John H Adams

Mahidol University, Bangkok, Bangkok, Thailand

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Publications (52)262.47 Total impact

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    ABSTRACT: Plasmodium falciparum, the causative agent of malaria, contributes to significant morbidity and mortality worldwide. Forward genetic analysis of the blood-stage asexual cycle identified the putative phosphatase from PF3D7_1305500 as an important element of intraerythrocytic development expressed throughout the life cycle. Our preliminary evaluation identified it as an atypical MAPK phosphatase. Additional bioinformatics analysis delineated a conserved signature motif and three residues with potential importance to functional activity of the atypical dual-specificity phosphatase (DUSP) domain. A homology model of the DUSP domain was developed for use in high-throughput in silico screening of the available library of antimalarial compounds from ChEMBL-NTD. Seven compounds from this set with predicted affinity to the active site were tested against in vitro cultures and three had reduced activity against a ∆PF3D7_1305500 parasite, suggesting PF3D7_1305500 is a potential target of the selected compounds. Identification of these compounds provides a novel starting point for a structure-based drug discovery strategy that moves us closer towards the discovery of new classes of clinical antimalarial drugs. These data suggest that MAPK phosphatases represent a potentially new class of P. falciparum drug target. This article is protected by copyright. All rights reserved.
    Chemical Biology &amp Drug Design 03/2014; · 2.47 Impact Factor
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    ABSTRACT: Plasmodium vivax preferentially infects Duffy-positive reticulocytes and infections typically have few parasite-infected cells in the peripheral circulation. These features complicate detection and quantification by flow cytometry (FC) using standard nucleic acid-based staining methods. A simple antibody-based FC method was developed for rapid parasite detection along with simultaneous detection of other parasite and erythrocyte markers. Clinical samples were collected from patients diagnosed with P. vivax at a district Malaria Clinic in Kanchanaburi, Thailand. One muL of infected blood was washed, fixed, stained with a Plasmodium pan-specific anti-PfBiP antibody conjugated with Alexa Fluor 660, and analysed by FC. Additional primary conjugated antibodies for stage-specific markers of P. vivax for late trophozoite-early schizonts (MSP1-Alexa Fluor 660), late-stage schizonts (DBP-Alexa Fluor 555), and sexual stages (Pvs16) were used to differentiate intra-erythrocytic developmental stages. The percentages of P. vivax-infected cells determined by the FC method and manually by microscopic examination of Giemsa-stained thick blood smears were positively correlated by Spearman's rank correlation coefficient (R2 = 0.93843) from 0.001 to 1.00% P. vivax-infected reticulocytes. The FC-based method is a simple, robust, and efficient method for detecting P. vivax-infected reticulocytes.
    Malaria Journal 02/2014; 13(1):55. · 3.40 Impact Factor
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    ABSTRACT: The Duffy binding protein (DBP) of Plasmodium vivax is vital for host erythrocyte invasion. DBP region II (DBPII) contains critical residues for receptor recognition and anti-DBPII antibodies have been shown to inhibit erythrocyte binding and invasion, thereby making the molecule an attractive vaccine candidate against P. vivax blood stages. Similar to other blood-stage antigens, allelic variation within the DBPII and associated strain-specific immunity is a major challenge for development of a broadly effective vaccine against P. vivax malaria. We hypothesized that immunization with a vaccine composed of multiple DBP alleles or a modified epitope DBP (DEKnull) will be more effective in producing a broadly reactive and inhibitory antibody response to diverse DBPII alleles than a single allele vaccine. In this study, we compared single, naturally occurring DBPII allele immunizations (Sal1, 7.18, P) and DEKnull with a combination of (Sal1, 7.18, P) alleles. Quantitative analysis by ELISA demonstrated that the multiple allele vaccine tend to be more immunogenic than any of the single allele vaccines when tested for reactivity against a panel of DBPII allelic variants whereas DEKnull was less immunogenic than the mixed-allele vaccine but similar in reactivity to the single allele vaccines. Further analysis for functional efficacy by in vitro erythrocyte-binding inhibition assays demonstrated that the multiple allele immunization produced a stronger strain-neutralizing response than the other vaccination strategies even though inhibition remained biased toward some alleles. Overall, there was no correlation between antibody titer and functional inhibition. These data suggest that a multiple allele vaccine may enhance immunogenicity of a DBPII vaccine but further investigation is required to optimize this vaccine strategy to achieve broader coverage against global P. vivax strains.
