Inhibition of TIR Domain Signaling by TcpC: MyD88-Dependent and Independent Effects on Virulence

English version České info

Toll-like receptor signaling requires functional Toll/interleukin-1 (IL-1) receptor (TIR) domains to activate innate immunity. By producing TIR homologous proteins, microbes inhibit host response induction and improve their own survival. The TIR homologous protein TcpC was recently identified as a virulence factor in uropathogenic Escherichia coli (E. coli), suppressing innate immunity by binding to MyD88. This study examined how the host MyD88 genotype modifies the in vivo effects of TcpC and whether additional, TIR-domain containing proteins might be targeted by TcpC. In wild type mice (wt), TcpC enhanced bacterial virulence, increased acute mortality, bacterial persistence and tissue damage after infection with E. coli CFT073 (TcpC+), compared to a ΔTcpC deletion mutant. These effects were attenuated in Myd88^−/− and Tlr4^−/− mice. Transcriptomic analysis confirmed that TcpC inhibits MYD88 dependent gene expression in CFT073 infected human uroepithelial cells but in addition the inhibitory effect included targets in the TRIF and IL-6/IL-1 signaling pathways, where MYD88 dependent and independent signaling may converge. The effects of TcpC on bacterial persistence were attenuated in Trif ^−/− or Il-1β ^−/− mice and innate immune responses to ΔTcpC were increased, confirming that Trif and Il-1β dependent targets might be involved in vivo, in addition to Myd88. Furthermore, soluble TcpC inhibited Myd88 and Trif dependent TLR signaling in murine macrophages. Our results suggest that TcpC may promote UTI-associated pathology broadly, through inhibition of TIR domain signaling and downstream pathways. Dysregulation of the host response by microbial TcpC thus appears to impair the protective effects of innate immunity, while promoting inflammation and tissue damage.

Vyšlo v časopise: Inhibition of TIR Domain Signaling by TcpC: MyD88-Dependent and Independent Effects on Virulence. PLoS Pathog 6(9): e32767. doi:10.1371/journal.ppat.1001120
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1001120

Souhrn

Zdroje

1. PoltorakA

HeX

SmirnovaI

LiuMY

Van HuffelC

1998 Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282 2085 2088

2. RodriguezN

WantiaN

FendF

DurrS

WagnerH

2006 Differential involvement of TLR2 and TLR4 in host survival during pulmonary infection with Chlamydia pneumoniae. Eur J Immunol 36 1145 1155

3. KawaiT

AkiraS

2006 TLR signaling. Cell Death Differ 13 816 825

4. KawaiT

SatoS

IshiiKJ

CobanC

HemmiH

2004 Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat Immunol 5 1061 1068

5. ThomassenE

RenshawBR

SimsJE

1999 Identification and characterization of SIGIRR, a molecule representing a novel subtype of the IL-1R superfamily. Cytokine 11 389 399

6. WaldD

QinJ

ZhaoZ

QianY

NaramuraM

2003 SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signaling. Nat Immunol 4 920 927

7. BurnsK

JanssensS

BrissoniB

OlivosN

BeyaertR

2003 Inhibition of interleukin 1 receptor/Toll-like receptor signaling through the alternatively spliced, short form of MyD88 is due to its failure to recruit IRAK-4. J Exp Med 197 263 268

8. KobayashiK

HernandezLD

GalanJE

JanewayCAJr

MedzhitovR

2002 IRAK-M is a negative regulator of Toll-like receptor signaling. Cell 110 191 202

9. FearnsC

PanQ

MathisonJC

ChuangTH

2006 Triad3A regulates ubiquitination and proteasomal degradation of RIP1 following disruption of Hsp90 binding. J Biol Chem 281 34592 34600

10. CartyM

GoodbodyR

SchroderM

StackJ

MoynaghPN

2006 The human adaptor SARM negatively regulates adaptor protein TRIF-dependent Toll-like receptor signaling. Nat Immunol 7 1074 1081

11. FischerH

YamamotoM

AkiraS

BeutlerB

SvanborgC

2006 Mechanism of pathogen-specific TLR4 activation in the mucosa: fimbriae, recognition receptors and adaptor protein selection. Eur J Immunol 36 267 277

12. CirlC

WieserA

YadavM

DuerrS

SchubertS

2008 Subversion of Toll-like receptor signaling by a unique family of bacterial Toll/interleukin-1 receptor domain-containing proteins. Nat Med 14 399 406

13. SpearAM

LomanNJ

AtkinsHS

PallenMJ

2009 Microbial TIR domains: not necessarily agents of subversion? Trends Microbiol 17 393 398

14. BowieA

Kiss-TothE

SymonsJA

SmithGL

DowerSK

2000 A46R and A52R from vaccinia virus are antagonists of host IL-1 and toll-like receptor signaling. Proc Natl Acad Sci U S A 97 10162 10167

15. NewmanRM

SalunkheP

GodzikA

ReedJC

2006 Identification and characterization of a novel bacterial virulence factor that shares homology with mammalian Toll/interleukin-1 receptor family proteins. Infect Immun 74 594 601

16. RadhakrishnanGK

YuQ

HarmsJS

SplitterGA

2009 Brucella TIR Domain-containing Protein Mimics Properties of the Toll-like Receptor Adaptor Protein TIRAP. J Biol Chem 284 9892 9898

