1887

Abstract

Recently, we reported that the type 6 secretion system (T6SS) of SSU plays an important role in bacterial virulence in a mouse model, and immunization of animals with the T6SS effector haemolysin co-regulated protein (Hcp) protected them against lethal infections with wild-type bacteria. Additionally, we showed that the mutant bacteria deleted for the gene within the T6SS gene cluster did not express the gene, while the mutant could express and translocate Hcp, but was unable to secrete it into the extracellular milieu. Both of these SSU mutants were readily phagocytosed by murine macrophages, pointing to the possible role of the secreted form of Hcp in the evasion of the host innate immunity. By using the Δ mutant of , our data showed that the addition of exogenous recombinant Hcp (rHcp) reduced bacterial uptake by macrophages. These results were substantiated by increased bacterial virulence when rHcp was added along with the Δ mutant in a septicaemic mouse model of infection. Analysis of the cytokine profiling in the intraperitoneal lavage as well as activation of host cells after 4 h of infection with the Δ mutant supplemented with rHcp indicated that this T6SS effector inhibited production of pro-inflammatory cytokines and induced immunosuppressive cytokines, such as interleukin-10 and transforming growth factor-, which could circumvent macrophage activation and maturation. This mechanism of innate immune evasion by Hcp possibly inhibited the recruitment of cellular immune components, which allowed bacterial multiplication and dissemination in animals, thereby leading to their mortality.

Loading

Article metrics loading...

/content/journal/micro/10.1099/mic.0.041277-0
2010-12-01
2019-09-17
Loading full text...

Full text loading...

/deliver/fulltext/micro/156/12/3678.html?itemId=/content/journal/micro/10.1099/mic.0.041277-0&mimeType=html&fmt=ahah

