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157


Rodent models of malaria in the genomics era

Carlton, Jane M; Carucci, Daniel J
The Rodent Malaria Genomics Symposium: Current Status and Future Directions was held on 15-16 November 2001 in Atlanta, GA, USA
PMID: 11854077
ISSN: 1471-4922
CID: 64369

The shikimate pathway and its branches in apicomplexan parasites

Roberts, Craig W; Roberts, Fiona; Lyons, Russell E; Kirisits, Michael J; Mui, Ernest J; Finnerty, John; Johnson, Jennifer J; Ferguson, David J P; Coggins, John R; Krell, Tino; Coombs, Graham H; Milhous, Wilbur K; Kyle, Dennis E; Tzipori, Saul; Barnwell, John; Dame, John B; Carlton, Jane; McLeod, Rima
The shikimate pathway is essential for production of a plethora of aromatic compounds in plants, bacteria, and fungi. Seven enzymes of the shikimate pathway catalyze sequential conversion of erythrose 4-phosphate and phosphoenol pyruvate to chorismate. Chorismate is then used as a substrate for other pathways that culminate in production of folates, ubiquinone, napthoquinones, and the aromatic amino acids tryptophan, phenylalanine, and tyrosine. The shikimate pathway is absent from animals and present in the apicomplexan parasites Toxoplasma gondii, Plasmodium falciparum, and Cryptosporidium parvum. Inhibition of the pathway by glyphosate is effective in controlling growth of these parasites. These findings emphasize the potential benefits of developing additional effective inhibitors of the shikimate pathway. Such inhibitors may function as broad-spectrum antimicrobial agents that are effective against bacterial and fungal pathogens and apicomplexan parasites
PMID: 11865437
ISSN: 0022-1899
CID: 64368

Profiling the malaria genome: a gene survey of three species of malaria parasite with comparison to other apicomplexan species

Carlton JM; Muller R; Yowell CA; Fluegge MR; Sturrock KA; Pritt JR; Vargas-Serrato E; Galinski MR; Barnwell JW; Mulder N; Kanapin A; Cawley SE; Hide WA; Dame JB
We have undertaken the first comparative pilot gene discovery analysis of approximately 25,000 random genomic and expressed sequence tags (ESTs) from three species of Plasmodium, the infectious agent that causes malaria. A total of 5482 genome survey sequences (GSSs) and 5582 ESTs were generated from mung bean nuclease (MBN) and cDNA libraries, respectively, of the ANKA line of the rodent malaria parasite Plasmodium berghei, and 10,874 GSSs generated from MBN libraries of the Salvador I and Belem lines of Plasmodium vivax, the most geographically wide-spread human malaria pathogen. These tags, together with 2438 Plasmodium falciparum sequences present in GenBank, were used to perform first-pass assembly and transcript reconstruction, and non-redundant consensus sequence datasets created. The datasets were compared against public protein databases and more than 1000 putative new Plasmodium proteins identified based on sequence similarity. Homologs of previously characterized Plasmodium genes were also identified, increasing the number of P. vivax and P. berghei sequences in public databases at least 10-fold. Comparative studies with other species of Apicomplexa identified interesting homologs of possible therapeutic or diagnostic value. A gene prediction program, Phat, was used to predict probable open reading frames for proteins in all three datasets. Predicted and non-redundant BLAST-matched proteins were submitted to InterPro, an integrated database of protein domains, signatures and families, for functional classification. Thus a partial predicted proteome was created for each species. This first comparative analysis of Plasmodium protein coding sequences represents a valuable resource for further studies on the biology of this important pathogen
PMID: 11738710
ISSN: 0166-6851
CID: 66426

Conservation of a novel vacuolar transporter in Plasmodium species and its central role in chloroquine resistance of P. falciparum

Carlton JM; Fidock DA; Djimde A; Plowe CV; Wellems TE
Chloroquine resistance in Plasmodium falciparum has recently been shown to result from mutations in the novel vacuolar transporter, PfCRT. Field studies have demonstrated the importance of these mutations in clinical resistance. Although a pfcrt ortholog has been identified in Plasmodiumvivax, there is no association between in vivo chloroquine resistance and codon mutations in the P. vivax gene. This is consistent with lines of evidence that suggest alternative mechanisms of chloroquine resistance among various malaria parasite species
PMID: 11495804
ISSN: 1369-5274
CID: 66427

Evidence for different mechanisms of chloroquine resistance in 2 Plasmodium species that cause human malaria

