Molecular Genetics

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Peter Upcroft

Lab Head: Professor Peter Upcroft

Jacqui and Peter Upcroft Metabolic Studies, Drugs & Drug Resistance of Giardia & Other Anaerobic Protozoa of Medical Importance
Jacqui Upcroft (photo), Patrice Vanelle (Marseille) and Peter Upcroft
Metronidazole is the most widely used drug to treat the pathogenic protozoa, Giardia, Trichomonas and Entamoeba. Our studies of drug resistant parasites have elucidated the basic enzymatic mechanisms of drug resistance which will allow informed drug design. In collaboration with French colleagues we have synthesized and assayed novel antiparasitic drugs which are active against parasites resistant to metronidazole (Upcroft et al, 2006a) and alternatively used drugs. These drugs are now the subject of a collaborative project focussing on the Category B Biodefense organisms Giardia and Entmaoeba together with Fran Gillin and Lars Eckmann from University of California, San Diego, Patrice Vanelle in Marseille and Barry Sharpless in San Diego. We are also studying the unexpected anti-protozoal activity of some anti retroviral drugs.

Giardia Toxins, Pathogenicity, Virulence Factors & Host/Parasite Relationships
Jacqui Upcroft and Peter Upcroft
We have identified new toxins from a virulent Giardia isolate that killed sulphur-crested cockatoos and is genetically similar to strains which infect man. Mice infected with this strain suffer a failure-to-thrive syndrome, the first such model for human giardiasis. These are the first toxins described from Giardia and are targets for extensive immunological and host/parasite studies (Dunn et al, 2001).

Genome Research Microscopy, Image Analysis & 3D reconstruction BioEssays Microscopy, Image Analysis and 3D reconstruction Science Magazine

Immune Effectors
Linda Dunn, Jacqui Upcroft and Peter Upcroft
Cholera toxin is an effective adjuvant for generating an antigen-specific immune response at mucosal sites. Our studies have revealed a promising new avenue for the study of mucosal immune responses using novel compounds which adjuvant the immune response (Dunn et al, 2001).

Genome Organization and Structure, and the Evolution of the Ancient Eukaryote, Giardia.
Peter Upcroft, Mahin Abedinia and Jacqui Upcroft
We have undertaken a rigorous analysis of genome structure, organization and variation in human Giardia isolates, using gene cloning, mapping, DNA fingerprinting and electrophoretic karyotyping. The genome is very plastic at all these levels, showing extensive recombination, polyploidy, aneuploidy and derived accessory chromosomes. We have focused at the sequence level on the subtelomeric regions which undergo specialized recombination and gene silencing. We have also cloned and sequenced an unusual, novel plasmid which is an intermediate stage of a transposable element from Giardia which should be of great value in future, functional genomic studies.

More recently, the Upcrofts have collected some 50 isolates of T. vaginalis from Papua New Guinea, South Africa, USA and Australia (see Churchill Fellowship report below). These isolates were used to develop a genotyping technique to distinguish each isolate (Upcroft et al, 2006b). In addition preliminary mapping data and analyses of drug resistance related genes was carried out to contribute towards the understanding of the T. vaginalis genome sequence published in Science (Carlton et al, 2007). Current work in the laboratory focusses on identifying gene loci on one of the six T. vaginalis chromosomes.

Jacqui Upcroft 2003 Churchill Travel Fellowship
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Staff

Labhead:	Professor Peter Upcroft
Senior Research Fellow:	Dr Jacqui Upcroft

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Publications

Healey A, Mitchell R, Upcroft JA, Boreham PFL, Upcroft P. 1990. Complete nucleotide sequence of the ribosomal RNA tandem repeat unit from Giardia intestinalis. Nucleic Acids Res 18: 4006.

Upcroft JA, Healey A, Mitchell R, Boreham PFL, Upcroft P. 1990. Antigen expression from the ribosomal repeat of Giardia intestinalis. Nucleic Acids Res 18: 7077-7081.

Upcroft JA, Upcroft P. 1993. Drug resistance and Giardia. Parasitol Today 9: 187-190.

Upcroft JA, Healey A, Mitchell RW, Upcroft P. 1994. A new rDNA repeat unit in human Giardia. J Euk Microbiol 41: 639-642.

Upcroft JA, Chen N, Upcroft P. 1996. Mapping variation in chromosome homologues of different Giardia strains. Mol Biochem Parasitol 76: 135-143.

Upcroft JA, McDonnell PA, Upcroft P. 1998. Virulent avian Giardia duodenalis pathogenic for mice. Parasitol Today 14: 281-284.

Upcroft JA, Upcroft P. 1998. My favourite cell: Giardia. BioEssays 20: 256-263 (This review article was featured on the front cover of the journal issue).

Upcroft JA, Campbell RW, Benakli K, Upcroft P, Vanelle P. 1999. The efficacy of new 5-nitroimidazoles against metronidazole-susceptible and resistant anaerobic protozoa. Antimicrob Agents Chemother 43: 73-76.

Dunn LA, Upcroft JA, Fowler EV, Matthews BS, Upcroft P. 2001. Orally administered Giardia duodenalis extracts enhance an antigen-specific antibody response. Inf Immun 69: 6503-6510.

Upcroft P, Upcroft JA. 2001. Drug treatment and drug resistance in the anaerobic protozoa. Clin Microbiol Rev 14: 150-164.

Upcroft JA, Upcroft P. 2002. Giardia: Basic Biology, Genetics and Epidemiology. In:The Encyclopedia of Environmental Microbiology, Wiley, New York, pp 1469-1477 (Book Chapter).

Dunne RL, Dunn LA, Upcroft P, O'Donoghue P, Upcroft JA. 2003. Drug resistance in the sexually transmitted protozoan Trichomonas vaginalis. Cell Res 13: 239-249.

Wright JM, Dunn LA, Upcroft P, Upcroft JA. 2003. Efficacy of anti-giardial drugs. Expert Opinions in Drug Safety 2: 529-541.

Upcroft JA, Abedinia, M, Upcroft P. 2005. Rearranged sub-telomeric rRNA genes in Giardia. Eukaryotic Cell 4: 484-486.

Upcroft JA, Dunn LA, Wright JM, Benakli K, Upcroft P, Vanelle P. 2006a. 5-Nitroimidazole Drugs Effective Against Metronidazole-Resistant Trichomonas vaginalis and Giardia duodenalis. Antimicrob. Agents Chemother 50: 344-347

Upcroft JA, Delgadillo-Correa MG, Dunne RL, Sturm AW, Johnson PJ, Upcroft P. 2006b. Genotyping Trichomonas vaginalis. Int J Parasitol 36: 821-28.

Dunn LA, Andrews KT, McCarthy JS, Wright JM, Skinner-Adams TS, Upcroft P, Upcroft JA. 2007. The activity of protease inhibitors against Giardia duodenalis and metronidazole-resistant Trichomonas vaginalis. Int J Antimicrob Agents 29: 98-102.

Jane M. Carlton1, Robert P. Hirt, Joana C. Silva, et al., C. C. Wang, Rebecca L. Dunne, Jacqueline A. Upcroft, Peter Upcroft, Owen White, Steven L. Salzberg, Ying-shiung Lee, Cheng-hsun Chiu, Petrus Tang, T. Martin Embley, Graham H. Coombs, Jeremy C. Mottram, Jan Tachezy, Claire M. Fraser-Liggett and Patricia J. Johnson. 2007. The draft genome sequence of the sexually-transmitted pathogen Trichomonas vaginalis. Science 315: 207-212.