Primate Plasmodium Research Articles

Non-human primate malaria parasites: out of the forest and into the laboratory.

The study of malaria in the laboratory relies on either the in vitro culture of human parasites, or the use of non-human malaria parasites in laboratory animals. In this review, we address the use of non-human primate malaria parasite species (NHPMPs) in laboratory research. We describe the features of the most commonly used NHPMPs, review their contribution to our understanding of malaria to date, and discuss their potential contribution to future studies.

Investigating the Contribution of Peri-domestic Transmission to Risk of Zoonotic Malaria Infection in Humans.

BackgroundIn recent years, the primate malaria Plasmodium knowlesi has emerged in human populations throughout South East Asia, with the largest hotspot being in Sabah, Malaysian Borneo. Control efforts are hindered by limited knowledge of where and when people get exposed to mosquito vectors. It is assumed that exposure occurs primarily when people are working in forest areas, but the role of other potential exposure routes (including domestic or peri-domestic transmission) has not been thoroughly investigated.Methodology/Principal FindingsWe integrated entomological surveillance within a comprehensive case-control study occurring within a large hotspot of transmission in Sabah, Malaysia. Mosquitoes were collected at 28 pairs households composed of one where an occupant had a confirmed P. knowlesi infection within the preceding 3 weeks (“case”) and an associated “control” where no infection was reported. Human landing catches were conducted to measure the number and diversity of mosquitoes host seeking inside houses and in the surrounding peri-domestic (outdoors but around the household) areas. The predominant malaria vector species was Anopheles balabacensis, most of which were caught outdoors in the early evening (6pm - 9pm). It was significantly more abundant in the peri-domestic area than inside houses (5.5-fold), and also higher at case than control households (0.28±0.194 vs 0.17±0.127, p<0.001). Ten out of 641 An. balabacensis tested were positive for simian malaria parasites, but none for P. knowlesi.Conclusions/SignificanceThis study shows there is a possibility that humans can be exposed to P. knowlesi infection around their homes. The vector is highly exophagic and few were caught indoors indicating interventions using bednets inside households may have relatively little impact.

Baculovirus-expressed Plasmodium reichenowi EBA-140 merozoite ligand is host specific

Plasmodium reichenowi, an ape malaria parasite is morphologically identical and genetically similar to Plasmodium falciparum, infects chimpanzees but not humans. Genomic studies revealed that all primate malaria parasites belong to Laverania subgenus. Laverania parasites exhibit strict host specificity, but the molecular mechanisms underlying these host restrictions remain unexplained.Plasmodium merozoites express multiple binding ligands that recognize specific receptors on erythrocytes, including micronemal proteins belonging to P. falciparum EBL family. It was shown that erythrocyte binding antigen-175 (EBA-175), erythrocyte binding ligand-1 (EBL-1), erythrocyte binding antigen-140 (EBA-140) recognize erythrocyte surface sialoglycoproteins - glycophorins A, B, C, respectively. EBA-140 merozoite ligand hijacks glycophorin C (GPC), a minor erythrocyte sialoglycoprotein, to invade the erythrocyte through an alternative invasion pathway.A homolog of P. falciparum EBA-140 protein was identified in P. reichenowi. The amino acid sequences of both EBA-140 ligands are very similar, especially in the conservative erythrocyte binding region (Region II). It has been suggested that evolutionary changes in the sequence of EBL proteins may be associated with Plasmodium host restriction.In this study we obtained, for the first time, the recombinant P. reichenowi EBA-140 ligand Region II using baculovirus expression vector system. We show that the ape EBA-140 Region II is host specific and binds to chimpanzee erythrocytes in the dose and sialic acid dependent manner. Further identification of the erythrocyte receptor for this ape ligand is of great interests, since it may reveal the molecular basis of host restriction of both P. reichenowi and its deadliest human counterpart, P. falciparum.

Genetic Analysis and Species Specific Amplification of the Artemisinin Resistance-Associated Kelch Propeller Domain in P. falciparum and P. vivax.

