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Immunological and Molecular Aspects of Antigenic Variation During G Molecular analysis of antigenic variation in Giardia lamblia and influence of intestinal inflammatory reactions on a Giardia lamblia infection in mice Inauguraldissertation der Philosophisch-naturwissenschaftlichen Fakultät der Universität Bern vorgelegt von Nicole Eva von Allmen von Lauterbrunnen Leiter der Arbeit: Prof. Dr. Norbert Müller Institut für Parasitologie der Veterinärmedizinischen und der Medizinischen Fakultät Universität Bern Molecular analysis of antigenic variation in Giardia lamblia and influence of intestinal inflammatory reactions on a Giardia lamblia infection in mice Inauguraldissertation der Philosophisch-naturwissenschaftlichen Fakultät der Universität Bern vorgelegt von Nicole Eva von Allmen von Lauterbrunnen Leiter der Arbeit: Prof. Dr. Norbert Müller Institut für Parasitologie der Veterinärmedizinischen und der Medizinischen Fakultät Universität Bern Von der philosophisch-naturwissenschaftlichen Fakultät angenommen. Bern, 24. November 2005 Der Dekan: Prof. Dr. P. Messerli von Allmen Nicole Eva - 1 - 1 Abstract Giardia lamblia is a significant, environmentally transmitted, human pathogen and an amitochondriate protist, often hypothesized to be the most basal eukaryote. It is a major contributor to the enormous worldwide burden of human diarrheal diseases, yet the basic biology of this parasite is not well understood. Antigenic variation of G. lamblia is a widely investigated field of this protozoan parasite and has also driven our experimentations in the beginning of this study. Experimental infections in the mother-offspring mouse model were performed to investigate on one hand the antigenic variation process on the transcriptional level, and on the other to simulate the natural infection mode of the parasite. Our results demonstrated that antigenic switching of duodenal trophozoite and caecal cyst populations was accompanied with an obvious reduction in vsp H7 mRNA levels but without a simultaneous increase in transcripts of any of the analyzed subvariant vsp genes. The simulated natural transmission of the parasite revealed an antigenic reset of the excysted trophozoite population thereby the new generation essentially consisted of the original VSP H7 type. Investigations of antigenic variation on the molecular level were established by analysing giardial vsp RNA levels focusing on sense and complementary antisense vsp transcripts. The study analyzed not only vsp genes involved in antigenic variation but also a major gene of encystation, cwp 1 encoding cyst wall protein 1 (CWP 1). In the first case, we were able to demonstrate that sense vsp H7 RNA predominated in VSP H7-type trophozoites whereas sense RNA from only one of the 8 investigated subvariant vsp genes, vsp IVg, had increased in the subvariant trophozoite population. In both groups, H7-type and subvariant type trophozoites, similar relative distribution regarding vsp H7, or vsp IVg antisense RNA molecules could be found. Analogous to these findings were the results from sense and antisense RNA transcripts of cwp 1. Finally, these data demonstrated that giardial antisense RNA production was directly linked to complementary sense RNA production and made speculations about the RNA interference mechanism in Giardia lamblia doubtful. The contribution of intestinal inflammation and host immune responses are still a well discussed subject in Giardia research. There exist controversial studies about the importance and immunological relevance of mast cells for example as well as for effector mechanisms like T-cell and antibody-dependent immune responses. With the induction of a transient intestinal inflammation, realized by a co-infection experiment with Trichinella spiralis as inducer of the inflammation, we analyzed the G. lamblia parasite burden, the mucosal mast cells and associated IL-6 production of mast cells as well as the IgE von Allmen Nicole Eva - 2 - production. Our findings raised the possibility that the inflammatory responses to an intestinal infection favours establishment and maintenance of a G. lamblia infection in mice. von Allmen Nicole Eva - 3 - Table of Contents 1 Abstract 1 2 Abbreviations 4 3 List of figures 5 4 Introduction 6 4.1 Giardia lamblia 6 4.2 Life cycle 7 4.2.1 Trophozoites 8 4.2.2 Cysts 9 4.2.3 Transmission 10 4.3 Epidemiology 12 4.4 Pathogenesis and clinical symptoms 12 4.5 Diagnosis and treatment 13 4.6 Encystation 14 4.7 Excystation 15 4.8 Characterization of the G. lamblia transcriptome 16 4.9 Surface antigenic variation in G. lamblia 17 4.10 Immunological host reactions against G. lamblia infections 20 4.11 Physiological host reaction against G. lamblia infections 22 4.12 Intestinal pathogenesis associated with G. lamblia infections 24 5 Aim of the present thesis 28 6 Summary of publications 30 I) N. von Allmen, M. Bienz, A. Hemphill and N. Müller. 