    Vaccine 07/2013; · 3.77 Impact Factor
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    ABSTRACT: Intraerythrocytic development of the human malaria parasite Plasmodium falciparum appears as a continuous flow through growth and proliferation. To develop a greater understanding of the critical regulatory events, we utilized piggyBac insertional mutagenesis to randomly disrupt genes. Screening a collection of piggyBac mutants for slow growth we isolated the attenuated parasite C9 that carried a single insertion disrupting the ORF of PF3D7_1305500. This gene encodes a protein structurally similar to a MAPK phosphatase, except for two notable characteristics that alters the signature motif of the dual-specificity phosphatase domain, suggesting that it may be a low activity phosphatase or pseudophosphatase. C9 parasites demonstrated a significantly slower growth rate with delayed entry into the S/M phase of the cell cycle, which follows the stage of maximum PF3D7_1305500 expression in intact parasites. Genetic complementation with the full-length PF3D7_1305500 rescued the wild-type phenotype of C9 to validate the importance of the putative protein phosphatase PF3D7_1305500 as a regulator of pre-S phase cell cycle progression in P. falciparum.
    Eukaryotic Cell 06/2013; · 3.59 Impact Factor
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    ABSTRACT: j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / f e b s o p e n b i o Production of recombinant 1-deoxy-d-xylulose-5-phosphate synthase from Plasmod-ium vivax in Escherichia coli a b s t r a c t Humanity is burdened by malaria as millions are infected with this disease. Although advancements have been made in the treatment of malaria, optimism regarding our fight against malaria must be tempered against the problem of drug resistance in the Plasmodium parasites causing malaria. New targets are required to overcome the resistance problem. The enzymes of the mevalonate-independent pathway of isoprenoid biosynthesis are targets for the development of novel antimalarial drugs. One enzyme in this pathway, 1-deoxy-D-xylulose-5-phosphate synthase (DXS), catalyzes the conversion of 1-deoxy-D-xylulose-5-phosphate to isopentenylpyrophosphate and dimethylallyl phosphate. We demonstrate the use of a step deletion method to identify and eliminate the putative nuclear-encoded and transit peptides from full length DXS to yield a truncated, active, and soluble form of Plasmodium vivax DXS, the DXS catalytic core (DXS cc). C 2013 The Authors. Published by Elsevier B.V. on behalf of Federation of European Biochemical Societies. All rights reserved.
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    ABSTRACT: Humanity is burdened by malaria as millions are infected with this disease. Although advancements have been made in the treatment of malaria, optimism regarding our fight against malaria must be tempered against the problem of drug resistance in the Plasmodium parasites causing malaria. New targets are required to overcome the resistance problem. The enzymes of the mevalonate-independent pathway of isoprenoid biosynthesis are targets for the development of novel antimalarial drugs. One enzyme in this pathway, 1-deoxy-d-xylulose-5-phosphate synthase (DXS), catalyzes the conversion of 1-deoxy-d-xylulose-5-phosphate to isopentenylpyrophosphate and dimethylallyl phosphate. We demonstrate the use of a step deletion method to identify and eliminate the putative nuclear-encoded and transit peptides from full length DXS to yield a truncated, active, and soluble form of Plasmodium vivax DXS, the DXS catalytic core (DXScc).
    FEBS open bio. 01/2013; 3:124-9.
