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. 1997 Oct;65(10):4075–4081. doi: 10.1128/iai.65.10.4075-4081.1997

The mechanism of cell death in Listeria monocytogenes-infected murine macrophages is distinct from apoptosis.

J Barsig 1, S H Kaufmann 1
PMCID: PMC175586  PMID: 9317010

Abstract

Various pathogenic bacteria with the capacity to live within eukaryotic cells activate an apoptotic program in infected host cells. Induction of apoptosis by Listeria monocytogenes in murine dendritic cells and hepatocytes has been described. Here we address the questions of whether and how the pathogen kills macrophages, its most important habitat. Employing several complementary techniques aimed at discriminating between apoptosis and necrosis, we show that murine bone marrow-derived macrophages (BMM) undergo delayed necrosis but not apoptosis when infected with listeriolysin (Hly)-producing L. monocytogenes. This pathogen failed to elicit apoptotic morphology, DNA fragmentation, and surface annexin V binding of macrophages, in contrast to Shigella flexneri infection or gliotoxin treatment, which were used as positive controls. Furthermore, macrophages infected with L. monocytogenes released lower quantities of interleukin-1beta (IL-1beta) than did Shigella flexneri-infected ones, indicating diminished or even absent activation of IL-1-converting enzyme in macrophages harboring L. monocytogenes. We conclude that murine BMM die by necrosis after several hours of cytoplasmic replication of L. monocytogenes. The pathogen may benefit from this feature by the possibility of taking advantage of cells of "pseudo-healthy" appearance, thus avoiding rapid elimination by other phagocytes.