2004. Experimental infections of neonatal mice with cysts of Giardia lamblia clone GS/M-83-H7 are associated with an antigenic reset of the parasite. Infection and Immunity 72: 4763-4771. II) N. von Allmen, M. Bienz, A. Hemphill and N. Müller. 2005a. Quantitative assessment of sense and antisense transcripts from genes involved in antigenic variation (vsp genes) and encystation (cwp 1 gene) of Giardia lamblia clone GS/M-83-H7. Parasitology 130: 389-396. III) N. von Allmen, S. Christen, U. Forster, B. Gottstein, M. Welle and N. Müller. 2005b. Acute trichinellosis increases susceptibility of Giardia lamblia infections in the mouse model. Submitted to Infection and Immunity. IV) N. Müller, N. von Allmen. 2005. Recent insights into the mucosal reactions associated with Giardia lamblia infections. International Journal of Parasitology, in press (Review). 7 References 34 8 Publications 43 9 Acknowledgements 94 10 Curriculum Vitae 95 von Allmen Nicole Eva - 4 - 2 Abbreviations B-cell Bone marrow derived cell B10 Mice strain exhibit a low IgG production against a variety of T-dependent antigens CD8+ T lymphocytes Class I MHC-restricted, cytotoxic T cells CM Cyst membrane C-terminus Carboxy terminus of a peptide CWP Cyst wall protein cwp Gene encoding cyst wall protein EGF Epidermal growth factor ELISA Enzyme linked immunosorbent assay ESVs Encystation-specific vesicles IFN-γ Interferon gamma IgA Immunoglobulin A IL Interleukin (cytokine) iNOS Inducible nitric oxide synthase mAB Monoclonal antibody Mb Million base pairs MMP Matrix metalloproteinase NO Nitric oxide N-terminus Amino terminus of a peptide PCR Polymerase chain reaction RNAi RNA interference RT-PCR Reverse transcription polymerase chain reaction SAGE Serial analysis of gene expression STAT Transcription factor that stimulates transcription of IL-4 and other TH2 cytokine genes T-cell Thymus derived cell VSP Variant surface protein vsp Gene, encoding variant surface protein Zn Zinc von Allmen Nicole Eva - 5 - 3 List of figures Fig. 1: Giardia lamblia trophozoite (Dönges, 1988; von Allmen, N. 2003) Fig. 2: Giardia lamblia cyst (Dönges, 1988; von Allmen, N. 2003) Fig. 3: Giardia lamblia life cycle (http://sprojects.mmi.mcgill.ca/tropmed/disease/giardia/life.htm Fig. 4: VSP H7-type Giardia lamblia trophozoites (von Allmen N., 2004) von Allmen Nicole Eva - 6 - 4 Introduction 4.1 Giardia lamblia Giardia lamblia (syn. Giardia intestinalis, Giardia duodenalis) is a protozoan flagellate which colonises the lining of the upper part of the small intestine. This early diverged extant organism lives anarobically in the gut and causes gastrointestinal infections in humans and various other mammalian hosts (Adam, 1991). It is the most commonly diagnosed intestinal parasite worldwide with a prevalence of 2-3% in industrial and 20- 30% in development countries. Giardiasis infection begins in most cases with the ingestion of waterborne cysts or food contaminated with cysts. In addition to being significant for the medical importance of G. lamblia, the Giardia species are of interest because they belong to the Diplomonadida, one of the most basal eukaryotic branches on a phylogenetic tree (Sogin et al., 1989). G. lamblia and the other Diplomonadida are also of interest because of their possession of two nuclei. The two nuclei replicate approximately at the same time (Wiesenhahn et al., 1984), are both transcriptionally active (Kabnick et al., 1990) and contain similar quantities of DNA (Bernander et al., 2001). G. lamblia was first described by van Leeuwenhoek in 1681 when he investigated his own diarrhoeic stool under a microscope made by glass lenses and set them into metal frames. The protozoan was initially named Cercomonas intestinalis by Vilem Lambl in 1859, because he thought the organism belonged to the genus Cercomonas. Subsequently, Kofoid and Christiansen renamed the organism G. lamblia in 1915 (Adam, 2001). Giardia is in the subphylum Sarcomastigophora, the super class Mastigophora and in the order Diplomonadida. It belongs to the family Hexamiticae which contains six genera, three of which, including Giardia, are exclusively parasitic. There are three major morphological subtypes of Giarda: G. agilis from amphibians, G. muris from mice and G. intestinalis from humans and some other vertebrates. These three types can be distinguished by the overall shape and dimensions of the trophozoite body and also by the distinctive shapes of the median bodies. von Allmen Nicole Eva - 7 - 4.2 Life cycle (e.g. reviewed by Adam, 1991; Thompson, 2000) The Giardia life cycle is direct and asexual and begins with uptake of the cyst by the host. The exposure of cysts to gastric acid and to proteases as they move through the stomach
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