Plasmodium falciparum resistance to artemisinin has emerged in the Greater Mekong Subregion and now poses a threat to malaria control and prevention. Recent work has identified mutations in the kelch propeller domain of the P. falciparum K13 gene to be associated artemisinin resistance as defined by delayed parasite clearance and ex vivo ring stage survival assays. Species specific primers for the two most prevalent human malaria species, P. falciparum and P. vivax, were designed and tested on multiple parasite isolates including human, rodent, and non- humans primate Plasmodium species. The new protocol described here using the species specific primers only amplified their respective species, P. falciparum and P. vivax, and did not cross react with any of the other human malaria Plasmodium species. We provide an improved species specific PCR and sequencing protocol that could be effectively used in areas where both P. falciparum and P. vivax are circulating. To design this improved protocol, the kelch gene was analyzed and compared among different species of Plasmodium. The kelch propeller domain was found to be highly conserved across the mammalian Plasmodium species.

Humans frequently exposed to a range of non-human primate malaria parasite species through the bites of Anopheles dirus mosquitoes in South-central Vietnam.

BackgroundRecent studies have described natural human infections of the non-human primate parasites Plasmodium knowlesi and Plasmodium cynomolgi. In Southeast Asia, mosquitoes of the Anopheles leucosphyrus group bite both humans and monkeys in the forest and thus offer a possible route for Plasmodium species to bridge the species barrier. In this study we analysed the species composition of malarial sporozoites infecting the salivary glands of Anopheles dirus in order to determine their potential role as bridge vectors of Plasmodium parasites from monkeys to humans.MethodsMosquitoes were collected in the forest and forest fringe area of Khanh Phu commune by human-baited landing collection. Anopheles species were determined on the basis of morphologic features. Sporozoite-infected salivary glands were applied to filter paper and dried in an ambient atmosphere, before storage in closed vials at 4–6 °C. Detection and identification of Plasmodium species in salivary glands were carried out by nested-PCR of the small subunit ribosomal RNA gene.ResultsSix species of Plasmodium parasites were detected by PCR, of which P. vivax was the most common, followed by P. knowlesi, P. inui, P. cynomolgi, P. coatneyi and P. falciparum. Twenty-six of the 79 sporozoite infected mosquitoes showed multiple infections, most of which were a combination of P. vivax with one or more of the non-human primate Plasmodium species.ConclusionsThese results suggest that humans overnighting in this forest are frequently inoculated with both human and non-human primate malaria parasites, leading to a situation conducive for the emergence of novel zoonotic malaria.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-015-0995-y) contains supplementary material, which is available to authorized users.

Metabolomics in the fight against malaria.

Metabolomics uses high-resolution mass spectrometry to provide a chemical fingerprint of thousands of metabolites present in cells, tissues or body fluids. Such metabolic phenotyping has been successfully used to study various biologic processes and disease states. High-resolution metabolomics can shed new light on the intricacies of host-parasite interactions in each stage of the Plasmodium life cycle and the downstream ramifications on the host’s metabolism, pathogenesis and disease. Such data can become integrated with other large datasets generated using top-down systems biology approaches and be utilised by computational biologists to develop and enhance models of malaria pathogenesis relevant for identifying new drug targets or intervention strategies. Here, we focus on the promise of metabolomics to complement systems biology approaches in the quest for novel interventions in the fight against malaria. We introduce the Malaria Host-Pathogen Interaction Center (MaHPIC), a new systems biology research coalition. A primary goal of the MaHPIC is to generate systems biology datasets relating to human and non-human primate (NHP) malaria parasites and their hosts making these openly available from an online relational database. Metabolomic data from NHP infections and clinical malaria infections from around the world will comprise a unique global resource.

