title: Divergent Transcriptional Responses to Physiological and Xenobiotic Stress in Giardia duodenalis.
abstract: Understanding how parasites respond to stress can help to identify essential biological processes. Giardia duodenalis is a parasitic protist that infects the human gastrointestinal tract and causes 200 to 300 million cases of diarrhea annually. Metronidazole, a major antigiardial drug, is thought to cause oxidative damage within the infective trophozoite form. However, treatment efficacy is suboptimal, due partly to metronidazole-resistant infections. To elucidate conserved and stress-specific responses, we calibrated sublethal metronidazole, hydrogen peroxide, and thermal stresses to exert approximately equal pressure on trophozoite growth and compared transcriptional responses after 24 h of exposure. We identified 252 genes that were differentially transcribed in response to all three stressors, including glycolytic and DNA repair enzymes, a mitogen-activated protein (MAP) kinase, high-cysteine membrane proteins, flavin adenine dinucleotide (FAD) synthetase, and histone modification enzymes. Transcriptional responses appeared to diverge according to physiological or xenobiotic stress. Downregulation of the antioxidant system and α-giardins was observed only under metronidazole-induced stress, whereas upregulation of GARP-like transcription factors and their subordinate genes was observed in response to hydrogen peroxide and thermal stressors. Limited evidence was found in support of stress-specific response elements upstream of differentially transcribed genes; however, antisense derepression and differential regulation of RNA interference machinery suggest multiple epigenetic mechanisms of transcriptional control.
authors.affiliation: Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Melbourne, Victoria, Australia bransell@unimelb.edu.au.
authors.forename: Brendan R E
authors.identifier: 0000-0003-0297-897X
authors.initials: BR
authors.lastname: Ansell
authors.affiliation: Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Malcolm J
authors.initials: MJ
authors.lastname: McConville
authors.affiliation: Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Melbourne, Victoria, Australia Population Health and Immunity, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
authors.forename: Louise
authors.initials: L
authors.lastname: Baker
authors.affiliation: Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Pasi K
authors.initials: PK
authors.lastname: Korhonen
authors.affiliation: Population Health and Immunity, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Emery
authors.affiliation: Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.
authors.forename: Staffan G
authors.initials: SG
authors.lastname: Svärd
authors.affiliation: Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Robin B
authors.initials: RB
authors.lastname: Gasser
authors.affiliation: Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Melbourne, Victoria, Australia Population Health and Immunity, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Jex
mesh_terms: D000981:Antiprotozoal Agents / Q000494:pharmacology*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D016829:Giardia lamblia / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects / Q000235:genetics; D042421:Histone Code / Q000187:drug effects; D006358:Hot Temperature; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008795:Metronidazole / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D009713:Nucleotidyltransferases / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D053058:Trophozoites / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism
chemical_list: D000981:Antiprotozoal Agents; D003598:Cytoskeletal Proteins; C406724:GARP protein, Trypanosoma; D008565:Membrane Proteins; D015800:Protozoan Proteins; C038207:giardin protein, Giardia lamblia; D008795:Metronidazole; D006861:Hydrogen Peroxide; D020928:Mitogen-Activated Protein Kinases; D009713:Nucleotidyltransferases; C020143:FMN adenylyltransferase; D045643:DNA Repair Enzymes