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    ABSTRACT: Plasmodium vivax Duffy binding protein region II (DBPII) is an essential ligand for reticulocyte invasion, thereby making this molecule an attractive vaccine candidate against asexual blood-stage P. vivax. Similar to other Plasmodium blood-stage vaccine candidates, strain-specific immunity due to DBPII allelic variation may complicate vaccine efficacy. Targeting immune responses to more conserved epitopes that are potential targets of strain-transcending neutralising immunity is necessary to avoid induction of strain-specific responses to dominant variant epitopes. In this article, we focus on different approaches to optimise the design of DBP immunogenicity to target conserved epitopes, which is important for developing a broadly effective vaccine against P. vivax.
    International journal for parasitology 10/2012; · 3.39 Impact Factor
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    ABSTRACT: Plasmodium vivax invasion of human erythrocytes requires interaction of the P. vivax Duffy binding protein (PvDBP) with its host receptor, the Duffy antigen (Fy) on the erythrocyte surface. Consequently, PvDBP is a leading vaccine candidate. The binding domain of PvDBP lies in a cysteine-rich portion of the molecule called region II (PvDBPII). PvDBPII contains three distinct subdomains based upon intramolecular disulfide bonding patterns. Subdomain 2 (SD2) is highly polymorphic and is thought to contain many key residues for binding to Fy, while SD1 and SD3 are comparatively conserved and their role in Fy binding is not well understood. To examine the relative contributions of the different subdomains to binding to Fy and their abilities to elicit strain-transcending binding-inhibitory antibodies, we evaluated recombinant proteins from SD1+2, SD2, SD3, and SD3+, which includes 24 residues of SD2. All of the recombinant subdomains, except for SD2, bound variably to human erythrocytes, with constructs containing SD3 showing the best binding. Antisera raised in laboratory animals against SD3, SD3+, and SD2+3 inhibited the binding of full-length PvDBPII, which is strain transcending, whereas antisera generated to SD1+2 and SD2 failed to generate blocking antibodies. All of the murine monoclonal antibodies generated to full-length PvDBPII that had significant binding-inhibitory activity recognized only SD3. Thus, SD3 binds Fy and elicits blocking antibodies, indicating that it contains residues critical to Fy binding that could be the basis of a strain-transcending candidate vaccine against P. vivax.
    Infection and immunity 05/2012; 80(8):2920-8. · 4.21 Impact Factor
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    ABSTRACT: The Duffy binding protein (DBP) is a vital ligand for Plasmodium vivax blood-stage merozoite invasion, making the molecule an attractive vaccine candidate against vivax malaria. Similar to other blood-stage vaccine candidates, DBP allelic variation eliciting a strain-specific immunity may be a major challenge for development of a broadly effective vaccine against vivax malaria. To understand whether conserved epitopes can be the target of neutralizing anti-DBP inhibition, we generated a set of monoclonal antibodies to DBP and functionally analyzed their reactivity to a panel of allelic variants. Quantitative analysis by enzyme-linked immunosorbent assay (ELISA) determined that some monoclonal antibodies reacted strongly with epitopes conserved on all DBP variants tested, while reactivity of others was allele specific. Qualitative analysis characterized by anti-DBP functional inhibition using an in vitro erythrocyte binding inhibition assay indicated that there was no consistent correlation between the endpoint titers and functional inhibition. Some monoclonal antibodies were broadly inhibitory while inhibition of others varied significantly by target allele. These data demonstrate a potential for vaccine-elicited immunization to target conserved epitopes but optimization of DBP epitope target specificity and immunogenicity may be necessary for protection against diverse P. vivax strains.
