1887

Abstract

is an intracellular organism and the major aetiological agent of Legionnaires' disease. Although recent progress has identified Toll-like receptors (TLRs) as receptors for recognition of pathogen-associated molecular patterns in a variety of micro-organisms, understanding the contribution of TLRs to the host response in infection is still limited. This study examined the roles of TLR2 and TLR4 in murine pneumonia and an infection model using bone-marrow-derived macrophages. TLR2-deficient mice, but not TLR4-deficient mice, demonstrated higher lethal sensitivity to pulmonary challenge with than wild-type mice (<0.05). Although no differences in pulmonary bacterial burden were observed among the mouse strains examined, lower values of macrophage inflammatory protein-2 (MIP-2), keratinocyte-derived cytokine and interleukin (IL)-6 and higher IL-12 levels were noted in lung homogenates of TLR2-deficient mice compared with the wild-type control and TLR4-deficient mice. Recruitment of inflammatory cells, particularly neutrophils, was severely disturbed in the lungs of TLR2-deficient mice. Reduced MIP-2 production was demonstrated in bone-marrow-derived macrophages from TLR2-deficient mice in response to live and purified LPS of this strain, but not LPS. These data highlight the involvement and importance of TLR2 in the pathogenesis of pneumonia in mice. The results showed that TLR2-mediated recognition of LPS and subsequent chemokine-dependent cellular recruitment may be a crucial host innate response in pneumonia.

Loading

Article metrics loading...

/content/journal/jmm/10.1099/jmm.0.46913-0
2007-03-01
2024-12-13
Loading full text...

Full text loading...

/deliver/fulltext/jmm/56/3/305.html?itemId=/content/journal/jmm/10.1099/jmm.0.46913-0&mimeType=html&fmt=ahah

