Membrane Damage Elicits an Immunomodulatory Program in

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The Staphylococcus aureus HrtAB system is a hemin-regulated ABC transporter composed of an ATPase (HrtA) and a permease (HrtB) that protect S. aureus against hemin toxicity. S. aureus strains lacking hrtA exhibit liver-specific hyper-virulence and upon hemin exposure over-express and secrete immunomodulatory factors that interfere with neutrophil recruitment to the site of infection. It has been proposed that heme accumulation in strains lacking hrtAB is the signal which triggers S. aureus to elaborate this anti-neutrophil response. However, we report here that S. aureus strains expressing catalytically inactive HrtA do not elaborate the same secreted protein profile. This result indicates that the physical absence of HrtA is responsible for the increased expression of immunomodulatory factors, whereas deficiencies in the ATPase activity of HrtA do not contribute to this process. Furthermore, HrtB expression in strains lacking hrtA decreases membrane integrity consistent with dysregulated permease function. Based on these findings, we propose a model whereby hemin-mediated over-expression of HrtB in the absence of HrtA damages the staphylococcal membrane through pore formation. In turn, S. aureus senses this membrane damage, triggering the increased expression of immunomodulatory factors. In support of this model, wildtype S. aureus treated with anti-staphylococcal channel-forming peptides produce a secreted protein profile that mimics the effect of treating ΔhrtA with hemin. These results suggest that S. aureus senses membrane damage and elaborates a gene expression program that protects the organism from the innate immune response of the host.

Vyšlo v časopise: Membrane Damage Elicits an Immunomodulatory Program in. PLoS Pathog 6(3): e32767. doi:10.1371/journal.ppat.1000802
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1000802

Souhrn

Zdroje

1. WertheimHF

VosMC

OttA

van BelkumA

VossA

2004 Risk and outcome of nosocomial Staphylococcus aureus bacteraemia in nasal carriers versus non-carriers. Lancet 364 703 705

2. DiekemaDJ

PfallerMA

SchmitzFJ

SmayevskyJ

BellJ

2001 Survey of infections due to Staphylococcus species: frequency of occurrence and antimicrobial susceptibility of isolates collected in the United States, Canada, Latin America, Europe, and the Western Pacific region for the SENTRY Antimicrobial Surveillance Program, 1997-1999. Clin Infect Dis 32 Suppl 2 S114 132

3. KlevensRM

MorrisonMA

NadleJ

PetitS

GershmanK

2007 Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA 298 1763 1771

4. LowyFD

1998 Staphylococcus aureus infections. N Engl J Med 339 520 532

5. DeLeoFR

DiepBA

OttoM

2009 Host defense and pathogenesis in Staphylococcus aureus infections. Infect Dis Clin North Am 23 17 34

6. BullenDJ

GriffithsE

1999 Iron and Infection: Molecular, Physiological and Clinical Aspects, 2nd Edition ed. New York, NY John Wiley and Sons

7. SkaarEP

GasparAH

SchneewindO

2004 IsdG and IsdI, heme-degrading enzymes in the cytoplasm of Staphylococcus aureus. J Biol Chem 279 436 443

8. ReniereML

TorresVJ

SkaarEP

2007 Intracellular metalloporphyrin metabolism in Staphylococcus aureus. Biometals 20 333 345

9. PishchanyG

DickeySE

SkaarEP

2009 Subcellular localization of the Staphylococcus aureus heme-iron transport components IsdA and IsdB. Infect Immun

10. MazmanianSK

SkaarEP

GasparAH

HumayunM

GornickiP

2003 Passage of heme-iron across the envelope of Staphylococcus aureus. Science 299 906 909

11. TorresVJ

PishchanyG

HumayunM

SchneewindO

SkaarEP

2006 Staphylococcus aureus IsdB is a hemoglobin receptor required for heme iron utilization. J Bacteriol 188 8421 8429

12. StauffDL

TorresVJ

SkaarEP

2007 Signaling and DNA-binding activities of the Staphylococcus aureus HssR-HssS two-component system required for heme sensing. J Biol Chem 282 26111 26121

13. TorresVJ

StauffDL

PishchanyG

BezbradicaJS

GordyLE

2007 A Staphylococcus aureus regulatory system that responds to host heme and modulates virulence. Cell Host Microbe 1 109 119

14. StauffDL

BagaleyD

TorresVJ

JoyceR

AndersonKL

2008 Staphylococcus aureus HrtA is an ATPase required for protection against heme toxicity and prevention of a transcriptional heme stress response. J Bacteriol 190 3588 3596

