Interleukin-13 Promotes Susceptibility to Chlamydial Infection of the Respiratory and Genital Tracts

English version České info

Chlamydiae are intracellular bacteria that commonly cause infections of the respiratory and genital tracts, which are major clinical problems. Infections are also linked to the aetiology of diseases such as asthma, emphysema and heart disease. The clinical management of infection is problematic and antibiotic resistance is emerging. Increased understanding of immune processes that are involved in both clearance and immunopathology of chlamydial infection is critical for the development of improved treatment strategies. Here, we show that IL-13 was produced in the lungs of mice rapidly after Chlamydia muridarum (Cmu) infection and promoted susceptibility to infection. Wild-type (WT) mice had increased disease severity, bacterial load and associated inflammation compared to IL-13 deficient (−/−) mice as early as 3 days post infection (p.i.). Intratracheal instillation of IL-13 enhanced bacterial load in IL-13−/− mice. There were no differences in early IFN-g and IL-10 expression between WT and IL-13−/− mice and depletion of CD4+ T cells did not affect infection in IL-13−/− mice. Collectively, these data demonstrate a lack of CD4+ T cell involvement and a novel role for IL-13 in innate responses to infection. We also showed that IL-13 deficiency increased macrophage uptake of Cmu in vitro and in vivo. Moreover, the depletion of IL-13 during infection of lung epithelial cells in vitro decreased the percentage of infected cells and reduced bacterial growth. Our results suggest that enhanced IL-13 responses in the airways, such as that found in asthmatics, may promote susceptibility to chlamydial lung infection. Importantly the role of IL-13 in regulating infection was not limited to the lung as we showed that IL-13 also promoted susceptibility to Cmu genital tract infection. Collectively our findings demonstrate that innate IL-13 release promotes infection that results in enhanced inflammation and have broad implications for the treatment of chlamydial infections and IL-13-associated diseases.

Vyšlo v časopise: Interleukin-13 Promotes Susceptibility to Chlamydial Infection of the Respiratory and Genital Tracts. PLoS Pathog 7(5): e32767. doi:10.1371/journal.ppat.1001339
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1001339

Souhrn

Zdroje

1. KuoCC

JacksonLA

CampbellLA

GraystonJT

1995 Chlamydia pneumoniae (TWAR). Clin Microbiol Rev 8 451 461

2. BlasiF

2004 Atypical pathogens and respiratory tract infections. Eur Respir J 24 171 182

3. World Health Organisation, Department of HIV/AIDS 2001 Global prevalence and incidence of selected curable sexually transmitted infections: Overview and estimates. Available: http://whqlibdoc.who.int/hq/2001/WHO_HIV_AIDS_2001.02.pdf Accessed 17 March 2011

4. JainS

1999 Perinatally acquired Chlamydia trachomatis associated morbidity in young infants. J Matern Fetal Med 8 130 133

5. RoursGI

HammerschlagMR

Van DoornumGJ

HopWC

de GrootR

2009 Chlamydia trachomatis respiratory infection in Dutch infants. Arch Dis Child 94 705 707

6. GraystonJT

1992 Infections caused by Chlamydia pneumoniae strain TWAR. Clin Infect Dis 15 757 761

7. LyytikainenE

KaasilaM

KoskelaP

LehtinenM

PatamaT

2008 Chlamydia trachomatis seroprevalence atlas of Finland 1983-2003. Sex Transm Infect 84 19 22

8. SmithJS

MunozN

HerreroR

Eluf-NetoJ

NgelangelC

2002 Evidence for Chlamydia trachomatis as a human papillomavirus cofactor in the etiology of invasive cervical cancer in Brazil and the Philippines. J Infect Dis 185 324 331

9. HansbroPM

BeagleyKW

HorvatJC

GibsonPG

2004 Role of atypical bacterial infection of the lung in predisposition/protection of asthma. Pharmacol Ther 101 193 210

10. BrandenE

GnarpeJ

HillerdalG

OrreL

SkoldCM

2007 Detection of Chlamydia pneumoniae on cytospin preparations from bronchoalveolar lavage in COPD patients and in lung tissue from advanced emphysema. Int J Chron Obstruct Pulmon Dis 2 643 650

