Legionella pneumophila Invasion of Mononuclear Phagocytes

  • H. A. Shuman
  • M. A. Horwitz
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 209)


Legionella pneumophila is a gram-negative bacterium that causes legionnaires’ disease. This organism is widespread in fresh water and is typically found growing in association with protozoans and blue-green algae. In human beings, L pneumophila infects alveolar macrophages, wherein the organism survives and replicates within a specialized phagosome or vacuole (the Legionella-specialized phagosome, LSP). The interaction between L. pneumophila and human mononuclear phagocytes has been studied in considerable detail, and it provides an interesting and informative example of how one organism successfully achieves intracellular parasitism.


Human Monocyte Mononuclear Phagocyte Complement Receptor Major Outer Membrane Protein Intracellular Multiplication 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Armstrong JA, Hart PD (1971) Response of cultured macrophages to Mycobacterium tuberculosis with observations on fusion of lysosomes with phagosomes. J Exp Med 134:713–740PubMedCrossRefGoogle Scholar
  2. Bellinger-Kawahara C, Horwitz MA (1990) Complement component C3 fixes selectively to the major outer membrane protein (MOMP) of Legionella pneumophila and mediates phagocytosis of liposome-MOMP complexes by human monocytes. J Exp Med 172:1201–1210PubMedCrossRefGoogle Scholar
  3. Berger KH, Isberg RR (1993) Two distinct defects in intracellular growth complemented by a single genetic locus in Legionella pneumophila. Mol Microbiol 7:7–19PubMedCrossRefGoogle Scholar
  4. Berger KH, Merriam JJ, Isberg RR (1994) Altered intracellular targeting properties associated with mutations in the Legionella pneumophila dotA gene. Mol Microbiol 14:809–822PubMedCrossRefGoogle Scholar
  5. Bermudez LE, Young LS, Enkel H (1991) Interaction of Mycobacterium avium complex with human macrophages:roles of membrane receptors and serum proteins. Infect Immun 59:1697–1702PubMedGoogle Scholar
  6. Blackwell JM, Ezekowitz RAB, Roberts MB, Channon JY, Sim RB, Gordon S (1985) Macrophage complement and lectin-like receptors bind Leishmania in the absence of serum. J Exp Med 162:324–331PubMedCrossRefGoogle Scholar
  7. Blander SJ, Horwitz MA (1989) Vaccination with the major secretory protein of Legionella pneumophila induces cell-mediated and protective immunity in a guinea pig model of legionnaires’ disease. J Exp Med 169:691–705PubMedCrossRefGoogle Scholar
  8. Blander SJ, Breiman RF, Horwitz MA (1989) A live avirulent mutant Legionella pneumophila vaccine induces protective immunity against lethal aerosol challenge. J Clin Invest 83:810–815PubMedCrossRefGoogle Scholar
  9. Blander SJ, Szeto L, Shuman HA, Horwitz MA (1990) An immuno-protective molecule, the major secretory protein of Legionella pneumophila, is not a virulence factor in a guinea pig model of legionnaires’ disease. J Clin Invest 86:817–824PubMedCrossRefGoogle Scholar
  10. Brand BC, Sadosky AB, Shuman HA (1994) Molecular genetic analysis of the icm region in Legionella pneumophila. Mol Microbiol 14:797–808PubMedCrossRefGoogle Scholar
  11. Bullock WE, Wright SD (1987) Role of the adherence-promoting receptors, CR3, LFA-1, and p150, 95 in binding of Histoplasma capsulatum by human macrophages. J Exp Med 165:195–210PubMedCrossRefGoogle Scholar
  12. Byrd TF, Horwitz MA (1989) Interferon gamma-activated human monocytes down-regulate transferrin receptors and inhibit the intracellular multiplication of Legionella pneumophila by limiting the availability of iron. J Clin Invest 83:1457–1465PubMedCrossRefGoogle Scholar
  13. Byrd TF, Horwitz MA (1991a) Chloroquine inhibits the intracellular multiplication of Legionella pneumophila by limiting the availability of iron. A potential new mechanism for the therapeutic effect of chloroquine against intracellular pathogens. J Clin Invest 88:351–357Google Scholar
