Infection of Induces Antifungal Immune Defenses
Candida albicans yeast cells are found in the intestine of most humans, yet this opportunist can invade host tissues and cause life-threatening infections in susceptible individuals. To better understand the host factors that underlie susceptibility to candidiasis, we developed a new model to study antifungal innate immunity. We demonstrate that the yeast form of C. albicans establishes an intestinal infection in Caenorhabditis elegans, whereas heat-killed yeast are avirulent. Genome-wide, transcription-profiling analysis of C. elegans infected with C. albicans yeast showed that exposure to C. albicans stimulated a rapid host response involving 313 genes (124 upregulated and 189 downregulated, ∼1.6% of the genome) many of which encode antimicrobial, secreted or detoxification proteins. Interestingly, the host genes affected by C. albicans exposure overlapped only to a small extent with the distinct transcriptional responses to the pathogenic bacteria Pseudomonas aeruginosa or Staphylococcus aureus, indicating that there is a high degree of immune specificity toward different bacterial species and C. albicans. Furthermore, genes induced by P. aeruginosa and S. aureus were strongly over-represented among the genes downregulated during C. albicans infection, suggesting that in response to fungal pathogens, nematodes selectively repress the transcription of antibacterial immune effectors. A similar phenomenon is well known in the plant immune response, but has not been described previously in metazoans. Finally, 56% of the genes induced by live C. albicans were also upregulated by heat-killed yeast. These data suggest that a large part of the transcriptional response to C. albicans is mediated through “pattern recognition,” an ancient immune surveillance mechanism able to detect conserved microbial molecules (so-called pathogen-associated molecular patterns or PAMPs). This study provides new information on the evolution and regulation of the innate immune response to divergent pathogens and demonstrates that nematodes selectively mount specific antifungal defenses at the expense of antibacterial responses.
Vyšlo v časopise:
Infection of Induces Antifungal Immune Defenses. PLoS Pathog 7(6): e32767. doi:10.1371/journal.ppat.1002074
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1002074
Souhrn
Candida albicans yeast cells are found in the intestine of most humans, yet this opportunist can invade host tissues and cause life-threatening infections in susceptible individuals. To better understand the host factors that underlie susceptibility to candidiasis, we developed a new model to study antifungal innate immunity. We demonstrate that the yeast form of C. albicans establishes an intestinal infection in Caenorhabditis elegans, whereas heat-killed yeast are avirulent. Genome-wide, transcription-profiling analysis of C. elegans infected with C. albicans yeast showed that exposure to C. albicans stimulated a rapid host response involving 313 genes (124 upregulated and 189 downregulated, ∼1.6% of the genome) many of which encode antimicrobial, secreted or detoxification proteins. Interestingly, the host genes affected by C. albicans exposure overlapped only to a small extent with the distinct transcriptional responses to the pathogenic bacteria Pseudomonas aeruginosa or Staphylococcus aureus, indicating that there is a high degree of immune specificity toward different bacterial species and C. albicans. Furthermore, genes induced by P. aeruginosa and S. aureus were strongly over-represented among the genes downregulated during C. albicans infection, suggesting that in response to fungal pathogens, nematodes selectively repress the transcription of antibacterial immune effectors. A similar phenomenon is well known in the plant immune response, but has not been described previously in metazoans. Finally, 56% of the genes induced by live C. albicans were also upregulated by heat-killed yeast. These data suggest that a large part of the transcriptional response to C. albicans is mediated through “pattern recognition,” an ancient immune surveillance mechanism able to detect conserved microbial molecules (so-called pathogen-associated molecular patterns or PAMPs). This study provides new information on the evolution and regulation of the innate immune response to divergent pathogens and demonstrates that nematodes selectively mount specific antifungal defenses at the expense of antibacterial responses.