11. BrandenE

KoyiH

GnarpeJ

GnarpeH

TornlingG

2005 Chronic Chlamydia pneumoniae infection is a risk factor for the development of COPD. Respir Med 99 20 26

12. SessaR

NicolettiM

Di PietroM

SchiavoniG

SantinoI

2009 Chlamydia pneumoniae and atherosclerosis: current state and future prospectives. Int J Immunopathol Pharmacol 22 9 14

13. HonjoK

van ReekumR

VerhoeffNPLG

2009 Alzheimer's disease and infection: Do infectious agents contribute to progression of Alzheimer's disease? Alzheimers Dement 5 348 360

14. WangS

FanY

BrunhamRC

YangX

1999 IFN-γ knockout mice show Th2-associated delayed-type hypersensitivity and the inflammatory cells fail to localize and control chlamydial infection. Eur J Immunol 29 3782 3792

15. YangX

GartnerJ

ZhuL

WangS

BrunhamRC

1999 IL-10 gene knockout mice show enhanced Th1-like protective immunity and absent granuloma formation following Chlamydia trachomatis lung infection. J Immunol 162 1010 1017

16. YangX

HayGlassKT

BrunhamRC

1996 Genetically determined differences in IL-10 and IFN-gamma responses correlate with clearance of Chlamydia trachomatis mouse pneumonitis infection. J Immunol 156 4338 4344

17. ItoJI

LyonsJM

1999 Role of gamma interferon in controlling murine chlamydial genital tract infection. Infect Immun 67 5518 5521

18. RottenbergME

Gigliotti RothfuchsAC

GigliottiD

SvanholmC

BandholtzL

1999 Role of innate and adaptive immunity in the outcome of primary infection with Chlamydia pneumoniae, as analyzed in genetically modified mice. J Immunol 162 2829 2836

19. BeattyWL

ByrneGI

MorrisonRP

1993 Morphologic and antigenic characterization of interferon gamma-mediated persistent Chlamydia trachomatis infection in vitro. Proc Nat Acad Sci 90 3998 4002

20. ZhongGM

de la MazaLM

1988 Activation of mouse peritoneal macrophages in vitro or in vivo by recombinant murine gamma interferon inhibits the growth of Chlamydia trachomatis serovar L1. Infect Immun 56 3322 3325

21. ChenB

StoutR

CampbellWF

1996 Nitric oxide production: a mechanism of Chlamydia trachomatis inhibition in interferon-gamma-treated RAW264.7 cells. FEMS Immunol Med Microbiol 14 109 120

22. HassanainHH

ChonSY

GuptaSL

1993 Differential regulation of human indoleamine 2,3-dioxygenase gene expression by interferons-gamma and -alpha. Analysis of the regulatory region of the gene and identification of an interferon-gamma-inducible DNA-binding factor. J Biol Chem 268 5077 5084

23. MacMickingJ

XieQW

NathanC

1997 Nitric oxide and macrophage function. Annu Rev Immunol 15 323 350

24. MehtaSJ

MillerRD

RamirezJA

SummersgillJT

1998 Inhibition of Chlamydia pneumoniae replication in HEp-2 cells by interferon-gamma: role of tryptophan catabolism. J Infect Dis 177 1326 1331

25. IgietsemeJU

PerryLL

AnanabaGA

UririIM

OjiorOO

1998 Chlamydial infection in inducible nitric oxide synthase knockout mice. Infect Immun 66 1282 1286

26. KaikoGE

PhippsS

HickeyDK

LamCE

HansbroPM

2008 Chlamydia muridarum infection subverts dendritic cell function to promote Th2 immunity and airways hyperreactivity. J Immunol 180 2225 2232