References

  1. Aderem A., Ulevitch R. J. 2000; Toll-like receptors in the induction of the innate immune response. Nature 406:782–787 [CrossRef]
    [Google Scholar]
  2. Akamine M., Higa F., Arakaki N., Kawakami K., Takeda K., Akira S., Saito A. 2005; Differential roles of Toll-like receptors 2 and 4 in in vitro responses of macrophages to Legionella pneumophila . Infect Immun 73:352–361 [CrossRef]
    [Google Scholar]
  3. Akira S., Takeda K. 2004; Toll-like receptor signalling. Nat Rev Immunol 4:499–511 [CrossRef]
    [Google Scholar]
  4. Archer K. A., Roy C. R. 2006; MyD88-dependent responses involving toll-like receptor 2 are important for protection and clearance of Legionella pneumophila in a mouse model of Legionnaires' disease. Infect Immun 74:3325–3333 [CrossRef]
    [Google Scholar]
  5. Beutler B. 2004; Inferences, questions and possibilities in Toll-like receptor signalling. Nature 430:257–263 [CrossRef]
    [Google Scholar]
  6. Braedel-Ruoff S., Faigle M., Hilf N., Neumeister B., Schild H. 2005; Legionella pneumophila mediated activation of dendritic cells involves CD14 and TLR2. J Endotoxin Res 11:89–96 [CrossRef]
    [Google Scholar]
  7. Brieland J. K., Remick D. G., LeGendre M. L., Engleberg N. C., Fantone J. C. 1998; In vivo regulation of replicative Legionella pneumophila lung infection by endogenous interleukin-12. Infect Immun 66:65–69
    [Google Scholar]
  8. Brieland J. K., Jackson C., Hurst S., Loebenberg D., Muchamuel T., Debets R., Kastelein R., Churakova T., Abrams J. other authors 2000; Immunomodulatory role of endogenous interleukin-18 in gamma interferon-mediated resolution of replicative Legionella pneumophila lung infection. Infect Immun 68:6567–6573 [CrossRef]
    [Google Scholar]
  9. Byrne B., Swanson M. S. 1998; Expression of Legionella pneumophila virulence traits in response to growth conditions. Infect Immun 66:3029–3034
    [Google Scholar]
  10. Carratala J., Gudiol F., Pallares R., Dorca J., Verdaguer R., Ariza J., Manresa F. 1994; Risk factors for nosocomial Legionella pneumophila pneumonia. Am J Respir Crit Care Med 149:625–629 [CrossRef]
    [Google Scholar]
  11. Celada A., Gray P. W., Rinderknecht E., Schreiber R. D. 1984; Evidence for a gamma-interferon receptor that regulates macrophage tumoricidal activity. J Exp Med 160:55–74 [CrossRef]
    [Google Scholar]
  12. el-Ebiary M., Sarmiento X., Torres A., Nogue S., Mesalles E., Bodi M., Almirall J. 1997; Prognostic factors of severe Legionella pneumonia requiring admission to ICU. Am J Respir Crit Care Med 156:1467–1472 [CrossRef]
    [Google Scholar]
  13. Erridge C., Pridmore A., Eley A., Stewart J., Poxton I. R. 2004; Lipopolysaccharides of Bacteroides fragilis , Chlamydia trachomatis and Pseudomonas aeruginosa signal via toll-like receptor 2. J Med Microbiol 53:735–740 [CrossRef]
    [Google Scholar]
  14. Gebran S. J., Yamamoto Y., Newton C., Klein T. W., Friedman H. 1994; Inhibition of Legionella pneumophila growth by gamma interferon in permissive A/J mouse macrophages: role of reactive oxygen species, nitric oxide, tryptophan, and iron(III. Infect Immun 62:3197–3205
    [Google Scholar]
  15. Girard R., Pedron T., Uematsu S., Balloy V., Chignard M., Akira S., Chaby R. 2003; Lipopolysaccharides from Legionella and Rhizobium stimulate mouse bone marrow granulocytes via Toll-like receptor 2. J Cell Sci 116:293–302 [CrossRef]
    [Google Scholar]
  16. Hawn T. R., Verbon A., Lettinga K. D., Zhao L. P., Li S. S., Laws R. J., Skerrett S. J., Beutler B., Schroeder L. other authors 2003; A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to Legionnaires' disease. J Exp Med 198:1563–1572 [CrossRef]
    [Google Scholar]
  17. Hawn T. R., Smith K. D., Aderem A., Skerrett S. J. 2006; Myeloid differentiation primary response gene (88)- and toll-like receptor 2-deficient mice are susceptible to infection with aerosolized Legionella pneumophila . J Infect Dis 193:1693–1702 [CrossRef]
    [Google Scholar]
  18. Hirschfeld M., Weis J. J., Toshchakov V., Salkowski C. A., Cody M. J., Ward D. C., Qureshi N., Michalek S. M., Vogel S. N. 2001; Signaling by toll-like receptor 2 and 4 agonists results in differential gene expression in murine macrophages. Infect Immun 69:1477–1482 [CrossRef]
    [Google Scholar]
  19. Horwitz M. A., Silverstein S. C. 1980; Legionnaires' disease bacterium ( Legionella pneumophila ) multiples intracellularly in human monocytes. J Clin Invest 66:441–450 [CrossRef]
    [Google Scholar]
  20. Janeway C. A. Jr, Medzhitov R. 2002; Innate immune recognition. Annu Rev Immunol 20:197–216 [CrossRef]
    [Google Scholar]
  21. Knirel Y. A., Moll H., Zähringer U. 1996; Structural study of a highly O -acetylated core of Legionella pneumophila serogroup 1 lipopolysaccharide. Carbohydr Res 293:223–234 [CrossRef]
    [Google Scholar]
  22. Lettinga K. D., Florquin S., Speelman P., van Ketel R., van der Poll T., Verbon A. 2002; Toll-like receptor 4 is not involved in host defense against pulmonary Legionella pneumophila infection in a mouse model. J Infect Dis 186:570–573 [CrossRef]
    [Google Scholar]
  23. Marston B. J., Lipman H. B., Breiman R. F. 1994; Surveillance for Legionnaires' disease. Risk factors for morbidity and mortality. Arch Intern Med 154:2417–2422 [CrossRef]
    [Google Scholar]
  24. Medzhitov R. 2001; Toll-like receptors and innate immunity. Nat Rev Immunol 1:135–145 [CrossRef]
    [Google Scholar]
