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Legionnaires’ disease and its agent Legionella pneumophila

  • Dina M. Bitar
  • Marina Santic
  • Yousef Abu Kwaik
  • Maëlle Molmeret
Part of the Birkhäuser Advances in Infectious Diseases book series (BAID)

Abstract

Legionella pneumophila, the agent responsible for Legionnaire’s disease, is a facultative intracellular pathogen that can replicate within protozoa and macrophages. Protozoa are considered to play a central role in the pathogenesis and ecology of L. pneumophila. In humans, L. pneumophila reaches the lungs, where it is ingested by alveolar macrophages. Unlike phagosomes containing inert particles or avirulent bacteria, the L. pneumophila-containing vacuoles avoid fusion with lysosomes, recruiting rough endoplasmic reticulum and mitochondria. The formation of this specialized vacuole is directed by the type IV secretion system encoded by the dot/icm genes in mammalian and protozoan cells. Killing of mammalian cells by L. pneumophila has been proposed to occur through induction of apoptosis during the early stages of the infection. A rapid induction of necrosis by L. pneumophila also occurs upon entry into the post-exponential phase of growth within both macrophages and protozoa, when the bacteria become cytotoxic. Before the lysis of the mammalian or protozoan plasma membrane, the bacteria egress into the cytoplasm. In vivo, clearance of Legionella from the lungs depends on the host production of IFN-γ in A/J mice, while in BALB/c mice IFN-γ is not produced. Intracellular replication of L. pneumophila is inhibited in IFN-γ-activated mouse and human primary macrophages. Both antigen-specific humoral and cell-mediated immune responses are induced during Legionella infection. Although Legionella-specific antibodies are produced during human or murine infection, acquired cell-mediated immune response is believed to play a stronger role in Legionella clearance. Both macrophages and DCs are able to present microbial antigens on major histocompatibility class I and class II molecules, which stimulate antigen-specific T-cell response. Identification of antigens and determination of vesicular trafficking mechanisms involved in processing and presentation remain to be understood in greater detail.

Keywords

Secretion System Intracellular Growth Intracellular Replication Acanthamoeba Castellanii Phagosomal Membrane 
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.