Zdroje
1. BermanJSudberyPE 2002 Candida albicans: a molecular revolution built on lessons from budding yeast. Nat Rev Genet 3 918 930
2. LeroyOGangneuxJPMontraversPMiraJPGouinF 2009 Epidemiology, management, and risk factors for death of invasive Candida infections in critical care: a multicenter, prospective, observational study in France (2005–2006). Crit Care Med 37 1612 1618
3. GudlaugssonOGillespieSLeeKVande BergJHuJ 2003 Attributable mortality of nosocomial candidemia, revisited. Clin Infect Dis 37 1172 1177
4. LeleuGAegerterPGuidetB 2002 Systemic candidiasis in intensive care units: a multicenter, matched-cohort study. J Crit Care 17 168 175
5. AchkarJMFriesBC 2010 Candida infections of the genitourinary tract. Clin Microbiol Rev 23 253 273
6. BraunBRJohnsonAD 1997 Control of filament formation in Candida albicans by the transcriptional repressor TUP1. Science 277 105 109
7. CaoFLaneSRanigaPPLuYZhouZ 2006 The Flo8 transcription factor is essential for hyphal development and virulence in Candida albicans. Mol Biol Cell 17 295 307
8. LoHJKöhlerJRDiDomenicoBLoebenbergDCacciapuotiA 1997 Nonfilamentous C. albicans mutants are avirulent. Cell 90 939 949
9. GowNABrownAJOddsFC 2002 Fungal morphogenesis and host invasion. Curr Opin Microbiol 5 366 371
10. RosenbachADignardDPierceJVWhitewayMKumamotoCA 2010 Adaptations of Candida albicans for growth in the mammalian intestinal tract. Eukaryot Cell 9 1075 1086
11. SavilleSPLazzellALMonteagudoCLopez-RibotJL 2003 Engineered control of cell morphology in vivo reveals distinct roles for yeast and filamentous forms of Candida albicans during infection. Eukaryot Cell 2 1053 1060
12. KumamotoCAVincesMD 2005 Contributions of hyphae and hypha-co-regulated genes to Candida albicans virulence. Cell Microbiol 7 1546 1554
13. GantnerBNSimmonsRMUnderhillDM 2005 Dectin-1 mediates macrophage recognition of Candida albicans yeast but not filaments. EMBO J 24 1277 1286
14. MoyesDLRunglallMMurcianoCShenCNayarD 2010 A biphasic innate immune MAPK response discriminates between the yeast and hyphal forms of Candida albicans in epithelial cells. Cell Host Microbe 8 225 235
15. NeteaMGBrownGDKullbergBJGowNA 2008 An integrated model of the recognition of Candida albicans by the innate immune system. Nat Rev Microbiol 6 67 78
16. FerwerdaBFerwerdaGPlantingaTSWillmentJAvan SprielAB 2009 Human dectin-1 deficiency and mucocutaneous fungal infections. N Engl J Med 361 1760 1767
17. GlockerEOHennigsANabaviMSchafferAAWoellnerC 2009 A homozygous CARD9 mutation in a family with susceptibility to fungal infections. N Engl J Med 361 1727 1735
18. JouaultTSarazinAMartinez-EsparzaMFradinCSendidB 2009 Host responses to a versatile commensal: PAMPs and PRRs interplay leading to tolerance or infection by Candida albicans. Cell Microbiol 11 1007 1015
19. KurzCLEwbankJJ 2003 Caenorhabditis elegans: an emerging genetic model for the study of innate immunity. Nat Rev Genet 4 380 390
20. Pukkila-WorleyRMylonakisE 2010 From the outside in and the inside out: antifungal immune responses in Caenorhabditis elegans. Virulence 1 111 112
21. IrazoquiJEUrbachJMAusubelFM 2010 Evolution of host innate defence: insights from Caenorhabditis elegans and primitive invertebrates. Nat Rev Immunol 10 47 58
22. KimDHFeinbaumRAlloingGEmersonFEGarsinDA 2002 A conserved p38 MAP kinase pathway in Caenorhabditis elegans innate immunity. Science 297 623 626
23. ZieglerKKurzCLCypowyjSCouillaultCPophillatM 2009 Antifungal innate immunity in C. elegans: PKCdelta links G protein signaling and a conserved p38 MAPK cascade. Cell Host Microbe 5 341 352
24. RenMFengHFuYLandMRubinCS 2009 Protein kinase D is an essential regulator of C. elegans innate immunity. Immunity 30 521 532