17. HoebeK

DuX

GeorgelP

JanssenE

TabetaK

2003 Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 424 743 748

18. TaniguchiT

OgasawaraK

TakaokaA

TanakaN

2001 IRF family of transcription factors as regulators of host defense. Annu Rev Immunol 19 623 655

19. HondaK

TaniguchiT

2006 IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors. Nat Rev Immunol 6 644 658

20. BurnsK

MartinonF

EsslingerC

PahlH

SchneiderP

1998 MyD88, an adapter protein involved in interleukin-1 signaling. J Biol Chem 273 12203 12209

21. KawaiT

AdachiO

OgawaT

TakedaK

AkiraS

1999 Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 11 115 122

22. Svanborg EdenC

BrilesD

HagbergL

McGheeJ

MichalecS

1985 Genetic factors in host resistance to urinary tract infection. Infection 13 Suppl 2 S171 176

23. LundstedtAC

McCarthyS

GustafssonMC

GodalyG

JodalU

2007 A genetic basis of susceptibility to acute pyelonephritis. PLoS ONE 2 e825

24. RagnarsdottirB

SamuelssonM

GustafssonMC

LeijonhufvudI

KarpmanD

2007 Reduced toll-like receptor 4 expression in children with asymptomatic bacteriuria. J Infect Dis 196 475 484

25. ShiS

NathanC

SchnappingerD

DrenkowJ

FuortesM

2003 MyD88 primes macrophages for full-scale activation by interferon-gamma yet mediates few responses to Mycobacterium tuberculosis. J Exp Med 198 987 997

26. SunD

DingA

2006 MyD88-mediated stabilization of interferon-gamma-induced cytokine and chemokine mRNA. Nat Immunol 7 375 381

27. FitzgeraldKA

Palsson-McDermottEM

BowieAG

JefferiesCA

MansellAS

2001 Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature 413 78 83

28. YamamotoM

SatoS

HemmiH

HoshinoK

KaishoT

2003 Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 301 640 643

29. SatoS

SugiyamaM

YamamotoM

WatanabeY

KawaiT

2003 Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF) associates with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates two distinct transcription factors, NF-kappa B and IFN-regulatory factor-3, in the Toll-like receptor signaling. J Immunol 171 4304 4310

30. FitzgeraldKA

RoweDC

BarnesBJ

CaffreyDR

VisintinA

2003 LPS-TLR4 signaling to IRF-3/7 and NF-kappaB involves the toll adapters TRAM and TRIF. J Exp Med 198 1043 1055

31. YamamotoM

SatoS

HemmiH

UematsuS

HoshinoK

2003 TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat Immunol 4 1144 1150

32. RoweDC

McGettrickAF

LatzE

MonksBG

GayNJ

2006 The myristoylation of TRIF-related adaptor molecule is essential for Toll-like receptor 4 signal transduction. Proc Natl Acad Sci U S A 103 6299 6304

33. McGettrickAF

BrintEK

Palsson-McDermottEM

RoweDC

GolenbockDT

2006 Trif-related adapter molecule is phosphorylated by PKC{epsilon} during Toll-like receptor 4 signaling. Proc Natl Acad Sci U S A 103 9196 9201

34. OganesyanG

SahaSK

GuoB

HeJQ

ShahangianA

2006 Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response. Nature 439 208 211

35. BeutlerB

HoebeK

GeorgelP

TabetaK

DuX

2005 Genetic analysis of innate immunity: identification and function of the TIR adapter proteins. Adv Exp Med Biol 560 29 39

36. BergstenG

SamuelssonM

WulltB

LeijonhufvudI

FischerH

2004 PapG-dependent adherence breaks mucosal inertia and triggers the innate host response. J Infect Dis 189 1734 1742

37. JanssensS

BurnsK

VercammenE

TschoppJ

BeyaertR

2003 MyD88S, a splice variant of MyD88, differentially modulates NF-kappaB- and AP-1-dependent gene expression. FEBS Lett 548 103 107

38. HoshinoK

TakeuchiO

KawaiT

SanjoH

OgawaT

1999 Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol 162 3749 3752

39. AdachiO

KawaiT

TakedaK

MatsumotoM

TsutsuiH

1998 Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity 9 143 150

40. SatoM

SuemoriH

HataN

AsagiriM

OgasawaraK

2000 Distinct and essential roles of transcription factors IRF-3 and IRF-7 in response to viruses for IFN-alpha/beta gene induction. Immunity 13 539 548

41. HoraiR

AsanoM

SudoK

KanukaH

SuzukiM

1998 Production of mice deficient in genes for interleukin (IL)-1alpha, IL-1beta, IL-1alpha/beta, and IL-1 receptor antagonist shows that IL-1beta is crucial in turpentine-induced fever development and glucocorticoid secretion. J Exp Med 187 1463 1475

42. KaoJS

StuckerDM

WarrenJW

MobleyHL

1997 Pathogenicity island sequences of pyelonephritogenic Escherichia coli CFT073 are associated with virulent uropathogenic strains. Infect Immun 65 2812 2820

43. MobleyH

GreenD

TrifillisA

JohnsonD

ChippendaleG

1990 Pyelonephritogenic Escherichia coli and killing of cultured human renal proximal tubular epithelial cells: Role of hemolysin in some strains. Infect Immun 58 1281 1289

44. JohansonIM

PlosK

MarklundBI

SvanborgC

1993 Pap, papG and prsG DNA sequences in Escherichia coli from the fecal flora and the urinary tract. Microb Pathog 15 121 129

45. HagbergL

EngbergI

FreterR

LamJ

OllingS

1983 Ascending, unobstructed urinary tract infection in mice caused by pyelonephritogenic Escherichia coli of human origin. Infect Immun 40 273 283

46. MajewskaM