Role for β-catenin and HOX transcription factors in Caenorhabditis elegans and mammalian host epithelial-pathogen interactions

We used the model nematode Caenorhabditis elegans infected with the human pathogen Staphylococcus aureus to identify components of epithelial immunity. Transcriptional profiling and reverse genetic analysis revealed that mutation of the C. elegans β-catenin homolog bar-1 or the downstream homeobox gene egl-5 results in a defective response and hypersensitivity to S. aureus infection. Epistasis analysis showed that bar-1 and egl-5 function in parallel to previously described C. elegans immune-response pathways. Overexpression of human homologs of egl-5 modulated NF-κB-dependent TLR2 signaling in epithelial cells. These data suggest that β-catenin and homeobox genes play an important and conserved role in innate immune defense.

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

[2]  Adeline R. Whitney,et al.  Insights into Pathogen Immune Evasion Mechanisms: Anaplasma phagocytophilum Fails to Induce an Apoptosis Differentiation Program in Human Neutrophils 1 , 2005, The Journal of Immunology.

[3]  Jonathan Hodgkin,et al.  Multiple Genes Affect Sensitivity of Caenorhabditis elegans to the Bacterial Pathogen Microbacterium nematophilum , 2005, Genetics.

[4]  Nektarios Tavernarakis,et al.  Genome-wide investigation reveals pathogen-specific and shared signatures in the response of Caenorhabditis elegans to infection , 2007, Genome Biology.

[5]  Pierre Laurent-Puig,et al.  Crypt-restricted proliferation and commitment to the Paneth cell lineage following Apc loss in the mouse intestine , 2005, Development.

[6]  Valerie Reinke,et al.  p38 MAPK Regulates Expression of Immune Response Genes and Contributes to Longevity in C. elegans , 2006, PLoS genetics.

[7]  Hendrik C Korswagen,et al.  Functional Interaction Between ß-Catenin and FOXO in Oxidative Stress Signaling , 2005, Science.

[8]  M. Hung,et al.  β-catenin interacts with and inhibits NF-κB in human colon and breast cancer , 2002 .

[9]  P. Sternberg,et al.  Characterization of seven genes affecting Caenorhabditis elegans hindgut development. , 1999, Genetics.

[10]  H. Clevers,et al.  Wnt signalling induces maturation of Paneth cells in intestinal crypts , 2005, Nature Cell Biology.

[11]  H. Clevers,et al.  The Paneth cell alpha-defensin deficiency of ileal Crohn's disease is linked to Wnt/Tcf-4. , 2007, Journal of immunology.

[12]  C. Kurz,et al.  Caenorhabditis elegans: an emerging genetic model for the study of innate immunity , 2003, Nature Reviews Genetics.

[13]  Dean P. Jones,et al.  Commensal bacteria modulate cullin‐dependent signaling via generation of reactive oxygen species , 2007, The EMBO journal.

[14]  M. Buendia,et al.  Overexpression of regenerating islet-derived 1 alpha and 3 alpha genes in human primary liver tumors with β-catenin mutations , 2006, Oncogene.

[15]  Rekha C. Patel,et al.  Homeobox gene HOXA9 inhibits nuclear factor-kappa B dependent activation of endothelium. , 2007, Atherosclerosis.

[16]  H. Clevers,et al.  The Paneth Cell α-Defensin Deficiency of Ileal Crohn’s Disease Is Linked to Wnt/Tcf-41 , 2007, The Journal of Immunology.

[17]  C. Murphy,et al.  The C. elegans TGF-beta Dauer pathway regulates longevity via insulin signaling. , 2007, Current biology : CB.

[18]  Kunihiro Matsumoto,et al.  ROS-dependent activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity , 2005, Nature Immunology.

[19]  E. Cercenado,et al.  [Community-acquired methicillin-resistant Staphylococcus aureus]. , 2008, Enfermedades infecciosas y microbiologia clinica.