    Infection and immunity 01/2012; 80(3):1203-8. · 4.21 Impact Factor
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    ABSTRACT: Plasmodium vivax Duffy binding protein region II (DBPII) is an important vaccine candidate for antibody-mediated immunity against vivax malaria. A significant challenge for vaccine development of DBPII is its highly polymorphic nature that alters sensitivity to neutralizing antibody responses. Here, we aim to characterize naturally-acquired neutralizing antibodies against DBPII in individual Thai residents to give insight into P. vivax vaccine development in Thailand. Anti-DBPII IgG significantly increased in acute vivax infections compared to uninfected residents and naive controls. Antibody titers and functional anti-DBPII inhibition varied widely and there was no association between titer and inhibition activity. Most high titer plasmas had only a moderate to no functional inhibitory effect on DBP binding to erythrocytes, indicating the protective immunity against DBPII binding is strain specific. Only 5 of 54 samples were highly inhibitory against DBP erythrocyte-binding function. Previously identified target epitopes of inhibitory anti-DBPPII IgG (H1, H2 and H3) were localized to the dimer interface that forms the DARC binding pocket. Amino acid polymorphisms (monomorphic or dimorphic) in H1 and H3 protective epitopes change sensitivity of immune inhibition by alteration of neutralizing antibody recognition. The present study indicates Thai variant H1.T1 (R308S), H3.T1 (D384G) and H3.T3 (K386N) are the most important variants for a DBPII candidate vaccine needed to protect P. vivax in Thai residents.
    PLoS ONE 01/2012; 7(4):e35769. · 3.73 Impact Factor
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    ABSTRACT: Mechanisms of drug resistance in Plasmodium vivax have been difficult to study partially because of the difficulties in culturing the parasite in vitro. This hampers monitoring drug resistance and research to develop or evaluate new drugs. There is an urgent need for a novel method to study mechanisms of P. vivax drug resistance. In this paper we report the development and application of the first Plasmodium falciparum expression system to stably express P. vivax dhfr-ts alleles. We used the piggyBac transposition system for the rapid integration of wild-type, single mutant (117N) and quadruple mutant (57L/58R/61M/117T) pvdhfr-ts alleles into the P. falciparum genome. The majority (81%) of the integrations occurred in non-coding regions of the genome; however, the levels of pvdhfr transcription driven by the P. falciparum dhfr promoter were not different between integrants of non-coding and coding regions. The integrated quadruple pvdhfr mutant allele was much less susceptible to antifolates than the wild-type and single mutant pvdhfr alleles. The resistance phenotype was stable without drug pressure. All the integrated clones were susceptible to the novel antifolate JPC-2067. Therefore, the piggyBac expression system provides a novel and important tool to investigate drug resistance mechanisms and gene functions in P. vivax.
    PLoS ONE 01/2012; 7(7):e40416. · 3.73 Impact Factor
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    ABSTRACT: Plasmodium vivax (Pv) is a major cause of human malaria and is increasing in public health importance compared with falciparum malaria. Pv is unique among human malarias in that invasion of erythrocytes is almost solely dependent on the red cell's surface receptor, known as the Duffy blood-group antigen (Fy). Fy is an important minor blood-group antigen that has two immunologically distinct alleles, referred to as Fy(a) or Fy(b), resulting from a single-point mutation. This mutation occurs within the binding domain of the parasite's red cell invasion ligand. Whether this polymorphism affects susceptibility to clinical vivax malaria is unknown. Here we show that Fy(a), compared with Fy(b), significantly diminishes binding of Pv Duffy binding protein (PvDBP) at the erythrocyte surface, and is associated with a reduced risk of clinical Pv in humans. Erythrocytes expressing Fy(a) had 41-50% lower binding compared with Fy(b) cells and showed an increased ability of naturally occurring or artificially induced antibodies to block binding of PvDBP to their surface. Individuals with the Fy(a+b-) phenotype demonstrated a 30-80% reduced risk of clinical vivax, but not falciparum malaria in a prospective cohort study in the Brazilian Amazon. The Fy(a+b-) phenotype, predominant in Southeast Asian and many American populations, would confer a selective advantage against vivax malaria. Our results also suggest that efficacy of a PvDBP-based vaccine may differ among populations with different Fy phenotypes.
