Identification of innate immunity genes and pathways using a comparative genomics approach

To reveal regulators of innate immunity, we used RNAi assays to monitor the immune response when genes are inhibited in Caenorhabditis elegans and mouse macrophages. Genes that altered innate immune responsiveness in C. elegans were validated in murine macrophages, resulting in the discovery of 11 genes that regulate the innate immune response in both systems and the subsequent identification of a protein interaction network with a conserved role in innate immunity regulation. We confirmed the role of four of these 11 genes in antimicrobial gene regulation using available mutants in C. elegans. Several of these genes (acy-1, tub-2, and tbc-1) also regulate susceptibility to the pathogen Pseudomonas aeruginosa. These genes may prove critical to understanding host defense and represent potential therapeutic targets for infectious and immunological diseases.

[1]  Michael A. Langston,et al.  Extracting Gene Networks for Low-Dose Radiation Using Graph Theoretical Algorithms , 2006, PLoS Comput. Biol..

[2]  F. Ausubel,et al.  Requirement for a conserved Toll/interleukin-1 resistance domain protein in the Caenorhabditis elegans immune response. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[3]  T. P. Neufeld,et al.  A genetic screen to identify components of the sina signaling pathway in Drosophila eye development. , 1998, Genetics.

[4]  L. O’Neill.  TLRs: Professor Mechnikov, sit on your hat. , 2004, Trends in immunology.

[5]  S. Young,et al.  Transcriptional Profiling of Lipopolysaccharide-Induced Acute Lung Injury , 2004, Infection and Immunity.

[6]  P. Elliott,et al.  Proteasome inhibition: a new anti-inflammatory strategy , 2003, Journal of Molecular Medicine.

[7]  G. Casari,et al.  A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway. , 2004, Nature cell biology.

[8]  B. Fingleton,et al.  Abnormal TNF activity in Timp3−/− mice leads to chronic hepatic inflammation and failure of liver regeneration , 2004, Nature Genetics.

[9]  S. Ward,et al.  Spotlight on new anti-inflammatory drug targets in the immune system. , 2003, Current opinion in pharmacology.

[10]  Zhengfan Jiang,et al.  Genetic analysis of innate immunity. , 2006, Advances in immunology.

[11]  D. Schwartz,et al.  The transcriptional response to lipopolysaccharide reveals a role for interferon-gamma in lung neutrophil recruitment. , 2006, American journal of physiology. Lung cellular and molecular physiology.

[12]  M. Gougerot-Pocidalo,et al.  Differential regulation of IL 6, IL 1 A, IL 1 beta and TNF alpha production in LPS-stimulated human monocytes: role of cyclic AMP. , 1990, Cytokine.

[13]  John Quackenbush,et al.  Genetic regulation of endotoxin-induced airway disease. , 2004, Genomics.

[14]  D. H. Mitchell,et al.  Synchronous growth and aging of Caenorhabditis elegans in the presence of fluorodeoxyuridine. , 1979, Journal of gerontology.

[15]  Haruo Ichikawa,et al.  Interaction between p230 and MACF1 is associated with transport of a glycosyl phosphatidyl inositol-anchored protein from the Golgi to the cell periphery. , 2004, Experimental cell research.

[16]  S. L. Wong,et al.  A Map of the Interactome Network of the Metazoan C. elegans , 2004, Science.

[17]  P. O’Farrell,et al.  Functional Dissection of an Innate Immune Response by a Genome-Wide RNAi Screen , 2004, PLoS biology.

[18]  C. Scheidereit.  IkappaB kinase complexes: gateways to NF-kappaB activation and transcription. , 2006, Oncogene.

[19]  S. Akira,et al.  Pathogen Recognition and Innate Immunity , 2006, Cell.

[20]  S. Akira,et al.  Toll-like receptors in innate immunity. , 2004, International immunology.

[21]  R. Modlin.  Mammalian toll-like receptors. , 2002, Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology.

[22]  E. Peerschke,et al.  cC1q-R (calreticulin) and gC1q-R/p33: ubiquitously expressed multi-ligand binding cellular proteins involved in inflammation and infection. , 2004, Molecular immunology.

[23]  M. Schmitz,et al.  NF-kappaB inhibitors for the treatment of inflammatory diseases and cancer. , 2007, Current medicinal chemistry.

[24]  Stefan H. E. Kaufmann,et al.  The innate immune response to infection , 2004 .

[25]  J. Ewbank.  Signaling in the immune response. , 2006, WormBook : the online review of C. elegans biology.

[26]  D. Schwartz,et al.  Specificity and Complexity of the Caenorhabditis elegans Innate Immune Response , 2007, Molecular and Cellular Biology.

[27]  Y. Dong,et al.  Systematic functional analysis of the Caenorhabditis elegans genome using RNAi , 2003, Nature.

[28]  Andreas Zell,et al.  The compressed feature matrix—a fast method for feature based substructure search , 2003, Journal of molecular modeling.

[29]  M. Gougerot-Pocidalo,et al.  Differential regulation of IL 6, IL 1 A, IL 1β and TNFα production in LPS-stimulated human monocytes: Role of cyclic AMP , 1990 .

[30]  M. Dorf,et al.  Differential regulation of interleukin-6, macrophage inflammatory protein-1, and JE/MCP-1 cytokine expression in macrophage cell lines. , 1991, Cellular immunology.

[31]  M. Dorf,et al.  Differential regulation of lnterleukin-6, macrophage inflammatory protein-1, and JE/MCP-1 cytokine expression in macrophage cell lines☆ , 1991 .