Identification of avir-orthologous immune evasion gene family from primate malaria parasites

The immune evasion gene family of malaria parasites encodes variant surface proteins that are expressed at the surface of infected erythrocytes and help the parasite in evading the host immune response by means of antigenic variation. The identification of Plasmodium vivax vir orthologous immune evasion gene family from primate malaria parasites would provide new insight into the evolution of virulence and pathogenesis. Three vir subfamilies viz. vir-B, vir-D and vir-G were successfully PCR amplified from primate malaria parasites, cloned and sequenced. DNA sequence analysis confirmed orthologues of vir-D subfamily in Plasmodium cynomolgi, Plasmodium simium, Plasmodium simiovale and Plasmodium fieldi. The identified vir-D orthologues are 1-9 distinct members of the immune evasion gene family which have 68-83% sequence identity with vir-D and 71.2-98.5% sequence identity within the members identified from primate malaria parasites. The absence of other vir subfamilies among primate malaria parasites reflects the limitations in the experimental approach. This study clearly identified the presence of vir-D like sequences in four species of Plasmodium infecting primates that would be useful in understanding the evolution of virulence in malaria parasites.

Triangular test design to evaluate tinidazole in the prevention of Plasmodium vivax relapse.

BackgroundThere are very few drugs that prevent the relapse of Plasmodium vivax malaria in man. Tinidazole is a 5-nitroimidazole approved in the USA for the treatment of indications including amoebiasis and giardiasis. In the non-human primate relapsing Plasmodium cynomolgi/macaque malaria model, tinidazole cured one of six macaques studied with an apparent mild delay to relapse in the other five of 14–28 days compared to 11–12 days in controls. One study has demonstrated activity against P. vivax in man. Presented here are the results of a pilot phase II, randomized, open-label study conducted along the Thai-Myanmar border designed to evaluate the efficacy of tinidazole to prevent relapse of P. vivax when administered with chloroquine.MethodsThis study utilized a modified triangular test sequential analysis which allows repeated statistical evaluation during the course of enrolment while maintaining a specified power and type 1 error and minimizing recruitment of subjects. Enrolment was to be halted when a pre-specified success/failure ratio was surpassed. The study was designed to have a 5% type 1 error and 90% power to show whether tinidazole would produce a relapse rate of less than 20% or greater than 45% through Day 63 of weekly follow-up after initiation of treatment and initial parasite clearance with 3 days of an oral weight based dosing of chloroquine and five days of 2 grams/day of tinidazole.ResultsAll subjects cleared their parasitaemia by Day 3. Six of the first seven subjects treated with tinidazole relapsed prior to Day 63 (average Day 48.3 (range 42–56)). This exceeded the upper boundary of the triangular test and enrolment to receive tinidazole was halted. A concurrent cohort of five subjects definitively treated with standard doses of primaquine and chloroquine (historically 100% effective) showed no episodes of recurrent P. vivax parasitaemia during the 63-day protocol specified follow-up period.ConclusionsTinidazole is ineffective in preventing relapse of P. vivax at the dose used. The macaque relapsing model appeared to correctly predict outcome in humans. Use of the modified triangular test allowed minimal enrolment and limited unnecessary exposure to the study drug and reduced costs. This adds weight to the ethical and economic advantages of this study design to evaluate similarly situated drugs.Trial registrationClinicalTrials.gov NCT00811096

The Origin of Malarial Parasites in Orangutans

BackgroundRecent findings of Plasmodium in African apes have changed our perspectives on the evolution of malarial parasites in hominids. However, phylogenetic analyses of primate malarias are still missing information from Southeast Asian apes. In this study, we report molecular data for a malaria parasite lineage found in orangutans.Methodology/Principal FindingsWe screened twenty-four blood samples from Pongo pygmaeus (Kalimantan, Indonesia) for Plasmodium parasites by PCR. For all the malaria positive orangutan samples, parasite mitochondrial genomes (mtDNA) and two antigens: merozoite surface protein 1 42 kDa (MSP-142) and circumsporozoite protein gene (CSP) were amplified, cloned, and sequenced. Fifteen orangutans tested positive and yielded 5 distinct mitochondrial haplotypes not previously found. The haplotypes detected exhibited low genetic divergence among them, indicating that they belong to one species. We report phylogenetic analyses using mitochondrial genomes, MSP-142 and CSP. We found that the orangutan malaria parasite lineage was part of a monophyletic group that includes all the known non-human primate malaria parasites found in Southeast Asia; specifically, it shares a recent common ancestor with P. inui (a macaque parasite) and P. hylobati (a gibbon parasite) suggesting that this lineage originated as a result of a host switch. The genetic diversity of MSP-142 in orangutans seems to be under negative selection. This result is similar to previous findings in non-human primate malarias closely related to P. vivax. As has been previously observed in the other Plasmodium species found in non-human primates, the CSP shows high polymorphism in the number of repeats. However, it has clearly distinctive motifs from those previously found in other malarial parasites.ConclusionThe evidence available from Asian apes indicates that these parasites originated independently from those found in Africa, likely as the result of host switches from other non-human primates.

