Interferon-Inducible CXC Chemokines Directly Contribute to Host Defense against Inhalational Anthrax in a Murine Model of Infection


Chemokines have been found to exert direct, defensin-like antimicrobial activity in vitro, suggesting that, in addition to orchestrating cellular accumulation and activation, chemokines may contribute directly to the innate host response against infection. No observations have been made, however, demonstrating direct chemokine-mediated promotion of host defense in vivo. Here, we show that the murine interferon-inducible CXC chemokines CXCL9, CXCL10, and CXCL11 each exert direct antimicrobial effects in vitro against Bacillus anthracis Sterne strain spores and bacilli including disruptions in spore germination and marked reductions in spore and bacilli viability as assessed using CFU determination and a fluorometric assay of metabolic activity. Similar chemokine-mediated antimicrobial activity was also observed against fully virulent Ames strain spores and encapsulated bacilli. Moreover, antibody-mediated neutralization of these CXC chemokines in vivo was found to significantly increase host susceptibility to pulmonary B. anthracis infection in a murine model of inhalational anthrax with disease progression characterized by systemic bacterial dissemination, toxemia, and host death. Neutralization of the shared chemokine receptor CXCR3, responsible for mediating cellular recruitment in response to CXCL9, CXCL10, and CXCL11, was not found to increase host susceptibility to inhalational anthrax. Taken together, our data demonstrate a novel, receptor-independent antimicrobial role for the interferon-inducible CXC chemokines in pulmonary innate immunity in vivo. These data also support an immunomodulatory approach for effectively treating and/or preventing pulmonary B. anthracis infection, as well as infections caused by pathogenic and potentially, multi-drug resistant bacteria including other spore-forming organisms.


Vyšlo v časopise: Interferon-Inducible CXC Chemokines Directly Contribute to Host Defense against Inhalational Anthrax in a Murine Model of Infection. PLoS Pathog 6(11): e32767. doi:10.1371/journal.ppat.1001199
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1001199

Souhrn

Chemokines have been found to exert direct, defensin-like antimicrobial activity in vitro, suggesting that, in addition to orchestrating cellular accumulation and activation, chemokines may contribute directly to the innate host response against infection. No observations have been made, however, demonstrating direct chemokine-mediated promotion of host defense in vivo. Here, we show that the murine interferon-inducible CXC chemokines CXCL9, CXCL10, and CXCL11 each exert direct antimicrobial effects in vitro against Bacillus anthracis Sterne strain spores and bacilli including disruptions in spore germination and marked reductions in spore and bacilli viability as assessed using CFU determination and a fluorometric assay of metabolic activity. Similar chemokine-mediated antimicrobial activity was also observed against fully virulent Ames strain spores and encapsulated bacilli. Moreover, antibody-mediated neutralization of these CXC chemokines in vivo was found to significantly increase host susceptibility to pulmonary B. anthracis infection in a murine model of inhalational anthrax with disease progression characterized by systemic bacterial dissemination, toxemia, and host death. Neutralization of the shared chemokine receptor CXCR3, responsible for mediating cellular recruitment in response to CXCL9, CXCL10, and CXCL11, was not found to increase host susceptibility to inhalational anthrax. Taken together, our data demonstrate a novel, receptor-independent antimicrobial role for the interferon-inducible CXC chemokines in pulmonary innate immunity in vivo. These data also support an immunomodulatory approach for effectively treating and/or preventing pulmonary B. anthracis infection, as well as infections caused by pathogenic and potentially, multi-drug resistant bacteria including other spore-forming organisms.


Zdroje

1. EscheC

StellatoC

BeckLA

2005 Chemokines: key players in innate and adaptive immunity. J Invest Dermatol 125 615 628

2. ZaasAK

SchwartzDA

2005 Innate immunity and the lung: defense at the interface between host and environment. Trends Cardiovasc Med 15 195 202

3. LusterAD

2002 The role of chemokines in linking innate and adaptive immunity. Curr Opin Immunol 14 129 135

4. AllenSJ

CrownSE

HandelTM

2007 Chemokine: receptor structure, interactions, and antagonism. Annu Rev Immunol 25 787 820

5. ColeAM

GanzT

LieseAM

BurdickMD

LiuL

2001 Cutting edge: IFN-inducible ELR- CXC chemokines display defensin-like antimicrobial activity. J Immunol 167 623 627

6. HieshimaK

OhtaniH

ShibanoM

IzawaD

NakayamaT

2003 CCL28 has dual roles in mucosal immunity as a chemokine with broad-spectrum antimicrobial activity. J Immunol 170 1452 1461