  14. Byrd TF, Horwitz MA (1991b) Lactoferrin inhibits or promotes Legionella pneumophila intracellular multiplication in nonactivated and interferon gamma-activated human monocytes depending upon its degree of iron saturation. Iron-lactoferrin and nonphysiologic iron chelates reverse monocyte activation against Legionella pneumophila. J Clin Invest 88:1103–1112Google Scholar
  15. Byrd TF, Horwitz MA (1993) Regulation of transferrin receptor expression and ferritin content in human mononuclear phagocytes:coordinate upregulation by iron-transferrin and down-regulation by interferon gamma. J Clin Invest 91:969–976PubMedCrossRefGoogle Scholar
  16. Catrenich CE, Johnson W (1989) Characterization of the selective inhibition of growth of virulent Legionella pneumophila by supplemented Mueller-Hinton medium. Infect Immun 57:1862–1864PubMedGoogle Scholar
  17. Chang KP (1979) Leishmania donovani promastigote-macrophage surface interactions in vitro. Exp Parasitol 48:175–189PubMedCrossRefGoogle Scholar
  18. Cianciotto NP, Einstein Bl, Mody CH, Toews GB, Engelberg NC (1989) A Legionella pneumophila gene encoding a species-specific surface protein potentiates initiation of intracellular infection. Infect Immun 57:1225–1262Google Scholar
  19. Cianciotto NP, Einstein Bl, Mody CH, Engelberg NC (1990) A mutation in the mip gene results in attenuation of Legionella pneumophila virulence. J Infect Dis 162:121–126PubMedCrossRefGoogle Scholar
  20. Clemens DL, Horwitz MA (1992) Membrane sorting during phagocytosis:selective exclusion of MHC molecules but not complement receptor CR3 during conventional and coiling phagocytosis. J Exp Med 175:1317–1326PubMedCrossRefGoogle Scholar
  21. Clemens, DL, Horwitz MA (1993) Hypoexpression of major histocompatibility complex molecules on Legionella pneumophila phagosomes and phagolysosomes. Infect Immun 61:2803–2812PubMedGoogle Scholar
  22. Clemens DL, Horwitz MA (1995) Characterization of the Mycobacterium tuberculosis phagosome and evidence that phagosomal maturation is inhibited. J Exp Med 181:257–270PubMedCrossRefGoogle Scholar
  23. Crowle A, Dahl R, Ross E, May M (1991) Evidence that vesicles containing living virulent M. tuberculosis or M. avium in cultured human macrophages are not acidic. Infect Immun 59:1823–1831PubMedGoogle Scholar
  24. Drevets DA, Campbell PA (1991) Roles of complement and complement receptor type 3 in phagocytosis of Listeria monocytogenes by inflammatory mouse peritoneal macrophages. Infect Immun 59:2645–2652PubMedGoogle Scholar
  25. Engelberg NC, Pearlman E, Einstein Bl (1984) Legionella pneumophla surface antigens cloned and expressed in E. coli are translocated to the host cell surface and interact with specific anti Legionella antibodies. J Bacteriol 160:199–203Google Scholar
  26. Horwitz MA (1983a) Formation of a novel phagosome by the legionnaires’ disease bacterium Legionella pneumophila) in human monocytes. J Exp Med 158:1319–1331PubMedCrossRefGoogle Scholar
  27. Horwitz MA (1983b) The legionnaires’ disease bacterium (Legionella pneumophila) inhibits phagosome-lysosome fusion in human monocytes. J Exp Med 158:2108–2126PubMedCrossRefGoogle Scholar
  28. Horwitz MA (1983c) Cell-mediated immunity in legionnaires’ disease. J Clin Invest 71:1686–1697PubMedCrossRefGoogle Scholar
  29. Horwitz MA (1984) Phagocytosis of the legionnaires’ disease bacterium (Legionella pneumophila) occurs by a novel mechanism:engulfment within a pseudopod coil. Cell 36:27–33PubMedCrossRefGoogle Scholar
  30. Horwitz MA (1987) Characterization of avirulent mutant Legionella pneumophila that survive but do not multiply within human monocytes. J Exp Med 166:1310–1328PubMedCrossRefGoogle Scholar