    Proceedings of the National Academy of Sciences 11/2011; 108(50):20113-8. · 9.74 Impact Factor
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    Francis B Ntumngia, John H Adams
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    ABSTRACT: The Duffy binding protein is considered a leading vaccine candidate against asexual blood-stage Plasmodium vivax. The interaction of P. vivax merozoites with human reticulocytes through Duffy binding protein (DBP) and its cognate receptor is vital for parasite infection. The ligand domain of DBP (DBPII) is polymorphic, showing a diversity characteristic of selective immune pressure that tends to compromise vaccine efficacy associated with strain-specific immunity. A previous study resolved that a polymorphic region of DBPII was a dominant B-cell epitope target of human inhibitory anti-DBP antibodies, which we refer to as the DEK epitope for the amino acids in the SalI allele. We hypothesized that the polymorphic residues, which are not functionally important for erythrocyte binding but flank the receptor binding motif of DBPII, comprise variant epitopes that tend to divert the immune response away from more conserved epitopes. In this study, we designed, expressed, and evaluated the immunogenicity of a novel artificial DBPII allele, termed DEKnull, having nonpolar amino acids in the naturally occurring polymorphic charged residues of the DEK epitope. The DEKnull antigen retained erythrocyte-binding activity and elicited antibodies to shared epitopes of SalI DBPII from which it was derived. Our results confirmed that removal of the dominant variant epitope in the DEKnull vaccine lowered immunogenicity of DBPII, but inhibitory anti-DBPII antibodies were elicited against shared neutralizing epitopes on SalI. Focusing immune responses toward more conserved DBP epitopes may avoid development of a strain-specific immunity and enhance functional inhibition against broader range of DBPII variants.
    Clinical and vaccine Immunology: CVI 11/2011; 19(1):30-6. · 2.60 Impact Factor
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    ABSTRACT: Coordinated regulation of gene expression is a hallmark of the Plasmodium falciparum asexual blood-stage development cycle. We report that carbon catabolite repressor protein 4 (CCR4)-associated factor 1 (CAF1) is critical in regulating more than 1,000 genes during malaria parasites' intraerythrocytic stages, especially egress and invasion proteins. CAF1 knockout results in mistimed expression, aberrant accumulation and localization of proteins involved in parasite egress, and invasion of new host cells, leading to premature release of predominantly half-finished merozoites, drastically reducing the intraerythrocytic growth rate of the parasite. This study demonstrates that CAF1 of the CCR4-Not complex is a significant gene regulatory mechanism needed for Plasmodium development within the human host.
    Eukaryotic Cell 07/2011; 10(9):1257-63. · 3.59 Impact Factor
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    PLoS Neglected Tropical Diseases 06/2011; 5(6):e1160. · 4.57 Impact Factor
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    ABSTRACT: The genome of a number of species of malaria parasites (Plasmodium spp.) has been sequenced in the hope of identifying new drug and vaccine targets. However, almost one-half of predicted Plasmodium genes are annotated as hypothetical and are difficult to analyse in bulk due to the inefficiency of current reverse genetic methodologies for Plasmodium. Recently, it has been shown that the transposase piggyBac integrates at random into the genome of the human malaria parasite P. falciparum offering the possibility to develop forward genetic screens to analyse Plasmodium gene function. This study reports the development and application of the piggyBac transposition system for the rodent malaria parasite P. berghei and the evaluation of its potential as a tool in forward genetic studies. P. berghei is the most frequently used malaria parasite model in gene function analysis since phenotype screens throughout the complete Plasmodium life cycle are possible both in vitro and in vivo. We demonstrate that piggyBac based gene inactivation and promoter-trapping is both easier and more efficient in P. berghei than in the human malaria parasite, P. falciparum. Random piggyBac-mediated insertion into genes was achieved after parasites were transfected with the piggyBac donor plasmid either when transposase was expressed either from a helper plasmid or a stably integrated gene in the genome. Characterization of more than 120 insertion sites demonstrated that more than 70 most likely affect gene expression classifying their protein products as non-essential for asexual blood stage development. The non-essential nature of two of these genes was confirmed by targeted gene deletion one of which encodes P41, an ortholog of a human malaria vaccine candidate. Importantly for future development of whole genome phenotypic screens the remobilization of the piggyBac element in parasites that stably express transposase was demonstrated. These data demonstrate that piggyBac behaved as an efficient and random transposon in P. berghei. Remobilization of piggyBac element shows that with further development the piggyBac system can be an effective tool to generate random genome-wide mutation parasite libraries, for use in large-scale phenotype screens in vitro and in vivo.