27. BeagleyKW

HustonWM

HansbroPM

TimmsP

2009 Chlamydial infection of immune cells: altered function and implications for disease. Crit Rev Immunol 29 275 305

28. RedeckeV

DalhoffK

BohnetS

BraunJ

MaassM

1998 Interaction of Chlamydia pneumoniae and human alveolar macrophages: infection and inflammatory response. Am J Respir Cell Mol Biol 19 721 727

29. GaydosCA

SummersgillJT

SahneyNN

RamirezJA

QuinnTC

1996 Replication of Chlamydia pneumoniae in vitro in human macrophages, endothelial cells, and aortic artery smooth muscle cells. Infect Immun 64 1614 1620

30. HaranagaS

YamaguchiH

IkejimaH

FreidmanH

2003 Chlamydia pneumoniae infection of alveolar macrophages: A model. J Infect Dis 187 1107 1115

31. DebattistaJ

TimmsP

AllanJ

2003 Immunopathogenesis of Chlamydia trachomatis infections in women. Fertil Steril 79 1273 1287

32. DarvilleT

HiltkeTJ

2010 Pathogenesis of genital tract disease due to Chlamydia trachomatis. J Infect Dis 201 Suppl 2 S114 125

33. LeeHY

SchripsemaJH

SigarIM

MurrayCM

LacySR

2010 A link between neutrophils and chronic disease manifestations of Chlamydia muridarum urogenital infection of mice. FEMS Immunol Med Microbiol 59 108 116

34. HvidM

BaczynskaA

DeleuranB

FedderJ

KnudsenHJ

2007 Interleukin-1 is the initiator of fallopian tube destruction during Chlamydia trachomatis infection. Cell Microbiol 9 2795 2803

35. SkworTA

AtikB

KandelRP

AdhikariHK

SharmaB

2008 Role of secreted conjunctival mucosal cytokine and chemokine proteins in different stages of trachomatous disease. PLoS Negl Trop Dis 2 e264

36. WangC

van GinkelFW

KimT

LiD

LiY

2008 Temporal delay of peak T-cell immunity determines Chlamydia pneumoniae pulmonary disease in mice. Infect Immun 76 4913 4923

37. HorvatJC

BeagleyKW

WadeMA

PrestonJA

HansbroNG

2007 Neonatal chlamydial infection induces mixed T-cell responses that drive allergic airway disease. Am J Respir Crit Care Med 176 556 564

38. HorvatJC

StarkeyMR

KimRY

PhippsS

GibsonPG

2010 Early-life chlamydial lung infection enhances allergic airways disease through age-dependent differences in immunopathology. J Allergy Clin Immunol 125 617 625, 625 e611-625 e616

39. ChenL

LeiL

ChangX

LiZ

LuC

2010 Mice deficient in MyD88 Develop a Th2-dominant response and severe pathology in the upper genital tract following Chlamydia muridarum infection. J Immunol 184 2602 2610

40. HansbroPM

KaikoGE

FosterPS

2011 Cytokine/anti-cytokine therapy - novel treatments for asthma? Br J Pharmacol In Press

41. CunninghamAF

JohnstonSL

JuliousSA

LampeFC

WardME

1998 Chronic Chlamydia pneumoniae infection and asthma exacerbations in children. Eur Respir J 11 345 349

42. BlackPN

ScicchitanoR

JenkinsCR

BlasiF

AllegraL

2000 Serological evidence of infection with Chlamydia pneumoniae is related to the severity of asthma. Eur Respir J 15 254 259

43. WarkPAB

JohnstonSL

SimpsonJL

HensleyMJ

GibsonPG

2002 Chlamydia pneumoniae immunoglobulin A reactivation and airway inflammation in acute asthma. Eur Respir J 20 834 840

44. WebleyWC

TilahunY

LayK

PatelK

StuartES

2009 Occurrence of Chlamydia trachomatis and Chlamydia pneumoniae in paediatric respiratory infections. Eur Respir J 33 360 367