  25. Medzhitov R., Janeway C. Jr 2000; Innate immunity. N Engl J Med 343:338–344 [CrossRef]
    [Google Scholar]
  26. Mody C. H., Paine R. III, Shahrabadi M. S., Simon R. H., Pearlman E., Eisenstein B. I., Toews G. B. 1993; Legionella pneumophila replicates within rat alveolar epithelial cells. J Infect Dis 167:1138–1145 [CrossRef]
    [Google Scholar]
  27. Moll H., Knirel Y. A., Helbig J. H., Zähringer U. 1997; Identification of an alpha-d-Man p -(1→8)-Kdo disaccharide in the inner core region and the structure of the complete core region of the Legionella pneumophila serogroup 1 lipopolysaccharide. Carbohydr Res 304:91–95 [CrossRef]
    [Google Scholar]
  28. Molofsky A. B., Byrne B. G., Whitfield N. N., Madigan C. A., Fuse E. T., Tateda K., Swanson M. S. 2006; Cytosolic recognition of flagellin by mouse macrophages restricts Legionella pneumophila infection. J Exp Med 203:1093–1104 [CrossRef]
    [Google Scholar]
  29. Nash T. W., Libby D. M., Horwitz M. A. 1984; Interaction between the legionnaires' disease bacterium ( Legionella pneumophila ) and human alveolar macrophages. Influence of antibody, lymphokines, and hydrocortisone. J Clin Invest 74:771–782 [CrossRef]
    [Google Scholar]
  30. Neumeister B., Faigle M., Sommer M., Zähringer U., Stelter F., Menzel R., Schütt C., Northoff H. 1998; Low endotoxic potential of Legionella pneumophila lipopolysaccharide due to failure of interaction with the monocyte lipopolysaccharide receptor CD14. Infect Immun 66:4151–4157
    [Google Scholar]
  31. Pedro-Botet M. L., Sabria-Leal M., Sopena N., Manterola J. M., Morera J., Blavia R., Padilla E., Matas L., Gimeno J. M. 1998; Role of immunosuppression in the evolution of Legionnaires' disease. Clin Infect Dis 26:14–19 [CrossRef]
    [Google Scholar]
  32. Reingold A. L. 1988; Role of legionellae in acute infections of the lower respiratory tract. Rev Infect Dis 10:1018–1028 [CrossRef]
    [Google Scholar]
  33. Ren T., Zamboni D. S., Roy C. R., Dietrich W. F., Vance R. E. 2006; Flagellin-deficient Legionella mutants evade caspase-1- and Naip5-mediated macrophage immunity. PLoS Pathog 2:e18 [CrossRef]
    [Google Scholar]
  34. Salins S., Newton C., Widen R., Klein T. W., Friedman H. 2001; Differential induction of gamma interferon in Legionella pneumophila -infected macrophages from BALB/c and A/J mice. Infect Immun 69:3605–3610 [CrossRef]
    [Google Scholar]
  35. Skerrett S. J., Martin T. R. 1994; Intratracheal interferon-gamma augments pulmonary defenses in experimental legionellosis. Am J Respir Crit Care Med 149:50–58 [CrossRef]
    [Google Scholar]
  36. Swanson M. S., Isberg R. R. 1995; Association of Legionella pneumophila with the macrophage endoplasmic reticulum. Infect Immun 63:3609–3620
    [Google Scholar]
  37. Takeda K., Kaisho T., Akira S. 2003; Toll-like receptors. Annu Rev Immunol 21:335–376 [CrossRef]
    [Google Scholar]
  38. Tateda K., Matsumoto T., Ishii Y., Furuya N., Ohno A., Miyazaki S., Yamaguchi K. 1998; Serum cytokines in patients with Legionella pneumonia: relative predominance of Th1-type cytokines. Clin Diagn Lab Immunol 5:401–403
    [Google Scholar]
  39. Tateda K., Moore T. A., Deng J. C., Newstead M. W., Zeng X., Matsukawa A., Swanson M. S., Yamaguchi K., Standiford T. J. 2001a; Early recruitment of neutrophils determines subsequent T1/T2 host responses in a murine model of Legionella pneumophila pneumonia. J Immunol 166:3355–3361 [CrossRef]
    [Google Scholar]
  40. Tateda K., Moore T. A., Newstead M. W., Tsai W. C., Zeng X., Deng J. C., Chen G., Reddy R., Yamaguchi K., Standiford T. J. 2001b; Chemokine-dependent neutrophil recruitment in a murine model of Legionella pneumonia: potential role of neutrophils as immunoregulatory cells. Infect Immun 69:2017–2024 [CrossRef]
    [Google Scholar]
  41. Tkatch L. S., Kusne S., Irish W. D., Krystofiak S., Wing E. 1998; Epidemiology of Legionella pneumonia and factors associated with Legionella -related mortality at a tertiary care center. Clin Infect Dis 27:1479–1486 [CrossRef]
    [Google Scholar]
  42. Werts C., Tapping R. I., Mathison J. C., Chuang T.-H., Kravchenko V., Saint Girons I., Haake D. A., Godowski P. J., Hayashi F. other authors 2001; Leptospiral lipopolysaccharide activates cells through a TLR2-dependent mechanism. Nat Immunol 2:346–352 [CrossRef]
    [Google Scholar]
  43. Yoshida S., Goto Y., Miyamoto H., Fujio H., Mizuguchi Y. 1991; Association of Lps gene with natural resistance of mouse macrophages against Legionella pneumophila . FEMS Microbiol Immunol 4:51–56
    [Google Scholar]
  44. Yoshizawa S., Tateda K., Matsumoto T., Gondaira F., Miyazaki S., Standiford T. J., Yamaguchi K. 2005; Legionella pneumophila evades gamma interferon-mediated growth suppression through interleukin-10 induction in bone marrow-derived macrophages. Infect Immun 73:2709–2717 [CrossRef]
    [Google Scholar]
  45. Zamboni D. S., Kobayashi K. S., Kohlsdorf T., Ogura Y., Long E. M., Vance R. E., Kuida K., Mariathasan S., Dixit V. M. other authors 2006; The Birc1e cytosolic pattern-recognition receptor contributes to the detection and control of Legionella pneumophila infection. Nat Immunol 7:318–325 [CrossRef]
    [Google Scholar]
  46. Zhang P., Summer W. R., Bagby G. J., Nelson S. 2000; Innate immunity and pulmonary host defense. Immunol Rev 173:39–51 [CrossRef]
    [Google Scholar]
/content/journal/jmm/10.1099/jmm.0.46913-0
Loading
/content/journal/jmm/10.1099/jmm.0.46913-0
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