    BMC Genomics 03/2011; 12:155. · 4.40 Impact Factor
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    ABSTRACT: Invasion of human red blood cells by Plasmodium merozoites is vital for replication and survival of the parasite and, as such, is an attractive target for therapeutic intervention. Merozoite invasion is mediated by specific interactions between parasite ligands and host erythrocyte receptors. The P. vivax Duffy-binding protein (PvDBP) is heavily dependent on the interaction with the human Duffy blood group antigen/receptor for chemokines (DARC) for invasion. Region II of PvDBP contains many allelic polymorphisms likely to have arisen by host immune selection. Successful vaccine development necessitates a deeper understanding of the role of these polymorphisms in both parasite function and evasion of host immunity. A 3D structure of the homologous P. knowlesi DBP predicts that most variant residues are surface-exposed, including N417K, which is a dimorphic residue change that has previously been shown to be part of a linked haplotype that alters DBP sensitivity to inhibitory antibody. In natural isolates only two residues are found at this site, asparagine (N) and lysine (K). Site-directed mutagenesis of residue 417 was used to create a panel of 20 amino acid variants that were then examined for their binding phenotype and response to immune sera. Our results suggest that the observed dimorphism likely arose due to both structural requirements and immune selection pressure. To our knowledge, this is the first exhaustive examination of this kind of the role of a single amino acid residue in antigenic character and binding ability. Our results demonstrate that a single amino acid substitution can dramatically alter both the ability of the PvDBP to bind to human erythrocytes and its antigenic character.
    PLoS ONE 01/2011; 6(5):e20192. · 3.73 Impact Factor
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    ABSTRACT: Plasmodium vivax resistance to antifolates is prevalent throughout Australasia and is caused by point mutations within the parasite dihydrofolate reductase (DHFR)-thymidylate synthase. Several unique mutations have been reported in P. vivax DHFR, and their roles in resistance to classic and novel antifolates are not entirely clear due, in part, to the inability to culture P. vivax in vitro. In this study, we use a homologous system to episomally express both wild-type and various mutant P. vivax dhfr (pvdhfr) alleles in an antifolate-sensitive line of P. falciparum and to assess their influences on the susceptibility of the recipient P. falciparum line to commonly used and new antifolate drugs. Although the wild-type pvdhfr-transfected P. falciparum line was as susceptible to antifolate drugs as the P. falciparum parent line, the single (117N), double (57L/117T and 58R/117T), and quadruple (57L/58R/61M/117T) mutant pvdhfr alleles conferred a marked reduction in their susceptibilities to antifolates. The resistance index increased with the number of mutations in these alleles, indicating that these mutations contribute to antifolate resistance directly. In contrast, the triple mutant allele (58R/61M/117T) significantly reversed the resistance to all antifolates, indicating that 61M may be a compensatory mutation. These findings help elucidate the mechanism of antifolate resistance and the effect of existing mutations in the parasite population on the current and new generation of antifolate drugs. It also demonstrates that the episomal transfection system has the potential to provide a rapid screening system for drug development and for studying drug resistance mechanisms in P. vivax.