Positive diversifying selection onPlasmodium vivaxRON2 protein

Plasmodium rhoptry neck protein 2 (RON2), which is released from the neck portion of the merozoite rhoptries and interacts with the microneme protein Apical Membrane Antigen 1 (AMA1), plays a crucial role in erythrocyte invasion. In this study, we sequenced the Plasmodium vivax RON2 gene from 19 P. vivax isolates collected in central China in order to establish whether this protein is under positive diversifying selection, which may occur as a result of protective host immune pressure†. In comparison with the P. vivax Sal-1 reference line, we found 10 amino acid substitutions dispersed throughout the open reading frame as well as indels caused by polymorphism in a repeat unit (21-23 repeats of (Q/E/K/N/H)(G/D)G(H/L/Y/P)G) in the second tandem repeat region located at amino acid positions 541-650. A McDonald-Kreitman test with RON2 sequences from the primate malaria parasite Plasmodium knowlesi, detected significant departure from neutrality in the PvRON2 3' region (nucleotide positions 2668-6609). These results suggest that the PvRON2 gene has evolved under positive diversifying selection.

Clues to Evolution of the SERA Multigene Family in 18 Plasmodium Species

SERA gene sequences were newly determined from 11 primate Plasmodium species including two human parasites, P. ovale and P. malariae, and the evolutionary history of SERA genes was analyzed together with 7 known species. All have one each of Group I to III cysteine-type SERA genes and varying number of Group IV serine-type SERA genes in tandem cluster. Notably, Group IV SERA genes were ascertained in all mammalian parasite lineages; and in two primate parasite lineages gene events such as duplication, truncation, fragmentation and gene loss occurred at high frequency in a manner that mimics the birth-and-death evolution model. Transcription profile of individual SERA genes varied greatly among rodent and monkey parasites. Results support the lineage-specific evolution of the Plasmodium SERA gene family. These findings provide further impetus for studies that could clarify/provide proof-of-concept that duplications of SERA genes were associated with the parasites' expansion of host range and the evolutionary conundrums of multigene families in Plasmodium.

The evolution of virulence in primate malaria parasites based on Bayesian reconstructions of ancestral states

Plasmodium parasites, the causative agents of malaria, are generally considered as harmful parasites, but many of them cause mild symptoms. Little is known about the evolutionary history and phylogenetic constraints that generate this interspecific variation in virulence due to uncertainties about the phylogenetic associations of parasites. Here, to account for such phylogenetic uncertainty, phylogenetic methods based on Bayesian statistics were followed in combination with sequence data from five genes to estimate the ancestral state of virulence in primate Plasmodium parasites. When recent parasites were categorised according to the damage caused to the host, Bayesian estimates of ancestral states indicated that the acquisition of a harmful host exploitation strategy is more likely to be a recent evolutionary event than a result of an ancient change in a character state altering virulence. On the contrary, there was more evidence for moderate host exploitation having a deep origin along the phylogenetic tree. Moreover, the evolution of host severity is determined by the phylogenetic relationships of parasites, as severity gains did not appear randomly on the evolutionary tree. Such phylogenetic constraints can be mediated by the acquisition of virulence genes. As the impact of a parasite on a host is the result of both the parasite’s investment in reproduction and host sensitivity, virulence was also estimated by calculating peak parasitemia after eliminating host effects. A directional random-walk evolutionary model showed that the ancestral primate malarias reproduced at very low parasitemia in their hosts. Consequently, the extreme variation in the outcome of malaria infection in different host species can be better understood in light of the phylogeny of parasites.