45. MatthewsDJ

EmsonCL

McKenzieGJ

JolinHE

BlackwellJM

2000 IL-13 is a susceptibility factor for Leishmania major infection. J Immunol 164 1458 1462

46. MullerU

StenzelW

KohlerG

WernerC

PolteT

2007 IL-13 induces disease-promoting type 2 cytokines, alternatively activated macrophages and allergic inflammation during pulmonary infection of mice with Cryptococcus neoformans. J Immunol 179 5367 5377

47. BerryLJ

HickeyDK

SkeldingKA

BaoS

RendinaAM

2004 Transcutaneous immunization with combined cholera toxin and CpG adjuvant protects against Chlamydia muridarum genital tract infection. Infect Immun 72 1019 1028

48. YangM

HoganSP

HenryPJ

MatthaeiKI

McKenzieAN

2001 Interleukin-13 mediates airways hyperreactivity through the IL-4 receptor-alpha chain and STAT-6 independently of IL-5 and eotaxin. Am J Respir Cell Mol Biol 25 522 530

49. VarinA

MukhopadhyayS

HerbeinG

GordonS

2010 Alternative activation of macrophages by IL-4 impairs phagocytosis of pathogens but potentiates microbial-induced signalling and cytokine secretion. Blood 115 353 362

50. HarrisJ

De HaroSA

MasterSS

KeaneJ

RobertsEA

2007 T helper 2 cytokines inhibit autophagic control of intracellular Mycobacterium tuberculosis. Immunity 27 505 517

51. KuoCC

PuolakkainenM

LinTM

WitteM

CampbellLA

2002 Mannose-receptor positive and negative mouse macrophages differ in their susceptibility to infection by Chlamydia species. Microb Pathog 32 43 48

52. GessnerA

MohrsK

MohrsM

2005 Mast cells, basophils, and eosinophils acquire constitutive IL-4 and IL-13 transcripts during lineage differentiation that are sufficient for rapid cytokine production. J Immunol 174 1063 1072

53. SchroederJT

2009 Basophils beyond effector cells of allergic inflammation. Adv Immunol 101 123 161

54. KimEY

BattaileJT

PatelAC

YouY

AgapovE

2008 Persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease. Nat Med 14 633 640

55. KotsimbosTC

ErnstP

HamidQA

1996 Interleukin-13 and interleukin-4 are coexpressed in atopic asthma. Proc Assoc Am Physicians 108 368 373

56. TemannUA

RayP

FlavellRA

2002 Pulmonary overexpression of IL-9 induces Th2 cytokine expression, leading to immune pathology. J Clin Invest 109 29 39

57. AkbariO

StockP

MeyerE

KronenbergM

SidobreS

2003 Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity. Nat Med 9 582 588

58. MetzG

KraftM

2010 Effects of atypical infections with Mycoplasma and Chlamydia on asthma. Immunol Allergy Clin North Am 30 575 585, vii-viii

59. WebleyWC

SalvaPS

AndrzejewskiC

CirinoF

WestCA

2005 The bronchial lavage of pediatric patients with asthma contains infectious Chlamydia. Am J Respir Crit Care Med 171 1083 1088

60. HorvatJC

StarkeyMR

KimRY

BeagleyKW

PrestonJA

2010 Chlamydial respiratory infection during allergen sensitization drives neutrophilic allergic airways disease. J Immunol 184 4159 4169

61. BeisswengerC

KandlerK

HessC

GarnH

FelgentreffK

2006 Allergic airway inflammation inhibits pulmonary antibacterial host defense. J Immunol 177 1833 1837

62. FitzpatrickAM

HolguinF

TeagueWG

BrownLA

2008 Alveolar macrophage phagocytosis is impaired in children with poorly controlled asthma. J Allergy Clin Immunol 121 1372 1378, 1378 e1371-1373

63. SkeldingKA

HickeyDK

HorvatJC

BaoS

RobertsKG

2006 Comparison of intranasal and transcutaneous immunization for induction of protective immunity against Chlamydia muridarum respiratory tract infection. Vaccine 24 355 366