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Selected References

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  1. Beg A. A., Baltimore D. An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science. 1996 Nov 1;274(5288):782–784. doi: 10.1126/science.274.5288.782. [DOI] [PubMed] [Google Scholar]
  2. Beuscher H. U., Colten H. R. Structure and function of membrane IL-1. Mol Immunol. 1988 Nov;25(11):1189–1199. doi: 10.1016/0161-5890(88)90155-1. [DOI] [PubMed] [Google Scholar]
  3. Chen L. M., Kaniga K., Galán J. E. Salmonella spp. are cytotoxic for cultured macrophages. Mol Microbiol. 1996 Sep;21(5):1101–1115. doi: 10.1046/j.1365-2958.1996.471410.x. [DOI] [PubMed] [Google Scholar]
  4. Chen Y., Smith M. R., Thirumalai K., Zychlinsky A. A bacterial invasin induces macrophage apoptosis by binding directly to ICE. EMBO J. 1996 Aug 1;15(15):3853–3860. [PMC free article] [PubMed] [Google Scholar]
  5. Chen Y., Zychlinsky A. Apoptosis induced by bacterial pathogens. Microb Pathog. 1994 Oct;17(4):203–212. doi: 10.1006/mpat.1994.1066. [DOI] [PubMed] [Google Scholar]
  6. Conlan J. W. Early pathogenesis of Listeria monocytogenes infection in the mouse spleen. J Med Microbiol. 1996 Apr;44(4):295–302. doi: 10.1099/00222615-44-4-295. [DOI] [PubMed] [Google Scholar]
  7. Dalton C. B., Austin C. C., Sobel J., Hayes P. S., Bibb W. F., Graves L. M., Swaminathan B., Proctor M. E., Griffin P. M. An outbreak of gastroenteritis and fever due to Listeria monocytogenes in milk. N Engl J Med. 1997 Jan 9;336(2):100–105. doi: 10.1056/NEJM199701093360204. [DOI] [PubMed] [Google Scholar]
  8. Fernandez-Prada C. M., Hoover D. L., Tall B. D., Venkatesan M. M. Human monocyte-derived macrophages infected with virulent Shigella flexneri in vitro undergo a rapid cytolytic event similar to oncosis but not apoptosis. Infect Immun. 1997 Apr;65(4):1486–1496. doi: 10.1128/iai.65.4.1486-1496.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gregory S. H., Sagnimeni A. J., Wing E. J. Bacteria in the bloodstream are trapped in the liver and killed by immigrating neutrophils. J Immunol. 1996 Sep 15;157(6):2514–2520. [PubMed] [Google Scholar]
  10. Guzmán C. A., Domann E., Rohde M., Bruder D., Darji A., Weiss S., Wehland J., Chakraborty T., Timmis K. N. Apoptosis of mouse dendritic cells is triggered by listeriolysin, the major virulence determinant of Listeria monocytogenes. Mol Microbiol. 1996 Apr;20(1):119–126. doi: 10.1111/j.1365-2958.1996.tb02494.x. [DOI] [PubMed] [Google Scholar]
  11. Hof H., Nichterlein T., Kretschmar M. Management of listeriosis. Clin Microbiol Rev. 1997 Apr;10(2):345–357. doi: 10.1128/cmr.10.2.345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kathariou S., Metz P., Hof H., Goebel W. Tn916-induced mutations in the hemolysin determinant affecting virulence of Listeria monocytogenes. J Bacteriol. 1987 Mar;169(3):1291–1297. doi: 10.1128/jb.169.3.1291-1297.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kaufmann S. H. Immunity to intracellular bacteria. Annu Rev Immunol. 1993;11:129–163. doi: 10.1146/annurev.iy.11.040193.001021. [DOI] [PubMed] [Google Scholar]
  14. Mantis N., Prévost M. C., Sansonetti P. Analysis of epithelial cell stress response during infection by Shigella flexneri. Infect Immun. 1996 Jul;64(7):2474–2482. doi: 10.1128/iai.64.7.2474-2482.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Martin S. J., Reutelingsperger C. P., McGahon A. J., Rader J. A., van Schie R. C., LaFace D. M., Green D. R. Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of Bcl-2 and Abl. J Exp Med. 1995 Nov 1;182(5):1545–1556. doi: 10.1084/jem.182.5.1545. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Monack D. M., Raupach B., Hromockyj A. E., Falkow S. Salmonella typhimurium invasion induces apoptosis in infected macrophages. Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9833–9838. doi: 10.1073/pnas.93.18.9833. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Moore K. J., Matlashewski G. Intracellular infection by Leishmania donovani inhibits macrophage apoptosis. J Immunol. 1994 Mar 15;152(6):2930–2937. [PubMed] [Google Scholar]
  18. Nagata S. Apoptosis by death factor. Cell. 1997 Feb 7;88(3):355–365. doi: 10.1016/s0092-8674(00)81874-7. [DOI] [PubMed] [Google Scholar]