Diagnostic Difficulties withPlasmodium knowlesiInfection in Humans

Diagnostic Difficulties with<i>Plasmodium knowlesi</i>Infection in Humans

Human Malaria Parasites: Are We Ready for a New Species?

There are four well-established human malaria parasites, although a nonhuman primate malaria parasite, Plasmodium knowlesi, can also infect humans [1]. Plasmodium ovale is one of the human malaria parasites, but it traditionally receives little attention because of its mild disease and relatively low infection rate. An intriguing and provocative report in this issue of the Journal by Sutherland et al. raises the possibility of two distinct parasite species under the name P. ovale.

Defining species specific genome differences in malaria parasites

BackgroundIn recent years a number of genome sequences for different plasmodium species have become available. This has allowed the identification of numerous conserved genes across the different species and has significantly enhanced our understanding of parasite biology. In contrast little is known about species specific differences between the different genomes partly due to the lower sequence coverage and therefore relatively poor annotation of some of the draft genomes particularly the rodent malarias parasite species.ResultsTo improve the current annotation and gene identification status of the draft genomes of P. berghei, P. chabaudi and P. yoelii, we performed genome-wide comparisons between these three species. Through analyses via comparative genome hybridizations using a newly designed pan-rodent array as well as in depth bioinformatics analysis, we were able to improve on the coverage of the draft rodent parasite genomes by detecting orthologous genes between these related rodent parasite species. More than 1,000 orthologs for P. yoelii were now newly associated with a P. falciparum gene. In addition to extending the current core gene set for all plasmodium species this analysis also for the first time identifies a relatively small number of genes that are unique to the primate malaria parasites while a larger gene set is uniquely conserved amongst the rodent malaria parasites.ConclusionsThese findings allow a more thorough investigation of the genes that are important for host specificity in malaria.

Phylogeny of Asian primate malaria parasites inferred from apicoplast genome-encoded genes with special emphasis on the positions of Plasmodium vivax and P. fragile

Phylogenetic analyses of several marker genes have previously shown that Asian primate Plasmodium species (malaria parasites) were monophyletic including Plasmodium vivax, one of the four malaria parasites that infect humans. However, except for the presence of a few established groupings, phylogenetic relationships among the Asian primate Plasmodium species + P. vivax group have neither been clearly resolved with confident statistical supports, nor the closest relative to P. vivax was elucidated. Since comparative biological studies between P. vivax and its closest relative would provide valuable information on immunopathogenesity of vivax malaria, the phylogenetic positions of P. vivax in the clade comprised of Asian primate Plasmodium species are crucial. In order to clarify the phylogeny and evolution of Asian primate Plasmodium species including P. vivax, we obtained sequences of apicoplast genome-encoded genes for small subunit rRNA (SSUrRNA), large subunit rRNA (LSUrRNA), and caseinolytic protease C (ClpC) from 10 Plasmodium species: P. vivax, P. coatneyi, P. cynomolgi, P. fieldi, P. fragile, P. hylobati, P .inui, P. knowlesi, P. simiovale, and P. gonderi. Together with published sequences of apicoplast genome-encoded elongation factor Tu (EF-Tu) from these species, we performed phylogenetic analyses of a combined 4-gene data set using P. gonderi, an African old world monkey parasite, as an outgroup. The ML phylogeny based on a ‘concatenate model’ for combining information of the 4 genes clearly revealed close relationships between P. vivax and P. cynomolgi and monophyly of P. fragile with the P. coatneyi/ P. knowlesi clade. When ‘separate’ models were assumed for combining phylogenetic information from the 4 genes that were independently analyzed, the support for the P. vivax/ P. cynomolgi clade was substantially decreased, but the monophyly of P. fragile with the P. coatneyi/ P. knowlesi clade was still robustly confirmed. The present analyses place P. fragile in a position that is incongruent with the early branching status of P. fragile amongst P-vivax-related primate Plasmodium species propose by Escalante et al. (Proc Natl Acad Sci USA 2005 102: 1980).