[32]  T. van Laar,et al.  Mif1: a missing link between the unfolded protein response pathway and ER-associated protein degradation? , 2001, Current protein & peptide science.

[33]  D. Aronoff,et al.  Short communication: differences between macrophages and dendritic cells in the cyclic AMP-dependent regulation of lipopolysaccharide-induced cytokine and chemokine synthesis. , 2006, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[34]  Y. Ben-Neriah.  Regulatory functions of ubiquitination in the immune system , 2002, Nature Immunology.

[35]  B. Beutler,et al.  TLR signaling pathways: opportunities for activation and blockade in pursuit of therapy. , 2006, Current pharmaceutical design.

[36]  T. P. Neufeld,et al.  PHYL Acts to Down-Regulate TTK88, a Transcriptional Repressor of Neuronal Cell Fates, by a SINA-Dependent Mechanism , 1997, Cell.

[37]  L. O’Neill,et al.  Toll-like receptors: from the discovery of NFkappaB to new insights into transcriptional regulations in innate immunity. , 2006, Biochemical pharmacology.

[38]  M. Ronen,et al.  A conserved role for a GATA transcription factor in regulating epithelial innate immune responses , 2006, Proceedings of the National Academy of Sciences.

[39]  Shizuo Akira,et al.  TLR signaling pathways. , 2004, Seminars in immunology.

[40]  S. Dower,et al.  Toll-like receptors and chronic lung disease. , 2005, Clinical science.

[41]  B. Lemaître.  The road to Toll , 2004, Nature Reviews Immunology.

[42]  John D. Storey,et al.  A network-based analysis of systemic inflammation in humans , 2005, Nature.

[43]  M. Shapira,et al.  Caenorhabditis elegans pgp-5 is involved in resistance to bacterial infection and heavy metal and its regulation requires TIR-1 and a p38 map kinase cascade. , 2007, Biochemical and biophysical research communications.

[44]  Richard E. T. Smith,et al.  From the analyst's couch: TLR-targeted therapeutics. , 2005, Nature reviews. Drug discovery.

[45]  S. Granjeaud,et al.  Inducible Antibacterial Defense System in C. elegans , 2002, Current Biology.

[46]  M. Schmitz,et al.  NF-κB Inhibitors for the Treatment of Inflammatory Diseases and Cancer , 2007 .

[47]  I. Adcock,et al.  Single-nucleotide polymorphisms associated with symptomatic infection and differential human gene expression in healthy seropositive persons each implicate the cytoskeleton, integrin signaling, and oncosuppression in the pathogenesis of human parvovirus B19 infection. , 2005, The Journal of infectious diseases.

[48]  M. Maldonado,et al.  The ubiquitin-proteasome system and its role in inflammatory and autoimmune diseases. , 2006, Cellular & molecular immunology.

[49]  James R. Knight,et al.  A Protein Interaction Map of Drosophila melanogaster , 2003, Science.

[50]  Jeremy J. W. Chen,et al.  Differential gene expression in gram-negative and gram-positive sepsis. , 2004, American journal of respiratory and critical care medicine.

[51]  K. Ishii,et al.  'Toll' gates for future immunotherapy. , 2006, Current pharmaceutical design.

[52]  F. Ausubel,et al.  Common virulence factors for bacterial pathogenicity in plants and animals. , 1995, Science.

[53]  Donald L Riddle,et al.  Analysis of long-lived C. elegans daf-2 mutants using serial analysis of gene expression. , 2005, Genome research.

[54]  A. Aasen,et al.  Effects of Forskolin on Kupffer Cell Production of Interleukin-10 and Tumor Necrosis Factor Alpha Differ from Those of Endogenous Adenylyl Cyclase Activators: Possible Role for Adenylyl Cyclase 9 , 2005, Infection and Immunity.

[55]  K Tanaka,et al.  Structure and functions of the 20S and 26S proteasomes. , 1996, Annual review of biochemistry.

[56]  Mouldy Sioud,et al.  Gene silencing by systemic delivery of synthetic siRNAs in adult mice. , 2003, Journal of molecular biology.

[57]  Y. Kohara,et al.  TLR-independent control of innate immunity in Caenorhabditis elegans by the TIR domain adaptor protein TIR-1, an ortholog of human SARM , 2004, Nature Immunology.

[58]  Galina Polekhina,et al.  Siah ubiquitin ligase is structurally related to TRAF and modulates TNF-alpha signaling. , 2002, Nature structural biology.

[59]  P. Ralph,et al.  Phagocytosis and cytolysis by a macrophage tumour and its cloned cell line , 1975, Nature.

[60]  T. Mak,et al.  Cutting Edge: Tissue Inhibitor of Metalloproteinase 3 Regulates TNF-Dependent Systemic Inflammation , 2006, The Journal of Immunology.

[61]  Frederick M. Ausubel,et al.  A Conserved p38 MAP Kinase Pathway in Caenorhabditis elegans Innate Immunity , 2002, Science.

[62]  L. O’Neill.  Therapeutic targeting of Toll-like receptors for inflammatory and infectious diseases. , 2003, Current opinion in pharmacology.

[63]  D. Schwartz,et al.  Toll-like receptors in the pathogenesis of human disease , 2004, Nature Immunology.

[64]  Leo X. Liu,et al.  Addresses: 1Laboratoire de Génétique et , 2022 .

[65]  A. Bowie,et al.  The human adaptor SARM negatively regulates adaptor protein TRIF–dependent Toll-like receptor signaling , 2006, Nature Immunology.