15. DavidsonAL

ChenJ

2004 ATP-binding cassette transporters in bacteria. Annu Rev Biochem 73 241 268

16. HigginsCF

LintonKJ

2004 The ATP switch model for ABC transporters. Nat Struct Mol Biol 11 918 926

17. HollandIB

BlightMA

1999 ABC-ATPases, adaptable energy generators fuelling transmembrane movement of a variety of molecules in organisms from bacteria to humans. J Mol Biol 293 381 399

18. DavidsonAL

DassaE

OrelleC

ChenJ

2008 Structure, function, and evolution of bacterial ATP-binding cassette systems. Microbiol Mol Biol Rev 72 317 364

19. FraserJD

ProftT

2008 The bacterial superantigen and superantigen-like proteins. Immunol Rev 225 226 243

20. WilliamsRJ

WardJM

HendersonB

PooleS

O'HaraBP

2000 Identification of a novel gene cluster encoding staphylococcal exotoxin-like proteins: characterization of the prototypic gene and its protein product, SET1. Infect Immun 68 4407 4415

21. PratC

BestebroerJ

de HaasCJ

van StrijpJA

van KesselKP

2006 A new staphylococcal anti-inflammatory protein that antagonizes the formyl peptide receptor-like 1. J Immunol 177 8017 8026

22. WellerK

LauberS

LerchM

RenaudA

MerkleHP

2005 Biophysical and biological studies of end-group-modified derivatives of Pep-1. Biochemistry 44 15799 15811

23. PorcelliF

VerardiR

ShiL

Henzler-WildmanKA

RamamoorthyA

2008 NMR structure of the cathelicidin-derived human antimicrobial peptide LL-37 in dodecylphosphocholine micelles. Biochemistry 47 5565 5572

24. KrausD

HerbertS

KristianSA

KhosraviA

NizetV

2008 The GraRS regulatory system controls Staphylococcus aureus susceptibility to antimicrobial host defenses. BMC Microbiol 8 85

25. LaiY

VillaruzAE

LiM

ChaDJ

SturdevantDE

2007 The human anionic antimicrobial peptide dermcidin induces proteolytic defence mechanisms in staphylococci. Mol Microbiol 63 497 506

26. LangleyR

WinesB

WilloughbyN

BasuI

ProftT

2005 The staphylococcal superantigen-like protein 7 binds IgA and complement C5 and inhibits IgA-Fc alpha RI binding and serum killing of bacteria. J Immunol 174 2926 2933

27. BestebroerJ

PoppelierMJ

UlfmanLH

LentingPJ

DenisCV

2007 Staphylococcal superantigen-like 5 binds PSGL-1 and inhibits P-selectin-mediated neutrophil rolling. Blood 109 2936 2943

28. FriedmanDB

StauffDL

PishchanyG

WhitwellCW

TorresVJ

2006 Staphylococcus aureus redirects central metabolism to increase iron availability. PLoS Pathog 2 e87 doi:10.1371/journal.ppat.0020087

29. WagnerS

BaderML

DrewD

de GierJW

2006 Rationalizing membrane protein overexpression. Trends Biotechnol 24 364 371

30. GudmundssonGH

AgerberthB

1999 Neutrophil antibacterial peptides, multifunctional effector molecules in the mammalian immune system. J Immunol Methods 232 45 54

31. KomatsuzawaH

OuharaK

YamadaS

FujiwaraT

SayamaK

2006 Innate defences against methicillin-resistant Staphylococcus aureus (MRSA) infection. J Pathol 208 249 260

32. HarderJ

BartelsJ

ChristophersE

SchroderJM

2001 Isolation and characterization of human β-defensin-3, a novel human inducible peptide antibiotic. J Biol Chem 276 5707 5713

33. DinulosJG

MenteleL

FredericksLP

DaleBA

DarmstadtGL

2003 Keratinocyte expression of human β−defensin 2 following bacterial infection: role in cutaneous host defense. Clin Diagn Lab Immunol 10 161 166

34. KooSP

BayerAS

YeamanMR

2001 Diversity in antistaphylococcal mechanisms among membrane-targeting antimicrobial peptides. Infect Immun 69 4916 4922

35. BrogdenKA

2005 Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nat Rev Microbiol 3 238 250

36. HaleJD

HancockRE

2007 Alternative mechanisms of action of cationic antimicrobial peptides on bacteria. Expert Rev Anti Infect Ther 5 951 959