References

  1. Abrahams, G. L. & Hensel, M. ( 2006; ). Manipulating cellular transport and immune responses: dynamic interactions between intracellular Salmonella enterica and its host cells. Cell Microbiol 8, 728–737.[CrossRef]
    [Google Scholar]
  2. Agar, S. L., Sha, J., Foltz, S. M., Erova, T. E., Walberg, K. G., Baze, W. B., Suarez, G., Peterson, J. W. & Chopra, A. K. ( 2009; ). Characterization of the rat pneumonic plague model: infection kinetics following aerosolization of Yersinia pestis CO92. Microbes Infect 11, 205–214.[CrossRef]
    [Google Scholar]
  3. Barton, G. M. & Medzhitov, R. ( 2003; ). Toll-like receptor signaling pathways. Science 300, 1524–1525.[CrossRef]
    [Google Scholar]
  4. Berlato, C., Cassatella, M. A., Kinjyo, I., Gatto, L., Yoshimura, A. & Bazzoni, F. ( 2002; ). Involvement of suppressor of cytokine signaling-3 as a mediator of the inhibitory effects of IL-10 on lipopolysaccharide-induced macrophage activation. J Immunol 168, 6404–6411.[CrossRef]
    [Google Scholar]
  5. Bingle, L. E., Bailey, C. M. & Pallen, M. J. ( 2008; ). Type VI secretion: a beginner's guide. Curr Opin Microbiol 11, 3–8.[CrossRef]
    [Google Scholar]
  6. Carvalho-Castro, G. A., Lopes, C. O., Leal, C. A., Cardoso, P. G., Leite, R. C. & Figueiredo, H. C. ( 2010; ). Detection of type III secretion system genes in Aeromonas hydrophila and their relationship with virulence in Nile tilapia. Vet Microbiol 144, 371–376.[CrossRef]
    [Google Scholar]
  7. Cascales, E. ( 2008; ). The type VI secretion toolkit. EMBO Rep 9, 735–741.[CrossRef]
    [Google Scholar]
  8. Chopra, A. K. & Houston, C. W. ( 1999; ). Enterotoxins in Aeromonas-associated gastroenteritis. Microbes Infect 1, 1129–1137.[CrossRef]
    [Google Scholar]
  9. Chopra, A. K., Xu, X., Ribardo, D., Gonzalez, M., Kuhl, K., Peterson, J. W. & Houston, C. W. ( 2000; ). The cytotoxic enterotoxin of Aeromonas hydrophila induces proinflammatory cytokine production and activates arachidonic acid metabolism in macrophages. Infect Immun 68, 2808–2818.[CrossRef]
    [Google Scholar]
  10. Coombes, B. K., Valdez, Y. & Finlay, B. B. ( 2004; ). Evasive maneuvers by secreted bacterial proteins to avoid innate immune responses. Curr Biol 14, R856–R867.[CrossRef]
    [Google Scholar]
  11. Das, S. & Chaudhuri, K. ( 2003; ). Identification of a unique IAHP (IcmF associated homologous proteins) cluster in Vibrio cholerae and other proteobacteria through in silico analysis. In Silico Biol 3, 287–300.
    [Google Scholar]
  12. Diacovich, L. & Gorvel, J. P. ( 2010; ). Bacterial manipulation of innate immunity to promote infection. Nat Rev Microbiol 8, 117–128.[CrossRef]
    [Google Scholar]
  13. Diehl, S. & Rincon, M. ( 2002; ). The two faces of IL-6 on Th1/Th2 differentiation. Mol Immunol 39, 531–536.[CrossRef]
    [Google Scholar]
  14. Dong, Q., Fan, R., Zhao, S. & Wang, Y. ( 2009; ). Over-expression of SOCS-3 gene promotes IL-10 production by JEG-3 trophoblast cells. Placenta 30, 11–14.[CrossRef]
    [Google Scholar]
  15. Dramsi, S. & Cossart, P. ( 2002; ). Listeriolysin O: a genuine cytolysin optimized for an intracellular parasite. J Cell Biol 156, 943–946.[CrossRef]
    [Google Scholar]
  16. Ernst, R. K., Yi, E. C., Guo, L., Lim, K. B., Burns, J. L., Hackett, M. & Miller, S. I. ( 1999; ). Specific lipopolysaccharide found in cystic fibrosis airway Pseudomonas aeruginosa. Science 286, 1561–1565.[CrossRef]
    [Google Scholar]
  17. Filloux, A., Hachani, A. & Bleves, S. ( 2008; ). The bacterial type VI secretion machine: yet another player for protein transport across membranes. Microbiology 154, 1570–1583.[CrossRef]
    [Google Scholar]
  18. Gordon, S. ( 2003; ). Alternative activation of macrophages. Nat Rev Immunol 3, 23–35.[CrossRef]
    [Google Scholar]
  19. Gordon, S. & Taylor, P. R. ( 2005; ). Monocyte and macrophage heterogeneity. Nat Rev Immunol 5, 953–964.[CrossRef]
    [Google Scholar]
  20. Hajjar, A. M., Ernst, R. K., Tsai, J. H., Wilson, C. B. & Miller, S. I. ( 2002; ). Human Toll-like receptor 4 recognizes host-specific LPS modifications. Nat Immunol 3, 354–359.[CrossRef]
    [Google Scholar]
  21. Henneke, P. & Golenbock, D. T. ( 2004; ). Phagocytosis, innate immunity, and host–pathogen specificity. J Exp Med 199, 1–4.
    [Google Scholar]
  22. Hornef, M. W., Wick, M. J., Rhen, M. & Normark, S. ( 2002; ). Bacterial strategies for overcoming host innate and adaptive immune responses. Nat Immunol 3, 1033–1040.[CrossRef]
    [Google Scholar]