Structure and function of Plasmodium falciparum malate dehydrogenase: Role of critical amino acids in co-substrate binding pocket

The malaria parasite thrives on anaerobic fermentation of glucose for energy. Earlier studies from our laboratory have demonstrated that a cytosolic malate dehydrogenase (PfMDH) with striking similarity to lactate dehydrogenase (PfLDH) might complement PfLDH function in Plasmodium falciparum. The N-terminal glycine motif, which forms a characteristic Rossman dinucleotide-binding fold in the co-substrate binding pocket, differentiates PfMDH (GlyXGlyXXGly) from other eukaryotic and prokaryotic malate dehydrogenases (GlyXXGlyXXGly). The amino acids lining the co-substrate binding pocket are completely conserved in MDHs from different species of human, primate and rodent malaria parasites. Based on this knowledge and conserved domains among prokaryotic and eukaryotic MDH, the role of critical amino acids lining the co-substrate binding pocket was analyzed in catalytic functions of PfMDH using site-directed mutagenesis. Insertion of Ala at the 9th or 10th position, which converts the N-terminal GlyXGlyXXGly motif (characteristic of malarial MDH and LDH) to GlyXXGlyXXGly (as in bacterial and eukaryotic MDH), uncoupled regulation of the enzyme through substrate inhibition. The dinucleotide fold GlyXGlyXXGly motif seems not to be responsible for the distinct affinity of PfMDH to 3-acetylpyridine-adenine dinucleotide (APAD, a synthetic analog of NAD), since Ala9 and Ala10 insertion mutants still utilized APADH. The Gln11Met mutation, which converts the signature glycine motif in PfMDH to that of PfLDH, did not change the enzyme function. However, the Gln11Gly mutant showed approximately a 5-fold increase in catalytic activity, and higher susceptibility to inhibition with gossypol. Asn119 and His174 participate in binding of both co-substrate and substrate. The Asn119Gly mutant exhibited approximately a 3-fold decrease in catalytic efficiency, while mutation of His174 to Asn or Ala resulted in an inactive enzyme. These studies provide critical insights into the co-substrate binding pocket of PfMDH, which may be important in design of selective PfMDH/PfLDH inhibitors as potential antimalarials.

Transgenic Plasmodium knowlesi: relieving a bottleneck in malaria research?

Plasmodium knowlesi is a primate malaria parasite that is phylogenetically close to the major human parasite Plasmodium vivax. P. knowlesi causes life-threatening disease in humans, infects a wide range of non-human primates and is one of few malaria parasites amenable to cyclical in vitro propagation. A robust in vivo and in vitro genetic manipulation system has been developed for this parasite, enabling in vitro-in vivo shuttling of transgenes, which (together with recent characterization of its genome and that of its macaque experimental host) offers unique opportunities to gain insight in molecular function and parasite-host interactions.