  31. Horwitz MA (1989) The immunobiology of Legionella pneumophila. In: Mounder JW (ed) Intracellular parasitism. CRC Press, Boca Raton, pp 141–156Google Scholar
  32. Horwitz MA (1993) State-of-the-art address. Toward an understanding of host and bacterial molecules mediating Legionella pneumophila pathogenesis. Legionella, current status and emerging perspectives. Barbaree J, Breiman R, Dufour AP (eds) In: American Society of Microbiology, Washington DC, pp 55–62Google Scholar
  33. Horwitz MA, Silverstein SC (1981c) Activated human monocytes inhibit the intracellular multiplication of legionnaires’ disease bacteria. J Exp Med 154:1618–1635PubMedCrossRefGoogle Scholar
  34. Horwitz MA, Maxfield FR (1984) Legionella pneumophila inhibits acidification of its phagosome in human monocytes. J Cell Biol 99:1936–1943PubMedCrossRefGoogle Scholar
  35. Jones TC, Hirsch JG (1972) The interaction between Toxoplasma gondii and mammalian cells. II. The absence of lysosomal fusion with phagocytic vacuoles containing living parasites. J Exp Med 136:1173–1194Google Scholar
  36. Horwitz MA, Silverstein SC (1980) The legionnaires’ disease bacterium (Legionella pneumophila) multiplies intracellularly in human monocytes. J Clin Invest 66:441–450PubMedCrossRefGoogle Scholar
  37. Horwitz MA, Silverstein SC (1981a) Interaction of the legionnaires’ disease bacterium (Legionella pneumophila) with human phagocytes. I. L pneumophila resists killing by polymorphonuclear leukocytes, antibody, and complement. J Exp Med 153:386–397PubMedCrossRefGoogle Scholar
  38. Horwitz MA, Silverstein SC (1981b) Interaction of the legionnaires’ disease bacterium (Legionella pneumophila) with human phagocytes. II. Antibody promotes binding of L. pneumophila to monocytes but does not inhibit intracellular multiplication. J Exp Med 153:398–406PubMedCrossRefGoogle Scholar
  39. Jones TC, Yeh S, Hirsch JG (1972) The interaction between Toxoplasma gondii and mammalian cells. I. Mechanism of entry and intracellular fate of the parasite. J Exp Med 136:1157–1172PubMedCrossRefGoogle Scholar
  40. Marra A, Horwitz MA, Shuman HA (1990) The HL-60 model for the interaction of human macrophages with the legionnaires’ disease bacterium. J Immunol 144:2738–2744PubMedGoogle Scholar
  41. Marra A, Blander SJ, Horwitz MA, Shuman HA (1992) Identification of a Legionella pneumophila locus required for intracellular multiplication in human macrophages. Proc Natl Acad Sci USA 89:9607–9611PubMedCrossRefGoogle Scholar
  42. Mengaud, J, MA Horwitz (1993) The major iron-containing protein of Legionella pneumophila is an aconitase homologous with the human iron-responsive element-binding protein. J Bacteriol 175:5666–5676PubMedGoogle Scholar
  43. Moffat JF, Edelstein PH, Regula DP Jr, Cirillo JD, Tompkins LS (1994) Effects of an isogenic Znmetalloprotease-deficient mutant of Legionella pneumophila in a guinea-pig pneumonia model. Mol Microbiol 12:693–705PubMedCrossRefGoogle Scholar
  44. Mosser DM, Edelson PG (1985) The mouse macrophage receptor for C3bi (CR3) is a major mechanism in the phagocytosis of Leishmania promastigotes. J Immunol 135:2785–2789PubMedGoogle Scholar
  45. Nogueira N, Cohn ZA (1976) Trypanosoma cruzi mechanism of entry and intracellular fate in mammalian cells. J Exp Med 143:1402–1420PubMedCrossRefGoogle Scholar
  46. Payne NR, Horwitz MA (1987) Phagocytosis of Legionella pneumophila is mediated by human monocyte complement receptors. J Exp Med 166:1377–1389PubMedCrossRefGoogle Scholar
  47. Quinn FD, Tompkins LS (1989) Analysis of a cloned sequence of Legionella pneumophila encoding a 38-kDa metalloprotease possessing haemolytic and cytotoxic activities. Mol Microbiol 3:797–805PubMedCrossRefGoogle Scholar