  23. Hume, D. A. ( 2006; ). The mononuclear phagocyte system. Curr Opin Immunol 18, 49–53.[CrossRef]
    [Google Scholar]
  24. Hume, D. A. ( 2008; ). Macrophages as APC and the dendritic cell myth. J Immunol 181, 5829–5835.[CrossRef]
    [Google Scholar]
  25. Janda, J. M. & Abbott, S. L. ( 1998; ). Evolving concepts regarding the genus Aeromonas: an expanding Panorama of species, disease presentations, and unanswered questions. Clin Infect Dis 27, 332–344.[CrossRef]
    [Google Scholar]
  26. Janeway, C. A., Jr & Medzhitov, R. ( 2002; ). Innate immune recognition. Annu Rev Immunol 20, 197–216.[CrossRef]
    [Google Scholar]
  27. Kawasaki, K., Ernst, R. K. & Miller, S. I. ( 2004; ). 3-O-deacylation of lipid A by PagL, a PhoP/PhoQ-regulated deacylase of Salmonella typhimurium, modulates signaling through Toll-like receptor 4. J Biol Chem 279, 20044–20048.[CrossRef]
    [Google Scholar]
  28. Lejeune, D., Demoulin, J. B. & Renauld, J. C. ( 2001; ). Interleukin 9 induces expression of three cytokine signal inhibitors: cytokine-inducible SH2-containing protein, suppressor of cytokine signalling (SOCS)-2 and SOCS-3, but only SOCS-3 overexpression suppresses interleukin 9 signalling. Biochem J 353, 109–116.
    [Google Scholar]
  29. Ma, A. T. & Mekalanos, J. J. ( 2010; ). In vivo actin cross-linking induced by Vibrio cholerae type VI secretion system is associated with intestinal inflammation. Proc Natl Acad Sci U S A 107, 4365–4370.[CrossRef]
    [Google Scholar]
  30. Ma, A. T., McAuley, S., Pukatzki, S. & Mekalanos, J. J. ( 2009; ). Translocation of a Vibrio cholerae type VI secretion effector requires bacterial endocytosis by host cells. Cell Host Microbe 5, 234–243.[CrossRef]
    [Google Scholar]
  31. Mantovani, A., Sica, A., Sozzani, S., Allavena, P., Vecchi, A. & Locati, M. ( 2004; ). The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25, 677–686.[CrossRef]
    [Google Scholar]
  32. McGuirk, P., McCann, C. & Mills, K. H. ( 2002; ). Pathogen-specific T regulatory 1 cells induced in the respiratory tract by a bacterial molecule that stimulates interleukin 10 production by dendritic cells: a novel strategy for evasion of protective T helper type 1 responses by Bordetella pertussis. J Exp Med 195, 221–231.[CrossRef]
    [Google Scholar]
  33. Medzhitov, R. & Janeway, C. A., Jr ( 1999; ). Innate immune induction of the adaptive immune response. Cold Spring Harb Symp Quant Biol 64, 429–435.[CrossRef]
    [Google Scholar]
  34. Moore, K. W., O'Garra, A., de Waal Malefyt, R., Vieira, P. & Mosmann, T. R. ( 1993; ). Interleukin-10. Annu Rev Immunol 11, 165–190.[CrossRef]
    [Google Scholar]
  35. Mosser, D. M. ( 2003; ). The many faces of macrophage activation. J Leukoc Biol 73, 209–212.[CrossRef]
    [Google Scholar]
  36. Mosser, D. M. & Edwards, J. P. ( 2008; ). Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8, 958–969.[CrossRef]
    [Google Scholar]
  37. Park, J. M., Greten, F. R., Li, Z. W. & Karin, M. ( 2002; ). Macrophage apoptosis by anthrax lethal factor through p38 MAP kinase inhibition. Science 297, 2048–2051.[CrossRef]
    [Google Scholar]
  38. Plüddemann, A., Mukhopadhyay, S. & Gordon, S. ( 2006; ). The interaction of macrophage receptors with bacterial ligands. Expert Rev Mol Med 8, 1–25.
    [Google Scholar]
  39. Pujol, C. & Bliska, J. B. ( 2005; ). Turning Yersinia pathogenesis outside in: subversion of macrophage function by intracellular Yersiniae. Clin Immunol 114, 216–226.[CrossRef]
    [Google Scholar]
  40. Pukatzki, S., McAuley, S. B. & Miyata, S. T. ( 2009; ). The type VI secretion system: translocation of effectors and effector-domains. Curr Opin Microbiol 12, 11–17.[CrossRef]
    [Google Scholar]
  41. Ruckdeschel, K., Mannel, O. & Schrottner, P. ( 2002; ). Divergence of apoptosis-inducing and preventing signals in bacteria-faced macrophages through myeloid differentiation factor 88 and IL-1 receptor-associated kinase members. J Immunol 168, 4601–4611.[CrossRef]
    [Google Scholar]
  42. Seifert, H. S. ( 1996; ). Questions about gonococcal pilus phase- and antigenic variation. Mol Microbiol 21, 433–440.[CrossRef]
    [Google Scholar]
  43. Sha, J., Pillai, L., Fadl, A. A., Galindo, C. L., Erova, T. E. & Chopra, A. K. ( 2005; ). The type III secretion system and cytotoxic enterotoxin alter the virulence of Aeromonas hydrophila. Infect Immun 73, 6446–6457.[CrossRef]
    [Google Scholar]