  19. Pahl H. L., Krauss B., Schulze-Osthoff K., Decker T., Traenckner E. B., Vogt M., Myers C., Parks T., Warring P., Mühlbacher A. The immunosuppressive fungal metabolite gliotoxin specifically inhibits transcription factor NF-kappaB. J Exp Med. 1996 Apr 1;183(4):1829–1840. doi: 10.1084/jem.183.4.1829. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Portnoy D. A., Chakraborty T., Goebel W., Cossart P. Molecular determinants of Listeria monocytogenes pathogenesis. Infect Immun. 1992 Apr;60(4):1263–1267. doi: 10.1128/iai.60.4.1263-1267.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Rogers H. W., Callery M. P., Deck B., Unanue E. R. Listeria monocytogenes induces apoptosis of infected hepatocytes. J Immunol. 1996 Jan 15;156(2):679–684. [PubMed] [Google Scholar]
  22. Sansonetti P. J., Arondel J., Cavaillon J. M., Huerre M. Role of interleukin-1 in the pathogenesis of experimental shigellosis. J Clin Invest. 1995 Aug;96(2):884–892. doi: 10.1172/JCI118135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Sansonetti P. J., Mounier J., Prévost M. C., Mège R. M. Cadherin expression is required for the spread of Shigella flexneri between epithelial cells. Cell. 1994 Mar 11;76(5):829–839. doi: 10.1016/0092-8674(94)90358-1. [DOI] [PubMed] [Google Scholar]
  24. Sansonetti P., Phalipon A. Shigellosis: from molecular pathogenesis of infection to protective immunity and vaccine development. Res Immunol. 1996 Oct-Dec;147(8-9):595–602. doi: 10.1016/s0923-2494(97)85227-3. [DOI] [PubMed] [Google Scholar]
  25. Southwick F. S., Purich D. L. Intracellular pathogenesis of listeriosis. N Engl J Med. 1996 Mar 21;334(12):770–776. doi: 10.1056/NEJM199603213341206. [DOI] [PubMed] [Google Scholar]
  26. Szalay G., Hess J., Kaufmann S. H. Restricted replication of Listeria monocytogenes in a gamma interferon-activated murine hepatocyte line. Infect Immun. 1995 Aug;63(8):3187–3195. doi: 10.1128/iai.63.8.3187-3195.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Thirumalai K., Kim K. S., Zychlinsky A. IpaB, a Shigella flexneri invasin, colocalizes with interleukin-1 beta-converting enzyme in the cytoplasm of macrophages. Infect Immun. 1997 Feb;65(2):787–793. doi: 10.1128/iai.65.2.787-793.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Tilney L. G., Connelly P. S., Portnoy D. A. Actin filament nucleation by the bacterial pathogen, Listeria monocytogenes. J Cell Biol. 1990 Dec;111(6 Pt 2):2979–2988. doi: 10.1083/jcb.111.6.2979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Vazquez M. A., Sicher S. C., Wright W. J., Proctor M. L., Schmalzried S. R., Stallworth K. R., Crowley J. C., Lu C. Y. Differential regulation of TNF-alpha production by listeriolysin-producing versus nonproducing strains of Listeria monocytogenes. J Leukoc Biol. 1995 Nov;58(5):556–562. doi: 10.1002/jlb.58.5.556. [DOI] [PubMed] [Google Scholar]
  30. Waring P., Eichner R. D., Müllbacher A., Sjaarda A. Gliotoxin induces apoptosis in macrophages unrelated to its antiphagocytic properties. J Biol Chem. 1988 Dec 5;263(34):18493–18499. [PubMed] [Google Scholar]
  31. Zychlinsky A., Fitting C., Cavaillon J. M., Sansonetti P. J. Interleukin 1 is released by murine macrophages during apoptosis induced by Shigella flexneri. J Clin Invest. 1994 Sep;94(3):1328–1332. doi: 10.1172/JCI117452. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Zychlinsky A., Kenny B., Ménard R., Prévost M. C., Holland I. B., Sansonetti P. J. IpaB mediates macrophage apoptosis induced by Shigella flexneri. Mol Microbiol. 1994 Feb;11(4):619–627. doi: 10.1111/j.1365-2958.1994.tb00341.x. [DOI] [PubMed] [Google Scholar]
  33. Zychlinsky A., Prevost M. C., Sansonetti P. J. Shigella flexneri induces apoptosis in infected macrophages. Nature. 1992 Jul 9;358(6382):167–169. doi: 10.1038/358167a0. [DOI] [PubMed] [Google Scholar]
  34. Zychlinsky A., Sansonetti P. J. Apoptosis as a proinflammatory event: what can we learn from bacteria-induced cell death? Trends Microbiol. 1997 May;5(5):201–204. doi: 10.1016/S0966-842X(97)01044-5. [DOI] [PubMed] [Google Scholar]
  35. de Chastellier C., Berche P. Fate of Listeria monocytogenes in murine macrophages: evidence for simultaneous killing and survival of intracellular bacteria. Infect Immun. 1994 Feb;62(2):543–553. doi: 10.1128/iai.62.2.543-553.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]

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