Global Analysis of Neutrophil Responses to Reveals a Self-Propagating Inflammatory Program

English version České info

Gonorrhea is a sexually transmitted infection caused by the bacteria Neisseria gonorrhoeae. These bacteria have re-emerged as a public health priority due to its acquisition of resistance to multiple antibiotics, leading to fears of untreatable infection. The symptoms of gonorrhea include an intense inflammatory response that may lead to pus discharged from the infected genital tract and scarring of the reproductive tract caused by neutrophils recruited to the site of infection. Past studies have detailed molecular interactions that lead to neutrophil binding and engulfment of N. gonorrhoeae, yet it remains unclear why N. gonorrhoeae elicits such a pathogenic inflammatory response. In this study, we reveal that N. gonorrhoeae binding to the human innate decoy receptor, CEACAM3, elicits a potent intracellular signaling cascade that leads to neutrophil expression of cytokines that actively recruit other neutrophils to the infected tissues. As they encounter the gonococci, the next wave of neutrophils becomes similarly activated, leading to the progressive expansion in phagocytic cell numbers until they overwhelm the infected tissues. While this process promotes a rapid response to a troubling pathogen early during infection, the unrestrained recruitment of neutrophils and their toxic antimicrobial arsenal also lead to the pathogenic consequences associated with gonorrhea.

Vyšlo v časopise: Global Analysis of Neutrophil Responses to Reveals a Self-Propagating Inflammatory Program. PLoS Pathog 10(9): e32767. doi:10.1371/journal.ppat.1004341
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004341

Souhrn

Zdroje

1. World Health Organization DoRHaR (2012) Global action plan to control the spread and impact of antimicrobial resistance in Neisseria gonorrhoeae. http://www.who.int/reproductivehealth/publications/rtis/9789241503501/en/

2. World Health Organization DoRHaR (2012) Global incidence and prevalence of selected curable sexually transmitted infections - 2008. http://www.who.int/reproductivehealth/publications/rtis/stisestimates/en/

3. ZhuW, ChenCJ, ThomasCE, AndersonJE, JerseAE, et al. (2011) Vaccines for gonorrhea: can we rise to the challenge? Frontiers in Microbiology 2: 124.

4. BiaisN, LadouxB, HigashiD, SoM, SheetzM (2008) Cooperative retraction of bundled type IV pili enables nanonewton force generation. PLoS Biology 6: e87.

5. VirjiM, MakepeaceK, FergusonDJ, WattSM (1996) Carcinoembryonic antigens (CD66) on epithelial cells and neutrophils are receptors for Opa proteins of pathogenic Neisseria. Molecular Microbiology 22: 941–950.

6. Gray-OwenSD, DehioC, HaudeA, GrunertF, MeyerTF (1997) CD66 carcinoembryonic antigens mediate interactions between Opa-expressing Neisseria gonorrhoeae and human polymorphonuclear phagocytes. The EMBO Journal 16: 3435–3445.

7. Gray-OwenSD, LorenzenDR, HaudeA, MeyerTF, DehioC (1997) Differential Opa specificities for CD66 receptors influence tissue interactions and cellular response to Neisseria gonorrhoeae. Molecular Microbiology 26: 971–980.

8. ChenT, GrunertF, Medina-MarinoA, GotschlichEC (1997) Several carcinoembryonic antigens (CD66) serve as receptors for gonococcal opacity proteins. The Journal of Experimental Medicine 185: 1557–1564.

9. BosMP, GrunertF, BellandRJ (1997) Differential recognition of members of the carcinoembryonic antigen family by Opa variants of Neisseria gonorrhoeae. Infection and Immunity 65: 2353–2361.

10. VirjiM, EvansD, HadfieldA, GrunertF, TeixeiraAM, et al. (1999) Critical determinants of host receptor targeting by Neisseria meningitidis and Neisseria gonorrhoeae: identification of Opa adhesiotopes on the N-domain of CD66 molecules. Molecular Microbiology 34: 538–551.

11. BillkerO, PoppA, Gray-OwenSD, MeyerTF (2000) The structural basis of CEACAM-receptor targeting by neisserial Opa proteins. Trends in Microbiology 8: 258–260 discussion 260–251.

12. PoppA, DehioC, GrunertF, MeyerTF, Gray-OwenSD (1999) Molecular analysis of neisserial Opa protein interactions with the CEA family of receptors: identification of determinants contributing to the differential specificities of binding. Cellular Microbiology 1: 169–181.