25. CouillaultCPujolNReboulJSabatierLGuichouJF 2004 TLR-independent control of innate immunity in Caenorhabditis elegans by the TIR domain adaptor protein TIR-1, an ortholog of human SARM. Nat Immunol 5 488 494
26. TroemelERFélixMWhitemanNBarrièreAAusubelFM 2008 Microsporidia are natural intracellular parasites of the nematode Caenorhabditis elegans. PloS Biol 6 e309
27. AballayADrenkardEHilbunLRAusubelFM 2003 Caenorhabditis elegans innate immune response triggered by Salmonella enterica requires intact LPS and is mediated by a MAPK signaling pathway. Curr Biol 13 47 52
28. IrazoquiJENgAXavierRJAusubelFM 2008 Role for beta-catenin and HOX transcription factors in Caenorhabditis elegans and mammalian host epithelial-pathogen interactions. Proc Natl Acad Sci USA 105 17469 17474
29. BolzDDTenorJLAballayA 2010 A conserved PMK-1/p38 MAPK is required in Caenorhabditis elegans tissue-specific immune response to Yersinia pestis infection. J Biol Chem 285 10832 10840
30. AnyanfulAEasleyKABenianGMKalmanD 2009 Conditioning protects C. elegans from lethal effects of enteropathogenic E. coli by activating genes that regulate lifespan and innate immunity. Cell Host Microbe 5 450 462
31. PowellJRKimDHAusubelFM 2009 The G protein-coupled receptor FSHR-1 is required for the Caenorhabditis elegans innate immune response. Proc Natl Acad Sci U S A 106 2782 2787
32. TroemelERChuSWReinkeVLeeSSAusubelFM 2006 p38 MAPK regulates expression of immune response genes and contributes to longevity in C. elegans. PLoS Genet 2 e183
33. Pukkila-WorleyRPelegAYTampakakisEMylonakisE 2009 Candida albicans hyphal formation and virulence assessed using a Caenorhabditis elegans infection model. Eukaryot Cell 8 1750 1758
34. IrazoquiJETroemelERFeinbaumRLLuhachackLGCezairliyanBO 2010 Distinct pathogenesis and host responses during infection of C. elegans by P. aeruginosa and S. aureus. PLoS Pathog 6 e1000982
35. O'RourkeDBabanDDemidovaMMottRHodgkinJ 2006 Genomic clusters, putative pathogen recognition molecules, and antimicrobial genes are induced by infection of C. elegans with M. nematophilum. Genome Res 16 1005 1016
36. WongDBazopoulouDPujolNTavernarakisNEwbankJJ 2007 Genome-wide investigation reveals pathogen-specific and shared signatures in the response of Caenorhabditis elegans to infection. Genome Biol 8 R194
37. GarsinDASifriCDMylonakisEQinXSinghKV 2001 A simple model host for identifying Gram-positive virulence factors. Proc Natl Acad Sci USA 98 10892 10897
38. MoreyJSRyanJCVan DolahFM 2006 Microarray validation: factors influencing correlation between oligonucleotide microarrays and real-time PCR. Biol Proced Online 8 175 193
39. KatoYAizawaTHoshinoHKawanoKNittaK 2002 abf-1 and abf-2, ASABF-type antimicrobial peptide genes in Caenorhabditis elegans. Biochem J 361 221 230
40. PujolNZugastiOWongDCouillaultCKurzCL 2008 Anti-fungal innate immunity in C. elegans is enhanced by evolutionary diversification of antimicrobial peptides. PLoS Pathog 4 e1000105
41. ZugastiOEwbankJJ 2009 Neuroimmune regulation of antimicrobial peptide expression by a noncanonical TGF-beta signaling pathway in Caenorhabditis elegans epidermis. Nat Immunol 10 249 256
42. EliasJAHomerRJHamidQLeeCG 2005 Chitinases and chitinase-like proteins in T(H)2 inflammation and asthma. J Allergy Clin Immunol 116 497 500
43. FunkhouserJDAronsonNNJr 2007 Chitinase family GH18: evolutionary insights from the genomic history of a diverse protein family. BMC Evol Biol 7 96
44. ShapiraMHamlinBJRongJChenKRonenM 2006 A conserved role for a GATA transcription factor in regulating epithelial innate immune responses. Proc Natl Acad Sci USA 103 14086 14091