Nomura T; Carlton JM; Baird JK; del Portillo HA; Fryauff DJ; Rathore D; Fidock DA; Su X; Collins WE; McCutchan TF; Wootton JC; Wellems TE
Chloroquine (CQ)-resistant Plasmodium vivax malaria was first reported 12 years ago, nearly 30 years after the recognition of CQ-resistant P. falciparum. Loss of CQ efficacy now poses a severe problem for the prevention and treatment of both diseases. Mutations in a digestive vacuole protein encoded by a 13-exon gene, pfcrt, were shown recently to have a central role in the CQ resistance (CQR) of P. falciparum. Whether mutations in pfcrt orthologues of other Plasmodium species are involved in CQR remains an open question. This report describes pfcrt homologues from P. vivax, P. knowlesi, P. berghei, and Dictyostelium discoideum. Synteny between the P. falciparum and P. vivax genes is demonstrated. However, a survey of patient isolates and monkey-adapted lines has shown no association between in vivo CQR and codon mutations in the P. vivax gene. This is evidence that the molecular events underlying P. vivax CQR differ from those in P. falciparum
PMID: 11343215
ISSN: 0022-1899
CID: 66428

Of mice and malaria mutants: unravelling the genetics of drug resistance using rodent malaria models

Carlton JM; Hayton K; Cravo PV; Walliker D
It is well recognized that drug resistance is the most significant obstacle to gaining effective malaria control. Despite the enormous advances in the knowledge of the biochemistry and molecular biology of malaria parasites, only a few genes determining resistance to the commonly used drugs have been identified. The idea that rodent malaria parasites should be exploited more widely for such work, in view of the practical problems of studying this subject experimentally in human malaria, is presented
PMID: 11323308
ISSN: 1471-4922
CID: 66429

Mycoplasma alligatoris sp. nov., from American alligators

Brown DR; Farley JM; Zacher LA; Carlton JM; Clippinger TL; Tully JG; Brown MB
Mycoplasmas were isolated from multiple tissues of diseased American alligators (Alligator mississippiensis). This paper presents biochemical, serological and molecular genetic characterizations of a lethal pathogen of alligators for which the name Mycoplasma alligatoris sp. nov. is proposed. The type strain is A21JP2T (ATCC 700619T)
PMID: 11321088
ISSN: 1466-5026
CID: 66430

Host sequences in Plasmodium falciparum and Plasmodium vivax genomic DNA: horizontal transfer or contamination artifact? [Letter]

Deitsch KW; Carlton JM; Wootton JC; Wellems TE
PMID: 11245166
ISSN: 0014-5793
CID: 66432

Biomagnetic separation of contaminating host leukocytes from plasmodium-infected erythrocytes

Carlton JM; Yowell CA; Sturrock KA; Dame JB
Carlton, J. M-R., Yowell, C. A., Sturrock, K. A., and Dame, J. B. 2001. Biomagnetic separation of contaminating host leukocytes from Plasmodium-infected erythrocytes. Experimental Parasitology 97, 111-114
PMID: 11281708
ISSN: 0014-4894
CID: 66431

Co-ordinated programme of gene expression during asexual intraerythrocytic development of the human malaria parasite Plasmodium falciparum revealed by microarray analysis

Ben Mamoun C; Gluzman IY; Hott C; MacMillan SK; Amarakone AS; Anderson DL; Carlton JM; Dame JB; Chakrabarti D; Martin RK; Brownstein BH; Goldberg DE
Plasmodium falciparum is a protozoan parasite responsible for the most severe forms of human malaria. All the clinical symptoms and pathological changes seen during human infection are caused by the asexual blood stages of Plasmodium. Within host red blood cells, the parasite undergoes enormous developmental changes during its maturation. In order to analyse the expression of genes during intraerythrocytic development, DNA microarrays were constructed and probed with stage-specific cDNA. Developmental upregulation of specific mRNAs was found to cluster into functional groups and revealed a co-ordinated programme of gene expression. Those involved in protein synthesis (ribosomal proteins, translation factors) peaked early in development, followed by those involved in metabolism, most dramatically glycolysis genes. Adhesion/invasion genes were turned on later in the maturation process. At the end of intraerythrocytic development (late schizogony), there was a general shut-off of gene expression, although a small set of genes, including a number of protein kinases, were turned on at this stage. Nearly all genes showed some regulation over the course of development. A handful of genes remained constant and should be useful for normalizing mRNA levels between stages. These data will facilitate functional analysis of the P. falciparum genome and will help to identify genes with a critical role in parasite progression and multiplication in the human host
PMID: 11123685
ISSN: 0950-382x
CID: 66433