13. McGeeZA, StephensDS, HoffmanLH, SchlechWF3rd, HornRG (1983) Mechanisms of mucosal invasion by pathogenic Neisseria. Reviews of Infectious Diseases 5 Suppl 4: S708–714.

14. WangJ, Gray-OwenSD, KnorreA, MeyerTF, DehioC (1998) Opa binding to cellular CD66 receptors mediates the transcellular traversal of Neisseria gonorrhoeae across polarized T84 epithelial cell monolayers. Molecular Microbiology 30: 657–671.

15. BoultonIC, Gray-OwenSD (2002) Neisserial binding to CEACAM1 arrests the activation and proliferation of CD4+ T lymphocytes. Nature Immunology 3: 229–236.

16. LeeHS, BoultonIC, ReddinK, WongH, HalliwellD, et al. (2007) Neisserial outer membrane vesicles bind the coinhibitory receptor carcinoembryonic antigen-related cellular adhesion molecule 1 and suppress CD4+ T lymphocyte function. Infection and Immunity 75: 4449–4455.

17. LeeHS, OstrowskiMA, Gray-OwenSD (2008) CEACAM1 dynamics during Neisseria gonorrhoeae suppression of CD4+ T lymphocyte activation. Journal of Immunology 180: 6827–6835.

18. PantelicM, KimYJ, BollandS, ChenI, ShivelyJ, et al. (2005) Neisseria gonorrhoeae kills carcinoembryonic antigen-related cellular adhesion molecule 1 (CD66a)-expressing human B cells and inhibits antibody production. Infection and Immunity 73: 4171–4179.

19. YuQ, ChowEM, McCawSE, HuN, ByrdD, et al. (2013) Association of Neisseria gonorrhoeae Opa(CEA) with dendritic cells suppresses their ability to elicit an HIV-1-specific T cell memory response. PloS One 8: e56705.

20. SlevogtH, ZabelS, OpitzB, HockeA, EitelJ, et al. (2008) CEACAM1 inhibits Toll-like receptor 2-triggered antibacterial responses of human pulmonary epithelial cells. Nature Immunology 9: 1270–1278.

21. Gray-OwenSD, BlumbergRS (2006) CEACAM1: contact-dependent control of immunity. Nature Reviews Immunology 6: 433–446.

22. SchmitterT, AgererF, PetersonL, MunznerP, HauckCR (2004) Granulocyte CEACAM3 is a phagocytic receptor of the innate immune system that mediates recognition and elimination of human-specific pathogens. The Journal of Experimental Medicine 199: 35–46.

23. PilsS, GerrardDT, MeyerA, HauckCR (2008) CEACAM3: an innate immune receptor directed against human-restricted bacterial pathogens. International Journal of Medical Microbiology 298: 553–560.

24. SarantisH, Gray-OwenSD (2012) Defining the roles of human carcinoembryonic antigen-related cellular adhesion molecules during neutrophil responses to Neisseria gonorrhoeae. Infection and Immunity 80: 345–358.

25. SarantisH, Gray-OwenSD (2007) The specific innate immune receptor CEACAM3 triggers neutrophil bactericidal activities via a Syk kinase-dependent pathway. Cellular Microbiology 9: 2167–2180.

26. BoothJW, TelioD, LiaoEH, McCawSE, MatsuoT, et al. (2003) Phosphatidylinositol 3-kinases in carcinoembryonic antigen-related cellular adhesion molecule-mediated internalization of Neisseria gonorrhoeae. The Journal of Biological Chemistry 278: 14037–14045.

27. BuntruA, KoppK, VogesM, FrankR, BachmannV, et al. (2011) Phosphatidylinositol 3′-kinase activity is critical for initiating the oxidative burst and bacterial destruction during CEACAM3-mediated phagocytosis. The Journal of Biological Chemistry 286: 9555–9566.

28. SmirnovA, DailyKP, CrissAK (2014) Assembly of NADPH Oxidase in Human Neutrophils Is Modulated by the Opacity-Associated Protein Expression State of Neisseria gonorrhoeae. Infection and Immunity 82: 1036–1044.

29. McCawSE, SchneiderJ, LiaoEH, ZimmermannW, Gray-OwenSD (2003) Immunoreceptor tyrosine-based activation motif phosphorylation during engulfment of Neisseria gonorrhoeae by the neutrophil-restricted CEACAM3 (CD66d) receptor. Molecular Microbiology 49: 623–637.

30. BuntruA, RothA, Nyffenegger-JannNJ, HauckCR (2012) HemITAM signaling by CEACAM3, a human granulocyte receptor recognizing bacterial pathogens. Archives of Biochemistry and Biophysics 524: 77–83.

31. SadaranganiM, PollardAJ, Gray-OwenSD (2011) Opa proteins and CEACAMs: pathways of immune engagement for pathogenic Neisseria. FEMS Microbiology Reviews 35: 498–514.

32. BazzoniF, CassatellaMA, RossiF, CeskaM, DewaldB, et al. (1991) Phagocytosing neutrophils produce and release high amounts of the neutrophil-activating peptide 1/interleukin 8. The Journal of Experimental Medicine 173: 771–774.

33. KolaczkowskaE, KubesP (2013) Neutrophil recruitment and function in health and inflammation. Nature Reviews Immunology 13: 159–175.

34. JaillonS, GaldieroMR, Del PreteD, CassatellaMA, GarlandaC, et al. (2013) Neutrophils in innate and adaptive immunity. Seminars in Immunopathology 35: 377–394.

35. SubrahmanyamYV, YamagaS, PrasharY, LeeHH, HoeNP, et al. (2001) RNA expression patterns change dramatically in human neutrophils exposed to bacteria. Blood 97: 2457–2468.

36. KobayashiSD, VoyichJM, BuhlCL, StahlRM, DeLeoFR (2002) Global changes in gene expression by human polymorphonuclear leukocytes during receptor-mediated phagocytosis: cell fate is regulated at the level of gene expression. Proceedings of the National Academy of Sciences of the United States of America 99: 6901–6906.

37. ScapiniP, Lapinet-VeraJA, GasperiniS, CalzettiF, BazzoniF, et al. (2000) The neutrophil as a cellular source of chemokines. Immunological Reviews 177: 195–203.

38. KammererR, PoppT, HartleS, SingerBB, ZimmermannW (2007) Species-specific evolution of immune receptor tyrosine based activation motif-containing CEACAM1-related immune receptors in the dog. BMC Evolutionary Biology 7: 196.

39. VogesM, BachmannV, KammererR, GophnaU, HauckCR (2010) CEACAM1 recognition by bacterial pathogens is species-specific. BMC Microbiology 10: 117.

40. ChanCH, StannersCP (2004) Novel mouse model for carcinoembryonic antigen-based therapy. Molecular Therapy : the Journal of the American Society of Gene Therapy 9: 775–785.

41. BallLM, CrissAK (2013) Constitutively Opa-expressing and Opa-deficient Neisseria gonorrhoeae strains differentially stimulate and survive exposure to human neutrophils. Journal of Bacteriology 195: 2982–2990.

42. Huang daW, ShermanBT, LempickiRA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nature Protocols 4: 44–57.

43. GuA, ZhangZ, ZhangN, TsarkW, ShivelyJE (2010) Generation of human CEACAM1 transgenic mice and binding of Neisseria Opa protein to their neutrophils. PloS One 5: e10067.

44. TamasD, CeciliaC, Sanae BenM, ThiloMF, SiegfriedW, et al. (2010) Potentiation of Epithelial Innate Host Responses by Intercellular Communication. PLoS Pathogens

45. TamassiaN, Le MoigneV, CalzettiF, DoniniM, GasperiniS, et al. (2007) The MyD88-independent pathway is not mobilized in human neutrophils stimulated via TLR4. Journal of Immunology 178: 7344–7356.

46. CloutierA, EarT, Blais-CharronE, DuboisCM, McDonaldPP (2007) Differential involvement of NF-kappaB and MAP kinase pathways in the generation of inflammatory cytokines by human neutrophils. Journal of leukocyte biology 81: 567–577.

47. McDonaldPP, BaldA, CassatellaMA (1997) Activation of the NF-kappaB pathway by inflammatory stimuli in human neutrophils. Blood 89: 3421–3433.

48. AbramCL, LowellCA (2007) The expanding role for ITAM-based signaling pathways in immune cells. Science's STKE : signal transduction knowledge environment 2007: re2.

49. KingeterLM, LinX (2012) C-type lectin receptor-induced NF-kappaB activation in innate immune and inflammatory responses. Cellular & molecular immunology 9: 105–112.

50. FesslerMB, MalcolmKC, DuncanMW, WorthenGS (2002) A genomic and proteomic analysis of activation of the human neutrophil by lipopolysaccharide and its mediation by p38 mitogen-activated protein kinase. The Journal of Biological Chemistry 277: 31291–31302.