45. Van GilstMRHadjivassiliouHYamamotoKR 2005 A Caenorhabditis elegans nutrient response system partially dependent on nuclear receptor NHR-49. Proc Natl Acad Sci U S A 102 13496 13501
46. PujolNCypowyjSZieglerKMilletAAstrainA 2008 Distinct innate immune responses to infection and wounding in the C. elegans epidermis. Curr Biol 18 481 489
47. ShiversRPKooistraTChuSWPaganoDJKimDH 2009 Tissue-specific activities of an immune signaling module regulate physiological responses to pathogenic and nutritional bacteria in C. elegans. Cell Host Microbe 6 321 330
48. ShiversRPPaganoDJKooistraTRichardsonCEReddyKC 2010 Phosphorylation of the conserved transcription factor ATF-7 by PMK-1 p38 MAPK regulates innate immunity in Caenorhabditis elegans. PLoS Genet 6 e1000892
49. KerrySTeKippeMGaddisNCAballayA 2006 GATA transcription factor required for immunity to bacterial and fungal pathogens. PLoS ONE 1 e77
50. MalloGVKurzCLCouillaultCPujolNGranjeaudS 2002 Inducible antibacterial defense system in C. elegans. Curr Biol 12 1209 1214
51. NeteaMGGowNAMunroCABatesSCollinsC 2006 Immune sensing of Candida albicans requires cooperative recognition of mannans and glucans by lectin and Toll-like receptors. J Clin Invest 116 1642 1650
52. JanewayCAJrMedzhitovR 2002 Innate immune recognition. Annu Rev Immunol 20 197 216
53. JanewayCAJr 1989 Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol 54 Pt 1 1 13
54. CashHLWhithamCVBehrendtCLHooperLV 2006 Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science 313 1126 1130
55. MurphyCTMcCarrollSABargmannCIFraserAKamathRS 2003 Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature 424 277 283
56. GowNANeteaMGMunroCAFerwerdaGBatesS 2007 Immune recognition of Candida albicans beta-glucan by dectin-1. J Infect Dis 196 1565 1571
57. WheelerRTFinkGR 2006 A drug-sensitive genetic network masks fungi from the immune system. PLoS Pathog 2 e35
58. VanceREIsbergRRPortnoyDA 2009 Patterns of pathogenesis: discrimination of pathogenic and nonpathogenic microbes by the innate immune system. Cell Host Microbe 6 10 21
59. AlperSMcBrideSJLackfordBFreedmanJHSchwartzDA 2007 Specificity and complexity of the Caenorhabditis elegans innate immune response. Mol Cell Biol 27 5544 5553
60. Pukkila-WorleyRHolsonEWagnerFMylonakisE 2009 Antifungal drug discovery through the study of invertebrate model hosts. Curr Med Chem 16 1588 1595
61. KenyonC 2005 The plasticity of aging: insights from long-lived mutants. Cell 120 449 460
62. KenyonCChangJGenschERudnerATabtiangR 1993 A C. elegans mutant that lives twice as long as wild type. Nature 366 461 464
63. KimuraKDTissenbaumHALiuYRuvkunG 1997 daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277 942 946
64. CofferPJBurgeringBM 2004 Forkhead-box transcription factors and their role in the immune system. Nat Rev Immunol 4 889 899
65. SpoelSHDongX 2008 Making sense of hormone crosstalk during plant immune responses. Cell Host Microbe 3 348 351
66. NobileCJMitchellAP 2005 Regulation of cell-surface genes and biofilm formation by the C. albicans transcription factor Bcr1p. Curr Biol 15 1150 1155
67. KohAYKohlerJRCoggshallKTVan RooijenNPierGB 2008 Mucosal damage and neutropenia are required for Candida albicans dissemination. PLoS Pathog 4 e35
68. KobayashiSDCutlerJE 1998 Candida albicans hyphal formation and virulence: is there a clearly defined role? Trends Microbiol 6 92 94
69. FuchsBBEbyJNobileCJEl KhouryJBMitchellAP 2010 Role of filamentation in Galleria mellonella killing by Candida albicans. Microbes Infect 12 488 496
70. HubeBNaglikJ 2001 Candida albicans proteinases: resolving the mystery of a gene family. Microbiology 147 1997 2005
71. BrennerS 1974 The genetics of Caenorhabditis elegans. Genetics 77 71 94