7. TangYQ

YeamanMR

SelstedME

2002 Antimicrobial peptides from human platelets. Infect Immun 70 6524 6533

8. YangD

ChenQ

HooverDM

StaleyP

TuckerKD

2003 Many chemokines including CCL20/MIP-3alpha display antimicrobial activity. J Leukoc Biol 7 448 455

9. StrieterRM

KunkelSL

StandifordTJ

2003 Chemokines in the Lung. New York Dekker

10. MoberlyBJ

ShafaF

GerhardtP

1966 Structural details of anthrax spores during stages of transformation into vegetative cells. J Bacteriol 92 220 228

11. SetlowP

2006 Spores of Bacillus subtilis: their resistance to and killing by radiation, heat and chemicals. J Appl Microbiol 101 514 525

12. Guidi-RontaniC

Weber-LevyM

LabruyèreE

MockM

1999 Germination of Bacillus anthracis spores within alveolar macrophages. Mol Microbiol 31 9 17

13. CleretA

Quesnel-HellmannA

Vallon-EberhardA

VerrierB

JungS

2007 Lung dendritic cells rapidly mediate anthrax spore entry through the pulmonary route. J Immunol 178 7994 8001

14. GlomskiIJ

Piris-GimenezA

HuerreM

MockM

GoossensPL

2007 Primary involvement of pharynx and peyer's patch in inhalational and intestinal anthrax. PLoS Pathog 3 e76

15. SanzP

TeelLD

FarhangA

CarvalhoHM

DarnellSC

2008 Detection of Bacillus anthracis spore germination in vivo by bioluminescence imaging. Infect Immun 76 1036 1047

16. WelkosS

FriedlanderA

WeeksS

LittleS

MendelsonI

2002 In-vitro characterization of the phagocytosis and fate of anthrax spores in macrophages and the effects of anti-PA antibody. J Med Microbiol 51 821 831

17. DixonTC

FadlAA

KoehlerTM

SwansonJA

HannaPC

2000 Early Bacillus anthracis - macrophage interactions: intracellular survival and escape. Cell Microbiol 2 453 463

18. BanksDJ

WardSC

BradleyKA

2006 New insights into the functions of anthrax toxin. Expert Rev Mol Med 8 1 18

19. ScorpioA

ChabotDJ

DayWA

HooverTA

FriedlanderAM

2010 Capsule depolymerase overexpression reduces Bacillus anthracis virulence. Microbiology 156 1459 1467

20. GoossensPL

2009 Animal models of human anthrax: the Quest for the Holy Grail. Mol Aspects Med 30 467 480

21. LoetscherM

LoetscherP

BrassN

MeeseE

MoserB

1998 Lymphocyte-specific chemokine receptor CXCR3: regulation, chemokine binding and gene localization. Eur J Immunol 28 3696 3705

22. CrawfordMA

ZhuY

GreenCS

BurdickMD

SanzP

2009 Antimicrobial effects of interferon-inducible CXC chemokines against Bacillus anthracis spores and bacilli. Infect Immun 77 1664 1678

23. BelperioJA

KeaneMP

BurdickMD

LynchJP3rd

ZismanDA

2003 Role of CXCL9/CXCR3 chemokine biology during pathogenesis of acute lung allograft rejection. J Immunol 171 4844 4852

24. WallaceKL

MarshallMA

RamosSI

LanniganJA

FieldJJ

2009 NKT cells mediate pulmonary inflammation and dysfunction in murine sickle cell disease through production of IFN-gamma and CXCR3 chemokines. Blood 114 667 676

25. HarvillET

LeeG

GrippeVK

MerkelTJ

2005 Complement depletion renders C57BL/6 mice sensitive to the Bacillus anthracis Stern strain. Infect Immun 73 4420 4422

26. LyonsCR

LovchikJ

HuttJ

LipscombMF

WangE

2004 Murine model of pulmonary anthrax: kinetics of dissemination, histopathology, and mouse strain susceptibility. Infect Immun 72 4801 4809

27. LovingCL

KhuranaT

OsorioM

LeeGM

KellyVK

2009 Role of anthrax toxins in dissemination, disease progression, and induction of protective adaptive immunity in the mouse aerosol challenge model. Infect Immun 77 255 265

28. BoyerAE

QuinnCP

HoffmasterAR

KozelTR

SaileE

2009 Kinetics of lethal factor and poly-D-glutamic acid antigenemia during inhalation anthrax in Rhesus macaques. Infect Immun 77 3432 3411

29. TangS

MoayeriM

ChenZ

HarmaH

ZhaoJ

2009 Detection of anthrax toxin by an ultrasensitive immunoassay using europium nanoparticles. Clin Vaccine Immunol 16 408 413

