Heat-shock transcription factor (HSF)-1 pathway required for Caenorhabditis elegans immunity

Innate immunity comprises physical barriers, pattern-recognition receptors, antimicrobial substances, phagocytosis, and fever. Here we report that increased temperature results in the activation of a conserved pathway involving the heat-shock (HS) transcription factor (HSF)-1 that enhances immunity in the invertebrate Caenorhabditis elegans. The HSF-1 defense response is independent of the p38 MAPK/PMK-1 pathway and requires a system of chaperones including small and 90-kDa inducible HS proteins. In addition, HSF-1 is needed for the effects of the DAF-2 insulin-like pathway in defense to pathogens, indicating that interacting pathways control stress response, aging, and immunity. The results also show that HSF-1 is required for C. elegans immunity against Pseudomonas aeruginosa, Salmonella enterica, Yersinia pestis, and Enterococcus faecalis, indicating that HSF-1 is part of a multipathogen defense pathway. Considering that several coinducers of HSF-1 are currently in clinical trials, this work opens the possibility that activation of HSF-1 could be used to boost immunity to treat infectious diseases and immunodeficiencies.

[1]  Marc Tatar,et al.  Chaperoning extended life , 1997, Nature.

[2]  T. Johnson,et al.  daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans , 2001, Current Biology.

[3]  J. Hsuan,et al.  Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of hsp27 , 1994, Cell.

[4]  Cori Bargmann,et al.  Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans , 2003, Nature.

[5]  F. Ausubel,et al.  Salmonella typhimurium proliferates and establishes a persistent infection in the intestine of Caenorhabditis elegans , 2000, Current Biology.

[6]  Frederick M Ausubel,et al.  Evolutionary perspectives on innate immunity from the study of Caenorhabditis elegans. , 2005, Current opinion in immunology.

[7]  L Bibbs,et al.  A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. , 1994, Science.

[8]  A. Fraser,et al.  Genetic analysis of tissue aging in Caenorhabditis elegans: a role for heat-shock factor and bacterial proliferation. , 2002, Genetics.

[9]  G. Weinstock,et al.  Generation of restriction map of Enterococcus faecalis OG1 and investigation of growth requirements and regions encoding biosynthetic function , 1993, Journal of bacteriology.

[10]  R. Brubaker,et al.  In vivo comparison of avirulent Vwa- and Pgm- or Pstr phenotypes of yersiniae , 1984, Infection and immunity.

[11]  Jonathan Hodgkin,et al.  Caenorhabditis elegans as a model for innate immunity to pathogens , 2005, Cellular microbiology.

[12]  B. Prakken,et al.  Heat-shock proteins induce T-cell regulation of chronic inflammation , 2005, Nature Reviews Immunology.

[13]  Michel Morange,et al.  A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins , 1994, Cell.

[14]  G. Stormo,et al.  Identification of a novel cis-regulatory element involved in the heat shock response in Caenorhabditis elegans using microarray gene expression and computational methods. , 2002, Genome research.

[15]  C. Kenyon.  The Plasticity of Aging: Insights from Long-Lived Mutants , 2005, Cell.

[16]  C. Wray,et al.  Experimental Salmonella typhimurium infection in calves. , 1978, Research in veterinary science.

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

[18]  Cynthia Kenyon,et al.  Regulation of Aging and Age-Related Disease by DAF-16 and Heat-Shock Factor , 2003, Science.

[19]  R. Morimoto,et al.  Regulation of longevity in Caenorhabditis elegans by heat shock factor and molecular chaperones. , 2003, Molecular biology of the cell.

[20]  F. Ausubel,et al.  Killing of Caenorhabditis elegans by Pseudomonas aeruginosa used to model mammalian bacterial pathogenesis. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[21]  J. Shim,et al.  Tissue‐specific expression, heat inducibility, and biological roles of two hsp16 genes in Caenorhabditis elegans , 2003, FEBS letters.

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

[23]  Gary Ruvkun,et al.  DAF-16 Target Genes That Control C. elegans Life-Span and Metabolism , 2003, Science.

[24]  K. Matsumoto,et al.  ASK1 Inhibits Interleukin-1-induced NF-κB Activity through Disruption of TRAF6-TAK1 Interaction* , 2000, The Journal of Biological Chemistry.

[25]  C. Kurz,et al.  Caenorhabditis elegans is a model host for Salmonella typhimurium , 2000, Current Biology.

[26]  A. Fire,et al.  Specific interference by ingested dsRNA , 1998, Nature.

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

[28]  F. Ausubel,et al.  A simple model host for identifying Gram-positive virulence factors , 2001, Proceedings of the National Academy of Sciences of the United States of America.

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

[30]  F. Ausubel,et al.  Caenorhabditis elegans Innate Immune Response Triggered by Salmonella enterica Requires Intact LPS and Is Mediated by a MAPK Signaling Pathway , 2003, Current Biology.

[31]  F. Ausubel.  Are innate immune signaling pathways in plants and animals conserved? , 2005, Nature Immunology.

[32]  E. Mylonakis,et al.  Worms and Flies as Genetically Tractable Animal Models To Study Host-Pathogen Interactions , 2005, Infection and Immunity.

[33]  P. Sternberg,et al.  The L-Type Cyclin CYL-1 and the Heat-Shock-Factor HSF-1 Are Required for Heat-Shock-Induced Protein Expression in Caenorhabditis elegans , 2004, Genetics.

[34]  S. Brenner.  The genetics of Caenorhabditis elegans. , 1974, Genetics.

[35]  Raymond Y. N. Lee,et al.  Regulation of C. elegans DAF-16 and its human ortholog FKHRL1 by the daf-2 insulin-like signaling pathway , 2001, Current Biology.

[36]  P. Srivastava,et al.  Peptides chaperoned by heat-shock proteins are a necessary and sufficient source of antigen in the cross-priming of CD8+ T cells , 2005, Nature Immunology.

[37]  P. Zipperlen,et al.  Functional genomic analysis of C. elegans chromosome I by systematic RNA interference , 2000, Nature.

[38]  J. Corbeil,et al.  Mitogen-activated protein kinase pathways defend against bacterial pore-forming toxins. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[39]  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.

[40]  J. Bessereau,et al.  [C. elegans: of neurons and genes]. , 2003, Medecine sciences : M/S.

[41]  R. Hosono,et al.  Extended longevity of Caenorhabditis elegans by knocking in extra copies of hsp70F, a homolog of mot‐2 (mortalin)/mthsp70/Grp75 , 2002, FEBS letters.

[42]  R. Frothingham,et al.  Yersinia pestis kills Caenorhabditis elegans by a biofilm‐independent process that involves novel virulence factors , 2005, EMBO reports.