1887

Abstract

The intracellular bacterium ensures its survival and proliferation within phagocytes of the infected host through phagosomal escape and cytosolic replication, to cause the disease tularemia. The cytokine interferon- (IFN-) is important in controlling primary infections , and intracellular proliferation of in macrophages, but its actual effects on the intracellular cycle of the bacterium are ambiguous. Here, we have performed an extensive analysis of the intracellular fate of the virulent subsp. strain Schu S4 in primary IFN--activated murine and human macrophages to understand how this cytokine controls proliferation. In both murine bone marrow-derived macrophages (muBMMs) and human blood monocyte-derived macrophages (MDMs), IFN- controlled bacterial proliferation. Schu S4 growth inhibition was not due to a defect in phagosomal escape, since bacteria disrupted their phagosomes with indistinguishable kinetics in both muBMMs and MDMs, regardless of their activation state. Rather, IFN- activation restricted cytosolic replication of Schu S4 in a manner independent of reactive oxygen or nitrogen species. Hence, IFN- induces phagocyte NADPH oxidase Phox- and inducible nitric oxide synthase (iNOS)-independent cytosolic effector mechanisms that restrict growth of virulent in macrophages.

Loading

Article metrics loading...

/content/journal/micro/10.1099/mic.0.031716-0
2010-02-01
2024-03-29
Loading full text...

Full text loading...

/deliver/fulltext/micro/156/2/327.html?itemId=/content/journal/micro/10.1099/mic.0.031716-0&mimeType=html&fmt=ahah