Plasmodium knowlesi: An Important Yet Overlooked Human Malaria Parasite–Reply–I

We thank Yegneswaran et al for highlighting the fact that the primate malaria Plasmodium knowlesi has gained prominence during the past few years as an emerging species that causes clinical human infections in Southeast Asia.1Cox-Singh J Singh B Knowlesi malaria: newly emergent and of public health importance?.Trends Parasitol. 2008; 24 (Epub 2008 Aug 3.): 406-410Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar, 2Cox-Singh J Davis TM Lee KS et al.Plasmodium knowlesi malaria in humans is widely distributed and potentially life threatening.Clin Infect Dis. 2008; 46: 165-171Crossref PubMed Scopus (560) Google Scholar Other primate malaria species, such as P simium, P brasilianum, P cynomolgi, and P inui, have infrequently caused human infections as well. Thus far, P knowlesi infections have been reported only from China, Indonesia, Thailand, Myanmar, Malaysia (peninsular and Borneo), and the Palawan Island in the Philippines. There has been 1 imported case from Southeast Asia3Centers for Disease Control and Prevention Simian malaria in a U.S. traveler—New York, 2008.MMWR Morb Mortal Wkly Rep. 2009; 58: 229-232PubMed Google Scholar in the United States; however, there are no known cases of P knowlesi from Africa where the patient resided. Diagnosis of P knowlesi is based on geographic area of acquisition of malaria, clinical presentation, and microscopic findings. Clinically, patients with P knowlesi present with symptoms similar to those in patients with P falciparum, but microscopic findings are easily confused with those associated with P malariae. This disconnect in clinical picture and microscopy with acquisition of malaria from Southeast Asia is the clinical diagnostic clue for P knowlesi infection. Polymerase chain reaction is the only accurate technique for making a definitive diagnosis of P knowlesi infection. Treatment is similar to that for P falciparum; both of these infections are associated with high parasitemia and possibility of mortality. Plasmodium knowlesi: An Important Yet Overlooked Human Malaria ParasiteMayo Clinic ProceedingsVol. 84Issue 7PreviewTo the Editor: In the May 2009 issue of Mayo Clinic Proceedings, Reyburn and Virk1 reported a case of a young woman who had visited West Africa and presented with fever and jaundice. The authors did not mention the fifth human malaria parasite Plasmodium knowlesi, which like P falciparum, causes life-threatening illness.2 Although currently P knowlesi has been reported only from Southeast Asia3 and like P vivax needs the Duffy antigen,4 which is not found in people in West Africa,5 clinicians must keep in mind a broad differential diagnosis. Full-Text PDF

Patterns of co-speciation and host switching in primate malaria parasites

BackgroundThe evolutionary history of many parasites is dependent on the evolution of their hosts, leading to an association between host and parasite phylogenies. However, frequent host switches across broad phylogenetic distances may weaken this close evolutionary link, especially when vectors are involved in parasites transmission, as is the case for malaria pathogens. Several studies suggested that the evolution of the primate-infective malaria lineages may be constrained by the phylogenetic relationships of their hosts, and that lateral switches between distantly related hosts may have been occurred. However, no systematic analysis has been quantified the degree of phylogenetic association between primates and their malaria parasites.MethodsHere phylogenetic approaches have been used to discriminate statistically between events due to co-divergence, duplication, extinction and host switches that can potentially cause historical association between Plasmodium parasites and their primate hosts. A Bayesian reconstruction of parasite phylogeny based on genetic information for six genes served as basis for the analyses, which could account for uncertainties about the evolutionary hypotheses of malaria parasites.ResultsRelated lineages of primate-infective Plasmodium tend to infect hosts within the same taxonomic family. Different analyses testing for congruence between host and parasite phylogenies unanimously revealed a significant association between the corresponding evolutionary trees. The most important factor that resulted in this association was host switching, but depending on the parasite phylogeny considered, co-speciation and duplication may have also played some additional role. Sorting seemed to be a relatively infrequent event, and can occur only under extreme co-evolutionary scenarios. The concordance between host and parasite phylogenies is heterogeneous: while the evolution of some malaria pathogens is strongly dependent on the phylogenetic history of their primate hosts, the congruent evolution is less emphasized for other parasite lineages (e.g. for human malaria parasites). Estimation of ancestral states of host use along the phylogenetic tree of parasites revealed that lateral transfers across distantly related hosts were likely to occur in several cases. Parasites cannot infect all available hosts, and they should preferentially infect hosts that provide a similar environment for reproduction. Marginally significant evidence suggested that there might be a consistent variation within host ranges in terms of physiology.ConclusionThe evolution of primate malarias is constrained by the phylogenetic associations of their hosts. Some parasites can preserve a great flexibility to infect hosts across a large phylogenetic distance, thus host switching can be an important factor in mediating host ranges observed in nature. Due to this inherent flexibility and the potential exposure to various vectors, the emergence of new malaria disease in primates including humans cannot be predicted from the phylogeny of parasites.