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Nod1 and Nod2 in Innate Immune Responses, Adaptive Immunity and Bacterial Infection

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Nod1 and Nod2 in Innate Immune Responses, Adaptive Immunity and Bacterial Infection Nod1 and Nod2 in innate immune responses, adaptive immunity and bacterial infection. By Lionel Le Bourhis A thesis submitted in conformity with the requirements of the degree of Doctor of Philosophy Graduate Department of Immunology University of Toronto Nod1 and Nod2 in innate immune responses, adaptive immunity and bacterial infection. Lionel Le Bourhis, PhD thesis, 2009, Departmenent of Immunology, University of Toronto Abstract The last decade has been witness to a number of seminal discoveries in the field of innate immunity. The discovery that microbial molecules and endogenous danger signals can be detected by germ-line encoded receptors has changed the way we study the immune system. Indeed, the characterization of Toll in Drosophila as a sensor of microbial products in 1997 then led to the discovery of a family of Toll Like Receptors (TLRs) in mammals. TLRs are critical for the induction of inflammatory responses and the generation of a successful adaptive immune response. The array of ligands that these transmembrane proteins recognized mediates defense against bacteria, viruses, fungus and parasites, as well as, possibly, cancerous cells. In addition to this membrane-bound family of recognition proteins, two families of pattern recognition receptors have been recently shown to respond to microbial and chemical ligands within the cytosol. These represent the Nod Like Receptors (NLRs) and RIGI-like helicase receptor (RLH) families. Nod1 and Nod2 are members of the NLR family of proteins, which are responsible for the recognition of components derived from the bacterial cell wall, more precisely, moieties of peptidoglycan. As such, Nod1 and Nod2 are implicated in the recognition and the defense against bacterial pathogens. Importantly, the genes encoding these two proteins have also been linked to the etiology of several inflammatory disorders such as Crohn’s disease and asthma. In this thesis, we show that recognition of Nod1 and Nod2 ligands generates a rapid and transient inflammatory response in vivo. When co-injected with a model protein, Nod1 and Nod2 ligands exhibit adjuvant properties that lead to the generation of an antigen-specific Th2 type adaptive immune response. Surprisingly, recognition of the Nod1 ligand in non-hematopoietic cells ii is critical for the generation of this immune response. In contrast, TLRs classically tip the balance towards a Th1 response and interestingly, co-injection of TLR and Nod ligands synergize to generate a more potent immune response characterized by the generation of Th1, Th2 and Th17 T cell respones. To study the role of Nod1 and Nod2 in the context of a bacterial infection in vivo, we used an intestinal mouse pathogen, Salmonella enterica serovar Typhimurium . We were able to show that Nod1-deficient mice, but not Nod2-deficient mice, are more susceptible to the strain of this bacterium, which enters the host through the active pickup in the intestinal lumen by underlying myeloid cells. This sampling mechanism is mediated by a subset of dendritic cells that populate the intestinal lamina propria. Accordingly, the defect seen in Nod1-deficient mice localizes to the mucosal barrier where these dendritic cells appear to have an impaired response towards the bacteria. Taken together, these results increase our knowledge on the general role of Nod1 and Nod2 in immunity and might generate new avenues of research and potential therapeutic targets. iii Acknowledgements I would like to thank Dr Dana Philpott and Dr Stephen Girardin for their support, guidance and friendship. You gave me way more than the tools to be a good scientist. I am also greatful for the help that I received coming to Toronto by my committee members Dr Tania Watts and Dr James Carlyle, Rejeanne Puran and the graduate student of the department of immunology. I shouldn’t forget the members of the laboratories past and present, especially Jörg and Joao for science and much more. Je voudrais remercier mes parents, Chantal et André, pour leur confiance, une denrée dont tout scientifique à besoin. Je ne serais pas qui je suis sans mes trois frères, Gaël, Joël et Mikaël ; je les remercie pour m’avoir poussé à réussir, ils m’ont fait aimer le travail d’équipe et avoir un esprit compétitif, qualitées importantes chez un scientifique. Je voudrais remercier les amis qui m’ont accompagné, pour certains depuis longtemps. Enfin je voudrais remercier Julie pour sa patience, indispensable dans la vie d’un scientifique. Work for this thesis have been supported by the Pasteur Institut, l’Association François Aupetit, la Fondation pour la Recherche Médicale, as well as the Canadian Institutes of Health Research (CIHR) and the Howard Hughes Medical Institute (HHMI). 2 rights make 1 wrong… iv Table of Content Abstract 2 Acknowledgement 3 Table of content 4 List of Publications 8 List of Figures and Tables 9 List of Abbreviations 11 Chapter I: Introduction 14 1. Innate immune recognition 15 A. TLRs 15 1) Structure and signaling. 