37. ShaiY

2002 Mode of action of membrane active antimicrobial peptides. Biopolymers 66 236 248

38. BaderMW

SanowarS

DaleyME

SchneiderAR

ChoU

2005 Recognition of antimicrobial peptides by a bacterial sensor kinase. Cell 122 461 472

39. LiM

LaiY

VillaruzAE

ChaDJ

SturdevantDE

2007 Gram-positive three-component antimicrobial peptide-sensing system. Proc Natl Acad Sci U S A 104 9469 9474

40. HerbertS

BeraA

NerzC

KrausD

PeschelA

2007 Molecular basis of resistance to muramidase and cationic antimicrobial peptide activity of lysozyme in staphylococci. PLoS Pathog 3 e102 doi:10.1371/journal.ppat.0030102

41. NovickRP

2003 Autoinduction and signal transduction in the regulation of staphylococcal virulence. Mol Microbiol 48 1429 1449

42. CheungAL

BayerAS

ZhangG

GreshamH

XiongYQ

2004 Regulation of virulence determinants in vitro and in vivo in Staphylococcus aureus. FEMS Immunol Med Microbiol 40 1 9

43. GeigerT

GoerkeC

MainieroM

KrausD

WolzC

2008 The virulence regulator Sae of Staphylococcus aureus: promoter activities and response to phagocytosis-related signals. J Bacteriol 190 3419 3428

44. SassV

PagU

TossiA

BierbaumG

SahlHG

2008 Mode of action of human β−defensin 3 against Staphylococcus aureus and transcriptional analysis of responses to defensin challenge. Int J Med Microbiol 298 619 633

45. VoyichJM

BraughtonKR

SturdevantDE

WhitneyAR

Said-SalimB

2005 Insights into mechanisms used by Staphylococcus aureus to avoid destruction by human neutrophils. J Immunol 175 3907 3919

46. Palazzolo-BallanceAM

ReniereML

BraughtonKR

SturdevantDE

OttoM

2008 Neutrophil microbicides induce a pathogen survival response in community-associated methicillin-resistant Staphylococcus aureus. J Immunol 180 500 509

47. BestebroerJ

van KesselKP

AzouaghH

WalenkampAM

BoerIG

2009 Staphylococcal SSL5 inhibits leukocyte activation by chemokines and anaphylatoxins. Blood 113 328 337

48. WalenkampAM

BoerIG

BestebroerJ

RozeveldD

Timmer-BosschaH

2009 Staphylococcal superantigen-like 10 inhibits CXCL12-induced human tumor cell migration. Neoplasia 11 333 344

49. DunmanPM

MurphyE

HaneyS

PalaciosD

Tucker-KelloggG

2001 Transcription profiling-based identification of Staphylococcus aureus genes regulated by the agr and/or sarA loci. J Bacteriol 183 7341 7353

50. FungS

O'GradyS

KennedyC

DedierH

CampbellI

2000 The utility of polysporin ointment in the eradication of methicillin-resistant Staphylococcus aureus colonization: a pilot study. Infect Control Hosp Epidemiol 21 653 655

51. SchubertC

MoosaMR

2007 Infective endocarditis in a hemodialysis patient: a dreaded complication. Hemodial Int 11 379 384

52. DuthieES

LorenzLL

1952 Staphylococcal coagulase; mode of action and antigenicity. J Gen Microbiol 6 95 107

53. BaeT

BangerAK

WallaceA

GlassEM

AslundF

2004 Staphylococcus aureus virulence genes identified by bursa aurealis mutagenesis and nematode killing. Proc Natl Acad Sci U S A 101 12312 12317

54. BaeT

SchneewindO

2006 Allelic replacement in Staphylococcus aureus with inducible counter-selection. Plasmid 55 58 63

55. LukomskiS

HoeNP

AbdiI

RurangirwaJ

KordariP

2000 Nonpolar inactivation of the hypervariable streptococcal inhibitor of complement gene (sic) in serotype M1 Streptococcus pyogenes significantly decreases mouse mucosal colonization. Infect Immun 68 535 542

56. Bubeck WardenburgJ

WilliamsWA

MissiakasD

2006 Host defenses against Staphylococcus aureus infection require recognition of bacterial lipoproteins. Proc Natl Acad Sci U S A 103 13831 13836

57. NovickRP

1991 Genetic systems in staphylococci. Methods Enzymol 204 587 636

58. SchenkS

LaddagaRA

1992 Improved method for electroporation of Staphylococcus aureus. FEMS Microbiol Lett 73 133 138

59. TabbDL

FernandoCG

ChambersMC