  44. Sha, J., Wang, S. F., Suarez, G., Sierra, J. C., Fadl, A. A., Erova, T. E., Foltz, S. M., Khajanchi, B. K., Silver, A. & other authors ( 2007; ). Further characterization of a type III secretion system (T3SS) and of a new effector protein from a clinical isolate of Aeromonas hydrophila-Part I. Microb Pathog 43, 127–146.[CrossRef]
    [Google Scholar]
  45. Sierra, J. C., Suarez, G., Sha, J., Foltz, S. M., Popov, V. L., Galindo, C. L., Garner, H. R. & Chopra, A. K. ( 2007; ). Biological characterization of a new type III secretion system effector from a clinical isolate of Aeromonas hydrophila–Part II. Microb Pathog 43, 147–160.[CrossRef]
    [Google Scholar]
  46. Sierra, J. C., Suarez, G., Sha, J., Baze, W. B., Foltz, S. M. & Chopra, A. K. ( 2010; ). Unraveling the mechanism of action of a new type III secretion system effector AexU from Aeromonas hydrophila. Microb Pathog 49, 122–134.[CrossRef]
    [Google Scholar]
  47. Sing, A., Roggenkamp, A., Geiger, A. M. & Heesemann, J. ( 2002; ). Yersinia enterocolitica evasion of the host innate immune response by V antigen-induced IL-10 production of macrophages is abrogated in IL-10-deficient mice. J Immunol 168, 1315–1321.[CrossRef]
    [Google Scholar]
  48. Sturgill-Koszycki, S., Schlesinger, P. H., Chakraborty, P., Haddix, P. L., Collins, H. L., Fok, A. K., Allen, R. D., Gluck, S. L. & Heuser, J. ( 1994; ). Lack of acidification in Mycobacterium phagosomes produced by exclusion of the vesicular proton-ATPase. Science 263, 678–681.[CrossRef]
    [Google Scholar]
  49. Suarez, G., Sierra, J. C., Sha, J., Wang, S., Erova, T. E., Fadl, A. A., Foltz, S. M., Horneman, A. J. & Chopra, A. K. ( 2008; ). Molecular characterization of a functional type VI secretion system from a clinical isolate of Aeromonas hydrophila. Microb Pathog 44, 344–361.[CrossRef]
    [Google Scholar]
  50. Suarez, G., Sierra, J. C., Erova, T. E., Sha, J., Horneman, A. J. & Chopra, A. K. ( 2010; ). A type VI secretion system effector protein, VgrG1, from Aeromonas hydrophila that induces host cell toxicity by ADP ribosylation of actin. J Bacteriol 192, 155–168.[CrossRef]
    [Google Scholar]
  51. Sweet, C. R., Conlon, J., Golenbock, D. T., Goguen, J. & Silverman, N. ( 2007; ). YopJ targets TRAF proteins to inhibit TLR-mediated NF-κB, MAPK and IRF3 signal transduction. Cell Microbiol 9, 2700–2715.[CrossRef]
    [Google Scholar]
  52. Tan, Y. W., Yu, H. B., Leung, K. Y., Sivaraman, J. & Mok, Y. K. ( 2008; ). Structure of AscE and induced burial regions in AscE and AscG upon formation of the chaperone needle-subunit complex of type III secretion system in Aeromonas hydrophila. Protein Sci 17, 1748–1760.[CrossRef]
    [Google Scholar]
  53. Taylor, P. R., Martinez-Pomares, L., Stacey, M., Lin, H. H., Brown, G. D. & Gordon, S. ( 2005; ). Macrophage receptors and immune recognition. Annu Rev Immunol 23, 901–944.[CrossRef]
    [Google Scholar]
  54. Thiefes, A., Wolf, A., Doerrie, A., Grassl, G. A., Matsumoto, K., Autenrieth, I., Bohn, E., Sakurai, H., Niedenthal, R. & other authors ( 2006; ). The Yersinia enterocolitica effector YopP inhibits host cell signalling by inactivating the protein kinase TAK1 in the IL-1 signalling pathway. EMBO Rep 7, 838–844.
    [Google Scholar]
  55. Uchiya, K., Barbieri, M. A., Funato, K., Shah, A. H., Stahl, P. D. & Groisman, E. A. ( 1999; ). A Salmonella virulence protein that inhibits cellular trafficking. EMBO J 18, 3924–3933.[CrossRef]
    [Google Scholar]
  56. Viboud, G. I. & Bliska, J. B. ( 2005; ). Yersinia outer proteins: role in modulation of host cell signaling responses and pathogenesis. Annu Rev Microbiol 59, 69–89.[CrossRef]
    [Google Scholar]
  57. Vilches, S., Jimenez, N., Tomas, J. M. & Merino, S. ( 2009; ). Aeromonas hydrophila AH-3 type III secretion system expression and regulatory network. Appl Environ Microbiol 75, 6382–6392.[CrossRef]
    [Google Scholar]
  58. Xu, X. J., Ferguson, M. R., Popov, V. L., Houston, C. W., Peterson, J. W. & Chopra, A. K. ( 1998; ). Role of a cytotoxic enterotoxin in Aeromonas-mediated infections: development of transposon and isogenic mutants. Infect Immun 66, 3501–3509.
    [Google Scholar]
  59. Zuany-Amorim, C., Sawicka, E., Manlius, C., Le Moine, A., Brunet, L. R., Kemeny, D. M., Bowen, G., Rook, G. & Walker, C. ( 2002; ). Suppression of airway eosinophilia by killed Mycobacterium vaccae-induced allergen-specific regulatory T-cells. Nat Med 8, 625–629.[CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/micro/10.1099/mic.0.041277-0
Loading
/content/journal/micro/10.1099/mic.0.041277-0
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error