15 2) Ligands specificity 18 B. NLRs 21 1) Structure and signaling. 21 2) Ligands specificity 25 C. Other sensors 27 2. Role of the NLR in the immune response 28 A. Barrier and antimicrobial functions 29 B. Role in inflammation and cellular activation 30 C. Impact on the adaptive response 31 D. Gut mucosal immunity 33 3. Innate immune recognition and bacterial infection 38 A. NLRs and bacterial infections 38 i. Nod1 38 v ii. Nod2 39 B. Salmonella enterica Typhimurium 39 i. Overview 40 ii. Innate host factors 41 iii. Implication of the immune response 44 Chapter II: Research 46 1. Innate immune recognition by Nod1 in vivo 47 a. Introduction 47 b. Results 49 c. Discussion 55 2. Nod1 signaling induces adaptive immune response 56 a. Introduction 56 b. Results 58 Nod1 Is Required for Optimal Generation of T Cell Responses Optimal Antibody Responses Require Nod1 Triggering Induction of Adaptive Immunity by Nod1-Specific Stimulation TLRs and Nod1 Synergize to Elicit Adaptive Immune Responses Stimulation of Nod1 in Nonhematopoietic Cells Is Required for Priming Antigen-Specific Immunity c. Discussion 73 3. Nod2 signaling induces adaptive response 77 a. Introduction 77 b. Results 79 Induction of Th2 immunity by Nod2-specific stimulation Nod2 is required for optimal elicitation of T and B cell responses in a model of CFA immunization vi Nod2 cooperates with TLRs for the increased production of Th1-polarizing mediators c.Discussion 93 4. Nod1 and Nod2 in Salmonella enterica Typhimurium infection 97 a. Introduction 97 b. Results 99 Nod1 deficiency impairs intestinal LPMC homeostasis LPMC-dependent entry of Salmonella uncovers a role for Nod1 in host defense Nod1 expression in LPMCs controls host colonization Nod1 deficiency impairs the response of specific LPMC subsets to Salmonella infection. c. Discussion 114 5. Unpublished observation and work in progress 118 a. Detection of Salmonella enterica Typhimurium in epithelial cells 118 b. Adaptive response against S. Typhimurium attenuated strain 121 Conclusion and Future directions 125 Experimental procedures 128 Mice and Immunizations. 128 Bone marrow chimeric mice and adoptive transfer 128 Limulus amebocyte assay. 129 Expression plasmids and transient transfections. 129 Mouse peritoneal macrophages. 130 Peripheral blood mononuclear cell isolation. 130 Reagents. 130 Reporter Assay for NF-κB Activation. 131 Cytokine Dosage. 132 vii Flow Cytometry. 132 Analysis of T Cell Responses. 132 Analysis of B Cell Responses. 133 Bone Marrow-Derived DCs and Macrophages. 134 Lymphocyte Proliferation and RT-PCR Analysis. 134 Infections. 135 Analysis of immune cells from lamina propria. 136 References 138 viii List of Publications Le Bourhis L , Magalhaes JG, Selvanantham T, Travassos LH, Geddes K, Fritz JH, Viala J, Tedin K, Girardin SE, Philpott DJ. (2009) Nod1 controls Salmonella infection through regulation of intestinal lamina propria dendritic cells. (submitted) Magalhaes JG, Fritz JH, Le Bourhis L , Sellge G, Travassos LH, Selvanantham T, Girardin SE, Gommerman JL, Philpott DJ (2008) Nod2-dependent th2 polarization of antigen-specific immunity. J Immunol 181(11): 7925-7935 Joosten LA, Heinhuis B, Abdollahi-Roodsaz S, Ferwerda G, Le Bourhis L , Philpott DJ, Nahori MA, Popa C, Morre SA, van der Meer JW, Girardin SE, Netea MG, van den Berg WB (2008) Differential function of the NACHT-LRR (NLR) members Nod1 and Nod2 in arthritis. Proc Natl Acad Sci U S A 105(26): 9017-9022 Fritz JH, Le Bourhis L , Magalhaes JG, Philpott DJ. Innate immune recognition at the epithelial barrier drives adaptive immunity: APCs take the back seat. Trends Immunol. 2008 Jan;29(1):41-9. Le Bourhis L , Benko S, Girardin SE (2007) Nod1 and Nod2 in innate immunity and human inflammatory disorders. Biochem Soc Trans 35(Pt 6): 1479-1484 Werts C, Le Bourhis L , Liu J, Magalhaes JG, Carneiro LA, Fritz JH, Stockinger S, Balloy V, Chignard M, Decker T, Philpott DJ, Ma X, Girardin SE (2007) Nod1 and Nod2 induce CCL5/RANTES through the NF-kappaB pathway. Eur J Immunol 37(9): 2499-2508 Fritz JH, Le Bourhis L , Sellge G, Magalhaes JG, Fsihi H, Kufer TA, Collins C, Viala J, Ferrero RL, Girardin SE, Philpott DJ (2007) Nod1-mediated innate immune recognition of peptidoglycan contributes to the onset of adaptive immunity. Immunity 26(4): 445-459 Le Bourhis L , Werts C (2007) Role of Nods in bacterial infection. Microbes Infect 9(5): 629-636 Tien MT, Girardin SE, Regnault B, Le Bourhis L , Dillies MA, Coppee JY, Bourdet-Sicard R, Sansonetti PJ, Pedron T (2006) Anti-inflammatory effect of Lactobacillus casei on Shigella-infected human intestinal epithelial cells. J Immunol 176(2): 1228-1237 Ferwerda G, Girardin SE, Kullberg BJ, Le Bourhis L , de Jong DJ, Langenberg DM, van Crevel R, Adema GJ, Ottenhoff TH, Van der Meer JW, Netea MG (2005) NOD2 and toll-like receptors are nonredundant recognition systems of Mycobacterium tuberculosis. PLoS Pathog 1(3): 279-285 Magalhaes JG, Philpott DJ, Nahori MA, Jehanno M, Fritz J, Le Bourhis L , Viala J, Hugot JP, Giovannini M, Bertin J, Lepoivre M, Mengin-Lecreulx D, Sansonetti PJ, Girardin SE (2005) Murine Nod1 but not its human orthologue mediates innate immune detection of tracheal cytotoxin.
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