References

  1. Anthony L. S., Morrissey P. J., Nano F. E. 1992; Growth inhibition of Francisella tularensis live vaccine strain by IFN-gamma-activated macrophages is mediated by reactive nitrogen intermediates derived from l-arginine metabolism. J Immunol 148:1829–1834
    [Google Scholar]
  2. Beatty W. L., Belanger T. A., Desai A. A., Morrison R. P., Byrne G. I. 1994; Tryptophan depletion as a mechanism of gamma interferon-mediated chlamydial persistence. Infect Immun 62:3705–3711
    [Google Scholar]
  3. Bonquist L., Lindgren H., Golovliov I., Guina T., Sjostedt A. 2008; MglA and Igl proteins contribute to the modulation of Francisella tularensis live vaccine strain-containing phagosomes in murine macrophages. Infect Immun 76:3502–3510
    [Google Scholar]
  4. Bosio C. M., Dow S. W. 2005; Francisella tularensis induces aberrant activation of pulmonary dendritic cells. J Immunol 175:6792–6801
    [Google Scholar]
  5. Chase J. C., Celli J., Bosio C. M. 2009; Direct and indirect impairment of human dendritic cell function by virulent Francisella tularensis Schu S4. Infect Immun 77:180–195
    [Google Scholar]
  6. Checroun C., Wehrly T. D., Fischer E. R., Hayes S. F., Celli J. 2006; Autophagy-mediated reentry of Francisella tularensis into the endocytic compartment after cytoplasmic replication. Proc Natl Acad Sci U S A 103:14578–14583
    [Google Scholar]
  7. Chong A., Wehrly T. D., Nair V., Fischer E. R., Barker J. R., Klose K. E., Celli J. 2008; The early phagosomal stage of Francisella tularensis determines optimal phagosomal escape and Francisella pathogenicity island protein expression. Infect Immun 76:5488–5499
    [Google Scholar]
  8. Clemens D. L., Lee B. Y., Horwitz M. A. 2004; Virulent and avirulent strains of Francisella tularensis prevent acidification and maturation of their phagosomes and escape into the cytoplasm in human macrophages. Infect Immun 72:3204–3217
    [Google Scholar]
  9. Dahlgren C., Karlsson A. 1999; Respiratory burst in human neutrophils. J Immunol Methods 232:3–14
    [Google Scholar]
  10. Elkins K. L., Rhinehart-Jones T. R., Culkin S. J., Yee D., Winegar R. K. 1996; Minimal requirements for murine resistance to infection with Francisella tularensis LVS. Infect Immun 64:3288–3293
    [Google Scholar]
  11. Ellis J., Oyston P. C., Green M., Titball R. W. 2002; Tularemia. Clin Microbiol Rev 15:631–646
    [Google Scholar]
  12. Fortier A. H., Polsinelli T., Green S. J., Nacy C. A. 1992; Activation of macrophages for destruction of Francisella tularensis: identification of cytokines, effector cells, and effector molecules. Infect Immun 60:817–825
    [Google Scholar]
  13. Golovliov I., Baranov V., Krocova Z., Kovarova H., Sjostedt A. 2003; An attenuated strain of the facultative intracellular bacterium Francisella tularensis can escape the phagosome of monocytic cells. Infect Immun 71:5940–5950
    [Google Scholar]
  14. Hall J. D., Woolard M. D., Gunn B. M., Craven R. R., Taft-Benz S., Frelinger J. A., Kawula T. H. 2008; Infected-host-cell repertoire and cellular response in the lung following inhalation of Francisella tularensis Schu S4, LVS, or U112. Infect Immun 76:5843–5852
    [Google Scholar]
  15. Hiemstra P. S., van den Barselaar M. T., Roest M., Nibbering P. H., van Furth R. 1999; Ubiquicidin, a novel murine microbicidal protein present in the cytosolic fraction of macrophages. J Leukoc Biol 66:423–428
    [Google Scholar]
  16. Leiby D. A., Fortier A. H., Crawford R. M., Schreiber R. D., Nacy C. A. 1992; In vivo modulation of the murine immune response to Francisella tularensis LVS by administration of anticytokine antibodies. Infect Immun 60:84–89
    [Google Scholar]
  17. Levine B., Deretic V. 2007; Unveiling the roles of autophagy in innate and adaptive immunity. Nat Rev Immunol 7:767–777
    [Google Scholar]
  18. Lindgren H., Golovliov I., Baranov V., Ernst R. K., Telepnev M., Sjostedt A. 2004; Factors affecting the escape of Francisella tularensis from the phagolysosome. J Med Microbiol 53:953–958
    [Google Scholar]
  19. Lindgren H., Stenman L., Tarnvik A., Sjostedt A. 2005; The contribution of reactive nitrogen and oxygen species to the killing of Francisella tularensis LVS by murine macrophages. Microbes Infect 7:467–475
    [Google Scholar]
  20. Lindgren H., Shen H., Zingmark C., Golovliov I., Conlan W., Sjostedt A. 2007; Resistance of Francisella tularensis strains against reactive nitrogen and oxygen species with special reference to the role of KatG. Infect Immun 75:1303–1309
    [Google Scholar]
  21. Mariathasan S., Weiss D. S., Dixit V. M., Monack D. M. 2005; Innate immunity against Francisella tularensis is dependent on the ASC/caspase-1 axis. J Exp Med 202:1043–1049
    [Google Scholar]
  22. McCaffrey R. L., Allen L. A. 2006; Francisella tularensis LVS evades killing by human neutrophils via inhibition of the respiratory burst and phagosome escape. J Leukoc Biol 80:1224–1230
    [Google Scholar]
  23. Oyston P. C., Sjostedt A., Titball R. W. 2004; Tularaemia: bioterrorism defence renews interest in Francisella tularensis. Nat Rev Microbiol 2:967–978
    [Google Scholar]
  24. Paradkar P. N., De Domenico I., Durchfort N., Zohn I., Kaplan J., Ward D. M. 2008; Iron depletion limits intracellular bacterial growth in macrophages. Blood 112:866–874
    [Google Scholar]
  25. Polsinelli T., Meltzer M. S., Fortier A. H. 1994; Nitric oxide-independent killing of Francisella tularensis by IFN-gamma-stimulated murine alveolar macrophages. J Immunol 153:1238–1245
    [Google Scholar]
  26. Portnoy D. A., Schreiber R. D., Connelly P., Tilney L. G. 1989; γ Interferon limits access of Listeria monocytogenes to the macrophage cytoplasm. J Exp Med 170:2141–2146
    [Google Scholar]
  27. Radtke A. L., O'Riordan M. X. 2006; Intracellular innate resistance to bacterial pathogens. Cell Microbiol 8:1720–1729
    [Google Scholar]
  28. Santic M., Molmeret M., Abu Kwaik Y. 2005a; Modulation of biogenesis of the Francisella tularensis subsp. novicida-containing phagosome in quiescent human macrophages and its maturation into a phagolysosome upon activation by IFN- γ. Cell Microbiol 7:957–967
    [Google Scholar]
  29. Santic M., Molmeret M., Klose K. E., Jones S., Abu Kwaik Y. 2005b; The Francisella tularensis pathogenicity island protein IglC and its regulator MglA are essential for modulating phagosome biogenesis and subsequent bacterial escape into the cytoplasm. Cell Microbiol 7:969–979
    [Google Scholar]
  30. Santic M., Asare R., Skrobonja I., Jones S., Abu Kwaik Y. 2008; Acquisition of the vATPase proton pump and phagosome acidification is essential for escape of Francisella tularensis into the macrophage cytosol. Infect Immun 76:2671–2677
    [Google Scholar]
  31. Schaible U. E., Kaufmann S. H. 2004; Iron and microbial infection. Nat Rev Microbiol 2:946–953
    [Google Scholar]
  32. Shiloh M. U., MacMicking J. D., Nicholson S., Brause J. E., Potter S., Marino M., Fang F., Dinauer M., Nathan C. 1999; Phenotype of mice and macrophages deficient in both phagocyte oxidase and inducible nitric oxide synthase. Immunity 10:29–38
    [Google Scholar]
  33. Turco J., Winkler H. H. 1983; Cloned mouse interferon- γ inhibits the growth of Rickettsia prowazekii in cultured mouse fibroblasts. J Exp Med 158:2159–2164
    [Google Scholar]
  34. Way S. S., Borczuk A. C., Dominitz R., Goldberg M. B. 1998; An essential role for gamma interferon in innate resistance to Shigella flexneri infection. Infect Immun 66:1342–1348
    [Google Scholar]
  35. Wehrly T. D., Chong A., Virtaneva K., Sturdevant D. E., Child R., Edwards J. A., Brouwer D., Nair V., Fischer E. R. other authors 2009; Intracellular biology and virulence determinants of Francisella tularensis revealed by transcriptional profiling inside macrophages. Cell Microbiol 11:1128–1150
    [Google Scholar]
  36. Zasloff M. 2002; Antimicrobial peptides of multicellular organisms. Nature 415:389–395
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/micro/10.1099/mic.0.031716-0
Loading
/content/journal/micro/10.1099/mic.0.031716-0
Loading

Data & Media loading...

Supplements

Supplementary material 1

PDF

Supplementary material 2

PDF
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