30. BoyerAE

QuinnCP

WoolfittAR

PirkleJL

McWilliamsLG

2007 Detection and quantification of anthrax lethal factor in serum by mass spectrometry. Anal Chem 79 8463 8470

31. TosiMF

2005 Innate immune responses to infection. J Allergy Clin Immunol 116 241 249

32. StrieterRM

BelperioJA

KeaneMP

2002 Cytokines in innate host defense in the lung. J Clin Invest 109 699 705

33. EliassonM

EgestenA

2008 Antibacterial chemokines - actors in both innate and adaptive immunity.

EgestenA

SchmidtA

HerwaldH

Trends in Innate Immunity. Contrib Microbiol Basel Karger 101 117

34. BowdishDM

DavidsonDJ

HancockRE

2006 Immunomodulatory properties of defensins and cathelicidins. Curr Top Microbiol Immunol 306 27 66

35. BaconnaisS

TirouvanziamR

ZahmJM

de BentzmannS

PèaultB

1999 Ion composition and rheology of airway liquid from cystic fibrosis fetal tracheal xenografts. Am J Respir Cell Mol Biol 20 605 611

36. BalsR

2000 Epithelial antimicrobial peptides in host defense against infection. Respir Res 1 141 150

37. EvansSE

XuY

TuvimMJ

DickeyBF

2010 Inducible innate resistance of lung epithelium to infection. Annu Rev Physiol 72 413 435

38. EgestenA

EliassonM

JohanssonHM

OlinAI

MörgelinM

2007 The CXC chemokine MIG/CXCL9 is important in innate immunity against Streptococcus pyogenes. J Infect Dis 195 684 693

39. SautyA

DziejmanM

TahaRA

IarossiAS

NeoteK

1999 The T cell-specific CXC chemokines IP-10, Mig, and I-TAC are expressed by activated human bronchial epithelial cells. J Immunol 162 3549 3558

40. LewisCC

YangJY

HuangX

BanerjeeSK

BlackburnMR

2008 Disease-specific gene expression profiling in multiple models of lung disease. Am J Respir Crit Care Med 177 376 387

41. DoolanDL

FreilichDA

BriceGT

BurgessTH

BerzinsMP

2007 The US Capitol bioterrorism anthrax exposures: clinical epidemiological and immunological characteristics. J Infect Dis 195 174 184

42. KarlssonC

EliassonM

OlinAI

MörgelinM

KarlssonA

2009 SufA of the opportunistic pathogen Finegoldia magna modulates actions of the antibacterial chemokine MIG/CXCL9 promoting bacterial survival during epithelial inflammation. J Biol Chem 284 29499 29508

43. EgestenA

OlinAI

LingeHM

YadavM

MörgelinM

2009 SpeB of Streptococcus pyogenes differentially modulates antibacterial and receptor activating properties of human chemokines. PLoS One 4 e4769

44. KotarskyK

SitnikKM

StenstadH

KotarskyH

SchmidtchenA

2010 A novel role for constitutively expressed epithelial-derived chemokines as antibacterial peptides in the intestinal mucosa. Mucosal Immunol 3 40 48

45. LingeHM

CollinM

GiwercmanA

MalmJ

BjartellA

2008 The antibacterial chemokine MIG/CXCL9 is constitutively expressed in epithelial cells of the male urogenital tract and is present in seminal plasma. J Interferon Cytokine Res 28 191 196

46. LisanbyMW

SwieckiMK

DizonBL

PflughoeftKJ

KoehlerTM

2008 Cathelicidin administration protects mice from Bacillus anthracis spore challenge. J Immunol 181 4989 5000

47. GongJH

NichollsEF

ElliotMR

BrownKL

HokampK

2010 G-protein-coupled receptor independent, immunomodulatory properties of chemokine CXCL9. Cell Immunol 261 105 113

48. DeRykeCA

MaglioD

NicolauDP

2005 Defining the need for new antimicrobials: clinical and economic implications of resistance in the hospitalized patient. Expert Opin Pharmacother 6 873 889

49. FraserCM

DandoMR

2001 Genomics and future biological weapons: the need for preventive action by the biomedical community. Nat Genet 29 253 256

50. HancockRE

SahlHG

2006 Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat Biotechnol 24 1551 1557

51. YeamanMR

YountNY

2003 Mechanisms of antimicrobial peptide action and resistance. Pharmacol Rev 55 27 55

52. GoldJA

HoshinoY

HoshinoS

JonesMB

NolanA

2004 Exogenous gamma and alpha/beta interferon rescues human macrophages from cell death induced by Bacillus anthracis. Infect Immun 72 1291 1297

53. WalbergK

BaronS

PoastJ

SchwartzB

IzotovaL

2008 Interferon protects mice against inhalational anthrax. J Interferon Cytokine Res 28 597 601

54. ThorneCB

1968 Transducing bacteriophage for Bacillus cereus. J Virol 2 657 662

55. NicholsonWL

SetlowP

1990 Sporulation, germination, and outgrowth.

HarwoodCR

CuttingSM

Molecular Biological Methods for Bacillus Chichester John Wiley and Sons 391 450

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

Článok vyšiel v časopise

PLOS Pathogens


2010 Číslo 11
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Eozinofilní granulomatóza s polyangiitidou
nový kurz
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa