well represented in these analyses. Here we address this deficit by using complete mitochondrial (mt) genome sequences to elucidate the broad genetic diversity and population structure of <it>P. vivax </it>from temperate regions in East and Southeast Asia.</p> <p>Results</p> <p>From the complete mtDNA sequences of 99 clinical samples collected in China, Myanmar and Korea, a total of 30 different haplotypes were identified from 26 polymorphic sites. Significant differentiation between different East and Southeast Asian parasite populations was observed except for the comparison between populations from Korea and southern China. Haplotype patterns and structure diversity analysis showed coexistence of two different groups in East Asia, which were genetically related to the Southeast Asian population and Myanmar population, respectively. The demographic history of <it>P. vivax</it>, examined using neutrality tests and mismatch distribution analyses, revealed population expansion events across the entire <it>P. vivax </it>range and the Myanmar population. Bayesian skyline analysis further supported the occurrence of ancient <it>P. vivax </it>population expansion.</p> <p>Conclusions</p> <p>This study provided further resolution of the population structure and evolution of <it>P. vivax</it>, especially in temperate/warm-temperate endemic areas of Asia. The results revealed divergence of the <it>P. vivax </it>populations in temperate regions of China and Korea from other populations. Multiple analyses confirmed ancient population expansion of this parasite. The extensive genetic diversity of the <it>P. vivax </it>populations is consistent with phenotypic plasticity of the parasites, which has implications for malaria control.</p

Wild Primate Populations in Emerging Infectious Disease Research: The Missing Link?

Wild primate populations, an unexplored source of information regarding emerging infectious disease, may hold valuable clues to the origins and evolution of some important pathogens. Primates can act as reservoirs for human pathogens. As members of biologically diverse habitats, they serve as sentinels for surveillance of emerging pathogens and provide models for basic research on natural transmission dynamics. Since emerging infectious diseases also pose serious threats to endangered and threatened primate species, studies of these diseases in primate populations can benefit conservation efforts and may provide the missing link between laboratory studies and the well-recognized needs of early disease detection, identification, and surveillance

Genetic diversity of vaccine candidate antigens in Plasmodium falciparum isolates from the Amazon basin of Peru

<p>Abstract</p> <p>Background</p> <p>Several of the intended <it>Plasmodium falciparum </it>vaccine candidate antigens are highly polymorphic and could render a vaccine ineffective if their antigenic sites were not represented in the vaccine. In this study, characterization of genetic variability was performed in major B and T-cell epitopes within vaccine candidate antigens in isolates of <it>P. falciparum </it>from Peru.</p> <p>Methods</p> <p>DNA sequencing analysis was completed on 139 isolates of <it>P. falciparum </it>collected from endemic areas of the Amazon basin in Loreto, Peru from years 1998 to 2006. Genetic diversity was determined in immunological important regions in circumsporozoite protein (CSP), merozoite surface protein-1 (MSP-1), apical membrane antigen-1 (AMA-1), liver stage antigen-1 (LSA-1) and thrombospondin-related anonymous protein (TRAP). Alleles identified by DNA sequencing were aligned with the vaccine strain 3D7 and DNA polymorphism analysis and FST study-year pairwise comparisons were done using the DnaSP software. Multilocus analysis (MLA) was performed and average of expected heterozygosity was calculated for each loci and haplotype over time.</p> <p>Results</p> <p>Three different alleles for CSP, seven for MSP-1 Block 2, one for MSP-1 Block 17, three for AMA-1 and for LSA-1 each and one for TRAP were identified. There were 24 different haplotypes in 125 infections with complete locus typing for each gene.</p> <p>Conclusion</p> <p>Characterization of the genetic diversity in <it>Plasmodium </it>isolates from the Amazon Region of Peru showed that <it>P. falciparum </it>T and B cell epitopes in these antigens have polymorphisms more similar to India than to Africa. These findings are helpful in the formulation of a vaccine considering restricted repertoire populations.</p

Genetic diversity and population structure of genes encoding vaccine candidate antigens of Plasmodium vivax

<p>Abstract</p> <p>Background</p> <p>A major concern in malaria vaccine development is genetic polymorphisms typically observed among <it>Plasmodium </it>isolates in different geographical areas across the world. Highly polymorphic regions have been observed in <it>Plasmodium falciparum </it>and <it>Plasmodium vivax </it>antigenic surface proteins such as Circumsporozoite protein (CSP), Duffy-binding protein (DBP), Merozoite surface protein-1 (MSP-1), Apical membrane antigen-1 (AMA-1) and Thrombospondin related anonymous protein (TRAP).</p> <p>Methods</p> <p>Genetic variability was assessed in important polymorphic regions of various vaccine candidate antigens in <it>P. vivax </it>among 106 isolates from the Amazon Region of Loreto, Peru. In addition, genetic diversity determined in Peruvian isolates was compared to population studies from various geographical locations worldwide.</p> <p>Results</p> <p>The structured diversity found in <it>P. vivax </it>populations did not show a geographic pattern and haplotypes from all gene candidates were distributed worldwide. In addition, evidence of balancing selection was found in polymorphic regions of the <it>trap, dbp </it>and <it>ama-1 </it>genes.</p> <p>Conclusions</p> <p>It is important to have a good representation of the haplotypes circulating worldwide when implementing a vaccine, regardless of the geographic region of deployment since selective pressure plays an important role in structuring antigen diversity.</p

Prospective Study of Plasmodium vivax Malaria Recurrence after Radical Treatment with a Chloroquine-Primaquine Standard Regimen in Turbo, Colombia.

Plasmodium vivax recurrences help maintain malaria transmission. They are caused by recrudescence, reinfection, or relapse, which are not easily differentiated. A longitudinal observational study took place in Turbo municipality, Colombia. Participants with uncomplicated P. vivax infection received supervised treatment concomitantly with 25 mg/kg chloroquine and 0.25 mg/kg/day primaquine for 14 days. Incidence of recurrence was assessed over 180 days. Samples were genotyped, and origins of recurrences were established. A total of 134 participants were enrolled between February 2012 and July 2013, and 87 were followed for 180 days, during which 29 recurrences were detected. The cumulative incidence of first recurrence was 24.1% (21/87) (95% confidence interval [CI], 14.6 to 33.7%), and 86% (18/21) of these events occurred between days 51 and 110. High genetic diversity of P. vivax strains was found, and 12.5% (16/128) of the infections were polyclonal. Among detected recurrences, 93.1% (27/29) of strains were genotyped as genetically identical to the strain from the previous infection episode, and 65.5% (19/29) of infections were classified as relapses. Our results indicate that there is a high incidence of P. vivax malaria recurrence after treatment in Turbo municipality, Colombia, and that a large majority of these episodes are likely relapses from the previous infection. We attribute this to the primaquine regimen currently used in Colombia, which may be insufficient to eliminate hypnozoites

Blood parasites infecting the Hoatzin (Opisthocomus hoazin), a unique neotropical folivorous bird

The Hoatzin (Opisthocomus hoazin) is the only extant member of the order Opisthocomiformes. This unique South American bird lives in the riparian lowland vegetation characteristic of the Amazon and Orinoco basins. Hoatzins nest in communal social units close to water bodies; they are strictly folivores being the only bird with pregastric fermentation in the crop. Because of the complex logistics involved in capturing this bird, there is a knowledge gap on its parasites. This study documents two distant lineages of haemosporidian parasites (Plasmodium spp.) in a juvenile and two adults sampled in the Cojedes state, Venezuela. Although negative by microscopy, the parasite identification was possible by using molecular methods. We estimated the phylogenetic relationships on the parasite cytochrome b (cytb, 480 bp) gene and the mitochondrial DNA. We found one of the parasites lineages in two individuals (nestling and adult), and the corresponding fragment of cytb was identical to a one found in Wood Stork (Mycteria americana) from Brazil. The other lineage, found in an adult, has an identity of 469 out of 478 bp (98%) with Plasmodium sp. GAL-2012 (isolate THAMB08) from Brazil. Although a morphological description of these parasites was not possible, this is the first molecular study focusing on Hoatzin haemosporidian parasites and the first documentation of Plasmodium infections in the Hoatzin from Venezuela. Furthermore, we reported microfilaria in two adults as well as hematological parameters for six individuals. Information on hematological parameters could contribute to establishing the necessary baseline to detect underlying conditions, such as infections, in this bird species

Differences in selective pressure on dhps and dhfr drug resistant mutations in western Kenya

<p>Abstract</p> <p>Background</p> <p>Understanding the origin and spread of mutations associated with drug resistance, especially in the context of combination therapy, will help guide strategies to halt and prevent the emergence of resistance. Unfortunately, studies have assessed these complex processes when resistance is already highly prevalent. Even further, information on the evolutionary dynamics leading to multidrug-resistant parasites is scattered and limited to areas with low or seasonal malaria transmission. This study describes the dynamics of strong selection for mutations conferring resistance against sulphadoxine-pyrimethamine (SP), a combination therapy, in western Kenya between 1992 and 1999, just before SP became first-line therapy (1999). Importantly, the study is based on longitudinal data, which allows for a comprehensive analysis that contrasts with previous cross-sectional studies carried out in other endemic regions.</p> <p>Methods</p> <p>This study used 236 blood samples collected between 1992 and 1999 in the Asembo Bay area of Kenya. Pyrosequencing was used to determine the alleles of dihydrofolate reductase (<it>dhfr</it>) and dihydropterote synthase <it>(dhps) </it>genes. Microsatellite alleles spanning 138 kb around <it>dhfr </it>and <it>dhps</it>, as well as, neutral markers spanning approximately 100 kb on chromosomes 2 and 3 were characterized.</p> <p>Results</p> <p>By 1992, the South-Asian <it>dhfr </it>triple mutant was already spreading, albeit in low frequency, in this holoendemic Kenyan population, prior to the use of SP as a first-line therapy. Additionally, <it>dhfr </it>triple mutant alleles that originated independently from the predominant Southeast Asian lineage were present in the sample set. Likewise, <it>dhps </it>double mutants were already present as early as 1992. There is evidence for soft selective sweeps of two <it>dhfr </it>mutant alleles and the possible emergence of a selective sweep of double mutant <it>dhps </it>alleles between 1992 and 1997. The longitudinal structure of the dataset allowed estimation of selection pressures on various <it>dhfr </it>and <it>dhps </it>mutants relative to each other based on a theoretical model tailored to <it>P. falciparum</it>. The data indicate that drug selection acted differently on the resistant alleles of <it>dhfr </it>and <it>dhps</it>, as evidenced by fitness differences. Thus a combination drug therapy such as SP, by itself, does not appear to select for "multidrug"-resistant parasites in areas with high recombination rate.</p> <p>Conclusions</p> <p>The complexity of these observations emphasizes the importance of population-based studies to evaluate the effects of strong drug selection on <it>Plasmodium falciparum </it>populations.</p

Population dynamics of rhesus macaques and associated foamy virus in Bangladesh.

Foamy viruses are complex retroviruses that have been shown to be transmitted from nonhuman primates to humans. In Bangladesh, infection with simian foamy virus (SFV) is ubiquitous among rhesus macaques, which come into contact with humans in diverse locations and contexts throughout the country. We analyzed microsatellite DNA from 126 macaques at six sites in Bangladesh in order to characterize geographic patterns of macaque population structure. We also included in this study 38 macaques owned by nomadic people who train them to perform for audiences. PCR was used to analyze a portion of the proviral gag gene from all SFV-positive macaques, and multiple clones were sequenced. Phylogenetic analysis was used to infer long-term patterns of viral transmission. Analyses of SFV gag gene sequences indicated that macaque populations from different areas harbor genetically distinct strains of SFV, suggesting that geographic features such as forest cover play a role in determining the dispersal of macaques and SFV. We also found evidence suggesting that humans traveling the region with performing macaques likely play a role in the translocation of macaques and SFV. Our studies found that individual animals can harbor more than one strain of SFV and that presence of more than one SFV strain is more common among older animals. Some macaques are infected with SFV that appears to be recombinant. These findings paint a more detailed picture of how geographic and sociocultural factors influence the spectrum of simian-borne retroviruses

Two nonrecombining sympatric forms of the human malaria parasite Plasmodium ovale occur globally.

BACKGROUND: Malaria in humans is caused by apicomplexan parasites belonging to 5 species of the genus Plasmodium. Infections with Plasmodium ovale are widely distributed but rarely investigated, and the resulting burden of disease is not known. Dimorphism in defined genes has led to P. ovale parasites being divided into classic and variant types. We hypothesized that these dimorphs represent distinct parasite species. METHODS: Multilocus sequence analysis of 6 genetic characters was carried out among 55 isolates from 12 African and 3 Asia-Pacific countries. RESULTS: Each genetic character displayed complete dimorphism and segregated perfectly between the 2 types. Both types were identified in samples from Ghana, Nigeria, São Tomé, Sierra Leone, and Uganda and have been described previously in Myanmar. Splitting of the 2 lineages is estimated to have occurred between 1.0 and 3.5 million years ago in hominid hosts. CONCLUSIONS: We propose that P. ovale comprises 2 nonrecombining species that are sympatric in Africa and Asia. We speculate on possible scenarios that could have led to this speciation. Furthermore, the relatively high frequency of imported cases of symptomatic P. ovale infection in the United Kingdom suggests that the morbidity caused by ovale malaria has been underestimated