51. LandstromM (2010) The TAK1-TRAF6 signalling pathway. The international Journal of Biochemistry & Cell Biology 42: 585–589.

52. McCawSE, LiaoEH, Gray-OwenSD (2004) Engulfment of Neisseria gonorrhoeae: revealing distinct processes of bacterial entry by individual carcinoembryonic antigen-related cellular adhesion molecule family receptors. Infection and Immunity 72: 2742–2752.

53. HauckCR, MeyerTF, LangF, GulbinsE (1998) CD66-mediated phagocytosis of Opa52 Neisseria gonorrhoeae requires a Src-like tyrosine kinase- and Rac1-dependent signalling pathway. The EMBO Journal 17: 443–454.

54. MocsaiA, RulandJ, TybulewiczVL (2010) The SYK tyrosine kinase: a crucial player in diverse biological functions. Nature Reviews Immunology 10: 387–402.

55. SchmitterT, PilsS, SakkV, FrankR, FischerKD, et al. (2007) The granulocyte receptor carcinoembryonic antigen-related cell adhesion molecule 3 (CEACAM3) directly associates with Vav to promote phagocytosis of human pathogens. Journal of immunology 178: 3797–3805.

56. StrasserD, NeumannK, BergmannH, MarakalalaMJ, GulerR, et al. (2012) Syk kinase-coupled C-type lectin receptors engage protein kinase C-sigma to elicit Card9 adaptor-mediated innate immunity. Immunity 36: 32–42.

57. EdwardsJC, SedgwickAD, WilloughbyDA (1981) The formation of a structure with the features of synovial lining by subcutaneous injection of air: an in vivo tissue culture system. The Journal of Pathology 134: 147–156.

58. PiererM, RethageJ, SeiblR, LauenerR, BrentanoF, et al. (2004) Chemokine secretion of rheumatoid arthritis synovial fibroblasts stimulated by Toll-like receptor 2 ligands. Journal of Immunology 172: 1256–1265.

59. TatedaK, MooreTA, DengJC, NewsteadMW, ZengX, et al. (2001) Early recruitment of neutrophils determines subsequent T1/T2 host responses in a murine model of Legionella pneumophila pneumonia. Journal of Immunology 166: 3355–3361.

60. KerriganAM, BrownGD (2010) Syk-coupled C-type lectin receptors that mediate cellular activation via single tyrosine based activation motifs. Immunological Reviews 234: 335–352.

61. GoodridgeHS, UnderhillDM, TouretN (2012) Mechanisms of Fc receptor and Dectin-1 activation for phagocytosis. Traffic 13: 1062–1071.

62. ZhangX, MajlessiL, DeriaudE, LeclercC, Lo-ManR (2009) Coactivation of Syk kinase and MyD88 adaptor protein pathways by bacteria promotes regulatory properties of neutrophils. Immunity 31: 761–771.

63. MuenznerP, BachmannV, ZimmermannW, HentschelJ, HauckCR (2010) Human-restricted bacterial pathogens block shedding of epithelial cells by stimulating integrin activation. Science 329: 1197–1201.

64. MuenznerP, RohdeM, KneitzS, HauckCR (2005) CEACAM engagement by human pathogens enhances cell adhesion and counteracts bacteria-induced detachment of epithelial cells. The Journal of Cell Biology 170: 825–836.

65. JohswichKO, McCawSE, IslamE, SintsovaA, GuA, et al. (2013) In vivo adaptation and persistence of Neisseria meningitidis within the nasopharyngeal mucosa. PLoS Pathogens 9: e1003509.

66. KupschEM, KnepperB, KurokiT, HeuerI, MeyerTF (1993) Variable opacity (Opa) outer membrane proteins account for the cell tropisms displayed by Neisseria gonorrhoeae for human leukocytes and epithelial cells. The EMBO Journal 12: 641–650.

67. SunCX, DowneyGP, ZhuF, KohAL, ThangH, et al. (2004) Rac1 is the small GTPase responsible for regulating the neutrophil chemotaxis compass. Blood 104: 3758–3765.

68. KukulskiF, Ben YebdriF, BahramiF, LevesqueSA, Martin-SatueM, et al. (2010) The P2 receptor antagonist PPADS abrogates LPS-induced neutrophil migration in the murine air pouch via inhibition of MIP-2 and KC production. Molecular Immunology 47: 833–839.