72. OggSParadisSGottliebSPattersonGILeeL 1997 The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 389 994 999
73. HendersonSTJohnsonTE 2001 daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans. Curr Biol 11 1975 1980
74. DavisDWilsonRBMitchellAP 2000 RIM101-dependent and-independent pathways govern pH responses in Candida albicans. Mol Cell Biol 20 971 978
75. GillumAMTsayEYKirschDR 1984 Isolation of the Candida albicans gene for orotidine-5′-phosphate decarboxylase by complementation of S. cerevisiae ura3 and E. coli pyrF mutations. Mol Gen Genet 198 179 182
76. PowellJRAusubelFM 2007 Models of Caenorhabditis elegans infection by bacterial and fungal pathogens. EwbankJJVivierE Innate Immunity, Methods in Molecular Biology Totowa Humana Press. Vol. 415 403 427
77. WengLDaiHZhanYHeYStepaniantsSB 2006 Rosetta error model for gene expression analysis. Bioinformatics 22 1111 1121
78. KirienkoNVMcEnerneyJDFayDS 2008 Coordinated regulation of intestinal functions in C. elegans by LIN-35/Rb and SLR-2. PLoS Genet 4 e1000059
79. DennisGJrShermanBTHosackDAYangJGaoW 2003 DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol 4 P3
80. Huang daWShermanBTLempickiRA 2009 Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4 44 57
81. Hunt-NewburyRViveirosRJohnsenRMahAAnastasD 2007 High-throughput in vivo analysis of gene expression in Caenorhabditis elegans. PLoS Biol 5 e237
82. TadasuSKoharaY 2005 NEXTDB. Available: http://nematode.lab.nig.ac.jp/. Accessed September 2010
83. RichardsonCEKooistraTKimDH 2010 An essential role for XBP-1 in host protection against immune activation in C. elegans. Nature 463 1092 1095
84. PfafflMW 2001 A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29 e45
85. BendtsenJDNielsenHvon HeijneGBrunakS 2004 Improved prediction of signal peptides: SignalP 3.0. J Mol Biol 340 783 795
86. SinghVAballayA 2006 Heat-shock transcription factor (HSF)-1 pathway required for Caenorhabditis elegans immunity. Proc Natl Acad Sci USA 103 13092 13097
87. PrahladVCorneliusTMorimotoRI 2008 Regulation of the cellular heat shock response in Caenorhabditis elegans by thermosensory neurons. Science 320 811 814
88. Mohri-ShiomiAGarsinDA 2008 Insulin signaling and the heat shock response modulate protein homeostasis in the Caenorhabditis elegans intestine during infection. J Biol Chem 283 194 201
89. McElweeJJSchusterEBlancEThomasJHGemsD 2004 Shared transcriptional signature in Caenorhabditis elegans Dauer larvae and long-lived daf-2 mutants implicates detoxification system in longevity assurance. J Biol Chem 279 44533 44543
90. RomneySJThackerCLeiboldEA 2008 An iron enhancer element in the FTN-1 gene directs iron-dependent expression in Caenorhabditis elegans intestine. J Biol Chem 283 716 725
91. AlperSLawsRLackfordBBoydWADunlapP 2008 Identification of innate immunity genes and pathways using a comparative genomics approach. Proc Natl Acad Sci U S A 105 7016 7021
Štítky
Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
PLOS Pathogens
2011 Číslo 6
- Parazitičtí červi v terapii Crohnovy choroby a dalších zánětlivých autoimunitních onemocnění
- Koronavirus hýbe světem: Víte jak se chránit a jak postupovat v případě podezření?
- Očkování proti virové hemoragické horečce Ebola experimentální vakcínou rVSVDG-ZEBOV-GP
Najčítanejšie v tomto čísle
- High Affinity Nanobodies against the VSG Are Potent Trypanolytic Agents that Block Endocytosis
- Structural and Mechanistic Studies of Measles Virus Illuminate Paramyxovirus Entry
- Sporangiospore Size Dimorphism Is Linked to Virulence of
- Uses Host Triacylglycerol to Accumulate Lipid Droplets and Acquires a Dormancy-Like Phenotype in Lipid-Loaded Macrophages