  48. Sadosky AB, Wiater LA, Shuman HA (1993) Identification of Legionella pneumophila genes required for growth within and killing of human macrophages. Intact Immun 61:5361–5373Google Scholar
  49. Sadosky AB, Wilson JW, Steinman HM, Shuman HA (1994) The iron Superoxide dismutase of Legionella pneumophila is essential for viability. J Bacteriol 176:3790–3799PubMedGoogle Scholar
  50. Saukkonen K, Cabellos C, Burroughs M, Prasad S, Tuomanen E (1991) Integrin-mediated localization of Bordetella pertussis within macrophages:role in pulmonary colonization. J Exp Med 173:1143–1149PubMedCrossRefGoogle Scholar
  51. Schlesinger LS, Horwitz MA (1990a) Phagocytosis of leprosy bacilli is mediated by complement receptors CR1 and CR3 on human monocytes and complement component C3 in serum. J Clin Invest 85:1304–1314PubMedCrossRefGoogle Scholar
  52. Schlesinger LS, Horwitz MA (1990b) Complement receptors and complement component C3 mediate phagocytosis of Mycobactehum tuberculosis and Mycobacterium leprae. Int J Lepr 58:200–201Google Scholar
  53. Schlesinger LS, Bellinger-Kawahara CG, Payne NR, Horwitz MA (1990) Phagocytosis of Mycobacterium tuberculosis is mediated by human monocyte complement receptors and complement component C3. J Immunol 144:2771–2780PubMedGoogle Scholar
  54. Sibley LD, Weidner E, Krahenbuhl JL (1985) Phagosome acidification blocked by intracellular Toxoplasma gondli. Nature 315:416–419PubMedCrossRefGoogle Scholar
  55. Steinman, HM (1992) Construction of an Escherichia coli K-12 strain deleted for manganese and iron Superoxide dismutase genes and its use in cloning the iron Superoxide dismutase gene of Legionella pneumophila. Mol Gen Genet 232:427–430PubMedCrossRefGoogle Scholar
  56. Stevens DR, Moulton JE (1978) Ultrastructural and immunological aspects of the phagocytosis of Trypanosoma brucei by mouse peritoneal macrophages. Infect Immun 19:972–982PubMedGoogle Scholar
  57. Szczepanski A, Fleit HB (1988) Interaction between Borrelia burgdorferi and polymorphonuclear leukocytes. Phagocytosis and the induction of the respiratory burst. Ann NY Acad Sci 539:425–428CrossRefGoogle Scholar
  58. Szeto L, Shuman HA (1990) The major secreted protein (MSP) of Legionella pneumophila, a protease, is not required for intracellular growth or host cell killng. Infect Immun 58:2585–2592PubMedGoogle Scholar
  59. Tanowitz H, Wittner M, Kress Y, Bloom B (1975) Studies of in vitro infection by Trypanosoma cruzi. I. Ultrastructural studies on the invasion of macrophages and L-cells. Am J Trop Med Hyg 25:25–33Google Scholar
  60. Wiater LA, Sadosky AB, Shuman HA (1994) Transposon mutagenesis of Legionella pneumophila with Tn903dll lacZ identification of a growth phase-regulated pigmentation gene. Mol Microbiol 11:641–653PubMedCrossRefGoogle Scholar
  61. Wilson ME, Pearson RD (1987) Roles of CR3 and mannose receptors in the attachment and ingestion of Leishmania donovani by human mononuclear phagocytes. Infect Immun 56:363–369Google Scholar
  62. Wright SD, Silverstein SC (1983) Receptors for C3b and C3bi promote phagocytosis but not release of toxic oxygen from human phagocytes. J Exp Med 158:2016–2023PubMedCrossRefGoogle Scholar
  63. Wyrick PB, Brownridge EA (1978) Growth of Chlamydia psittaci in macrophages. Infect Immun 19:1054–1060PubMedGoogle Scholar
  64. Yamamoto K, Johnston RB jr (1984) Dissociation of phagocytosis from stimulation of the oxidative metabolic burst in macrophages. J Exp Med 159:405–416PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1996

Authors and Affiliations

  • H. A. Shuman
    • 1
  • M. A. Horwitz
    • 2
  1. 1.Department of Microbiology, College of Physicians and SurgeonsColumbia UniversityNew YorkUSA
  2. 2.Division of Infectious Diseases, Department of Medicine, School of MedicineUniversity of California, Los AngelesLos AngelesUSA

Personalised recommendations