    Antimicrobial Agents and Chemotherapy 09/2010; 54(9):3927-32. · 4.57 Impact Factor
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    ABSTRACT: A majority of the Plasmodium falciparum genome codes for genes with unknown functions, which presents a major challenge to understanding the parasite's biology. Large-scale functional analysis of the parasite genome is essential to pave the way for novel therapeutic intervention strategies against the disease and yet difficulties in genetic manipulation of this deadly human malaria parasite have been a major hindrance for functional analysis of its genome. Here, we used a forward functional genomic approach to study P. falciparum and identify genes important for optimal parasite development in the disease-causing, intraerythrocytic stages. We analyzed 123 piggyBac insertion mutants of P. falciparum for proliferation efficiency in the intraerythrocytic stages, in vitro. Almost 50% of the analyzed mutants showed significant reduction in proliferation efficiency, with 20% displaying severe defects. Functional categorization of genes in the severely attenuated mutants revealed significant enrichment for RNA binding proteins, suggesting the significance of post-transcriptional gene regulation in parasite development and emphasizing its importance as an antimalarial target. This study demonstrates the feasibility of much needed forward genetics approaches for P. falciparum to better characterize its genome and accelerate drug and vaccine development.
    PLoS ONE 01/2010; 5(10):e13282. · 3.73 Impact Factor
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    ABSTRACT: Polymorphism of the Duffy Antigen Receptor for Chemokines (DARC) is associated with susceptibility to and the severity of Plasmodium vivax malaria in humans. P. vivax uses DARC to invade erythrocytes. Individuals lacking DARC are 'resistant' to P. vivax erythrocytic infection. However, susceptibility to P. vivax in DARC+ individuals is reported to vary between specific DARC genotypes. We hypothesized that the natural acquisition of antibodies to P. vivax blood stages may vary with the host genotype and the level of DARC expression. Furthermore, high parasitemia has been reported to effect the acquisition of immunity against pre-erythrocytic parasites. We investigated the correlation between host DARC genotypes and the frequency and magnitude of antibodies against P. vivax erythrocytic stage antigens. We assessed the frequencies and magnitudes of antibody responses against P. vivax and P. falciparum sporozoite and erythrocytic antigens in Colombian donors from malaria-endemic regions. The frequency and level of naturally-acquired antibodies against the P. vivax erythrocytic antigens merozoite surface protein 1 (PvMSP1) and Duffy binding protein (PvDBP) varied with the host DARC genotypes. Donors with one negative allele (FY*B/FY*Bnull and FY*A/FY*Bnull) were more likely to have anti-PvMSP1 and anti-PvDBP antibodies than those with two positive alleles (FY*B/FY*B and FY*A/FY*B). The lower IgG3 and IgG1 components of the total IgG response may account for the decreased responses to P. vivax erythrocytic antigens with FY*A/FY*B and FY*B/FY*B genotypes. No such association was detected with P. falciparum erythrocytic antigens, which does not use DARC for erythrocyte invasion. Individuals with higher DARC expression, which is associated with higher susceptibility to P. vivax infection, exhibited low frequencies and magnitudes of P. vivax blood-stage specific antibody responses. This may indicate that one of the primary mechanisms by which P. vivax evades host immunity is through DARC indirectly down-regulating humoral responses against erythrocytic invasion and development.
    PLoS ONE 01/2010; 5(7):e11437. · 3.73 Impact Factor

Publication Stats

1k Citations
435 Downloads
262.47 Total Impact Points

Institutions

  • 2012
    • Mahidol University
      • Department of Clinical Microbiology and Applied Technology
      Bangkok, Bangkok, Thailand
    • Australian Army Malaria Institute
      Sydney, New South Wales, Australia
  • 2008–2012
    • University of South Florida
      • Department of Global Health
      Tampa, FL, United States
  • 2002–2012
    • Case Western Reserve University
      • Center for Global Health and Diseases
      Cleveland, OH, United States
  • 2011
    • Wellcome Trust Sanger Institute
      Cambridge, England, United Kingdom
  • 2002–2011
    • University of Notre Dame
      • Department of Biological Sciences
      South Bend, IN, United States
  • 2010
    • Walter Reed Army Institute of Research
      Silver Spring, Maryland, United States
  • 2006
    • University of Alabama at Birmingham
      Birmingham, Alabama, United States
  • 2004
    • MRC National Institute for Medical Research
      • Division of Parasitology
      London, ENG, United Kingdom