[20]  A. Chisholm,et al.  Control of cell fate in the tail region of C. elegans by the gene egl-5. , 1991, Development.

[21]  J. Whangbo,et al.  A Wnt signaling pathway controls hox gene expression and neuroblast migration in C. elegans. , 1999, Development.

[22]  S. K. Kim,et al.  Protruding vulva mutants identify novel loci and Wnt signaling factors that function during Caenorhabditis elegans vulva development. , 2000, Genetics.

[23]  Stuart K. Kim,et al.  The beta-catenin homolog BAR-1 and LET-60 Ras coordinately regulate the Hox gene lin-39 during Caenorhabditis elegans vulval development. , 1998, Development.

[24]  Yufeng Lu,et al.  HOXA9 Activates Transcription of the Gene Encoding gp91Phox during Myeloid Differentiation* , 2005, Journal of Biological Chemistry.

[25]  Naoki Hisamoto,et al.  Integration of Caenorhabditis elegans MAPK pathways mediating immunity and stress resistance by MEK-1 MAPK kinase and VHP-1 MAPK phosphatase. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[26]  T. He,et al.  Crosstalk between NF-κB and β-catenin pathways in bacterial-colonized intestinal epithelial cells , 2005 .

[27]  S. W. Emmons,et al.  Patterning of Caenorhabditis elegans posterior structures by the Abdominal-B homolog, egl-5. , 1999, Developmental biology.

[28]  M. Pfaffl,et al.  A new mathematical model for relative quantification in real-time RT-PCR. , 2001, Nucleic acids research.

[29]  P. Brown,et al.  Transcriptional Program Induced by Wnt Protein in Human Fibroblasts Suggests Mechanisms for Cell Cooperativity in Defining Tissue Microenvironments , 2007, PloS one.

[30]  Gary Ruvkun,et al.  Long-Lived C. elegans daf-2 Mutants Are Resistant to Bacterial Pathogens , 2003, Science.

[31]  Coleen T. Murphy,et al.  The C. elegans TGF-β Dauer Pathway Regulates Longevity via Insulin Signaling , 2007, Current Biology.

[32]  Frederick M Ausubel,et al.  The worm has turned--microbial virulence modeled in Caenorhabditis elegans. , 2005, Trends in microbiology.

[33]  P. Sternberg,et al.  Interactions of EGF, Wnt and HOM-C genes specify the P12 neuroectoblast fate in C. elegans. , 1998, Development.

[34]  P. Howe,et al.  HOXA9 Participates in the Transcriptional Activation of E-Selectin in Endothelial Cells , 2007, Molecular and Cellular Biology.

[35]  T. He,et al.  Crosstalk between NF-kappaB and beta-catenin pathways in bacterial-colonized intestinal epithelial cells. , 2005, American journal of physiology. Gastrointestinal and liver physiology.

[36]  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.

[37]  Richard Mott,et al.  Genomic clusters, putative pathogen recognition molecules, and antimicrobial genes are induced by infection of C. elegans with M. nematophilum. , 2006, Genome research.

[38]  M. Hung,et al.  beta-catenin interacts with and inhibits NF-kappa B in human colon and breast cancer. , 2002, Cancer cell.

[39]  F. Ausubel,et al.  Caenorhabditis elegans as a Model Host for Staphylococcus aureus Pathogenesis , 2003, Infection and Immunity.

[40]  M. Shapira,et al.  Genetic analysis of Caenorhabditis elegans innate immunity. , 2008, Methods in molecular biology.

[41]  H. Horvitz,et al.  Genetic analysis of Caenorhabditis elegans. , 1980 .

[42]  D. Baillie,et al.  Genetic Analysis in Caenorhabditis Elegans , 1994 .

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

[44]  Rekha C. Patel,et al.  Differential regulation of HOXA9 expression by nuclear factor kappa B (NF-kappaB) and HOXA9. , 2008, Gene.