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References

  1. 1.
    Fraser DW, Tsai TR, Orenstein W, Parkin WE, Beecham HJ, Sharrar RG, Harris J, Mallison GF, Martin SM, McDade JE et al (1977) Legionnaires’ disease: description of an epidemic of pneumonia. N Engl J Med 297: 1189–1197PubMedGoogle Scholar
  2. 2.
    McDade JE, Shepard CC, Fraser DW, Tsai TR, Redus MA, Dowdle WR (1977) Legionnaires’ disease: isolation of a bacterium and demonstration of its role in other respiratory disease. N Engl J Med 297: 1197–1203PubMedGoogle Scholar
  3. 3.
    Adeleke AA, Fields BS, Benson RF, Daneshvar MI, Pruckler JM, Ratcliff RM, Harrison TG, Weyant RS, Birtles RJ, Raoult D et al (2001) Legionella drozanskii sp nov, Legionella rowbothamii sp nov and Legionella fallonii sp nov: three unusual new Legionella species. Int J Syst Evol Microbiol 51(Pt 3): 1151–1160PubMedGoogle Scholar
  4. 4.
    Rodriguez-Zaragoza S (1994) Ecology of free-living amoebae. Crit Rev Microbiol 20(3): 225–241PubMedGoogle Scholar
  5. 5.
    Murga R, Forster TS, Brown E, Pruckler JM, Fields BS, Donlan RM (2001) Role of biofilms in the survival of Legionella pneumophila in a model potablewater system. Microbiology 147(Pt 11): 3121–3126PubMedGoogle Scholar
  6. 6.
    Sheehan KB, Henson JM, Ferris MJ (2005) Legionella species diversity in an acidic biofilm community in Yellowstone National Park. Appl EnvironMicrobiol 71(1): 507–11Google Scholar
  7. 7.
    Rowbotham TJ (1980) Preliminary report on the pathogenicity of Legionella pneumophila for freshwater and soil amoebae. J Clin Pathol 33: 1179–1183PubMedGoogle Scholar
  8. 8.
    Rowbotham TJ (1986) Current views on the relationships between amoebae, legionellae and man. Isr J Med Sci 22: 678–689PubMedGoogle Scholar
  9. 9.
    Molmeret M, Horn M, Wagner M, Santic M, Abu Kwaik Y (2005) Amoebae as training grounds for intracellular bacterial pathogens. Appl Environ Microbiol 71(1): 20–8PubMedGoogle Scholar
  10. 10.
    Newsome AL, Baker RL, Miller RD, Arnold RR (1985) Interactions between Naegleria fowleri and Legionella pneumophila. Infect Immun 50: 449–452PubMedGoogle Scholar
  11. 11.
    Abu Kwaik Y (1996) The phagosome containing Legionella pneumophila within the protozoan Hartmanella vermiformis is surrounded by the rough endoplasmic reticulum. Appl Environ Microbiol 62: 2022–2028PubMedGoogle Scholar
  12. 12.
    Bozue JA, Johnson W (1996) Interaction of Legionella pneumophila with Acanthamoeba catellanii: uptake by coiling phagocytosis and inhibition of phagosome-lysosome fusion. Infect Immun 64: 668–673PubMedGoogle Scholar
  13. 13.
    Barker J, Brown MR (1994) Trojan horses of the microbial world: protozoa and the survival of bacterial pathogens in the environment. Microbiology 140 (Pt 6): 1253–1259PubMedGoogle Scholar
  14. 14.
    Gao L-Y, Harb OS, Abu Kwaik Y (1997) Utilization of similar mechanisms by Legionella pneumophila to parasitize two evolutionarily distant hosts, mammalian and protozoan cells. Infect Immun 65: 4738–4746PubMedGoogle Scholar
  15. 15.
    Segal G, Shuman HA (1999) Legionella pneumophila utilizes the same genes to multiply within Acanthamoeba castellanii and human macrophages. Infect Immun 67: 2117–2124PubMedGoogle Scholar
  16. 16.
    Christie PJ, Vogel JP (2000) Bacterial type IV secretion: conjugation systems adapted to deliver effector molecules to host cells. Trends Microbiol 8(8): 354–360PubMedGoogle Scholar
  17. 17.
    Segal G, Shuman HA (1997) Characterization of a new region required for macrophage killing by Legionella pneumophila. Infect Immun 65(12): 5057–5066PubMedGoogle Scholar
  18. 18.
    Brand B, Sadosky AB, Shuman HA (1994) The Legionella pneumophila icm locus: a set of genes required for intracellular multiplication in human macrophages. Mol Microbiol 14: 797–808PubMedGoogle Scholar
  19. 19.
    Berger KH, Isberg RR (1993) Two distinct defects in intracellular growth complemented by a single genetic locus in Legionella pneumophila. Mol Microbiol 7: 7–19PubMedGoogle Scholar
  20. 20.
    Chen J, de Felipe KS, Clarke M, Lu H, Anderson OR, Segal G, Shuman HA (2004) Legionella effectors that promote nonlytic release from protozoa. Science 303(5662): 1358–1361PubMedGoogle Scholar
  21. 21.
    Nagai H, Kagan JC, Zhu X, Kahn RA, Roy CR (2002) A bacterial guanine nucleotide exchange factor activates ARF on Legionella phagosomes. Science 295(5555): 679–682PubMedGoogle Scholar
  22. 22.
    Luo ZQ, Isberg RR (2004) Multiple substrates of the Legionella pneumophila Dot/Icm system identified by interbacterial protein transfer. Proc Natl Acad SciUSA 101(3): 841–846Google Scholar
  23. 23.
    Conover GM, Derre I, Vogel JP, Isberg RR (2003) The Legionella pneumophila LidA protein: a translocated substrate of the Dot/Icm system associated with maintenance of bacterial integrity. Mol Microbiol 48(2): 305–321PubMedGoogle Scholar
  24. 24.
    Komano T, Yoshida T, Narahara K, Furuya N (2000) The transfer region of IncI1 plasmid R64: similarities between R64 tra and legionella icm/dot genes. Mol Microbiol 35(6): 1348–1359PubMedGoogle Scholar
  25. 25.
    Segal G, Purcell M, Shuman HA (1998) Host cell killing and bacterial conjugation require overlapping sets of genes within a 22-kb region of the Legionella pneumophila chromosome. Proc Natl Acad Sci USA 95: 1669–1674PubMedGoogle Scholar
  26. 26.
    Segal G, Russo JJ, Shuman HA (1999) Relationships between a new type IV secretion system and the icm/dot virulence system of Legionella pneumophila. Mol Microbiol 34(4): 799–809PubMedGoogle Scholar
  27. 27.
    Vogel JP, Andrews HL, Wong SK, Isberg RR (1998) Conjugative transfer by the virulence system of Legionella pneumophila. Science 279: 873–876PubMedGoogle Scholar
  28. 28.
    Sexton JA, Vogel JP (2002) Type IVB secretion by intracellular pathogens. Traffic 3(3): 178–185PubMedGoogle Scholar
  29. 29.
    Seshadri R, Paulsen IT, Eisen JA, Read TD, Nelson KE, Nelson WC, Ward NL, Tettelin H, Davidsen TM, Beanan MJ et al (2003) Complete genome sequence of the Q-fever pathogen Coxiella burnetii. Proc Natl Acad Sci USA 100(9): 5455–5460PubMedGoogle Scholar
  30. 30.
    Zamboni DS, McGrath S, Rabinovitch M, Roy CR (2003) Coxiella burnetii express type IV secretion system proteins that function similarly to components of the Legionella pneumophila Dot/Icm system. Mol Microbiol 49(4): 965–976PubMedGoogle Scholar
  31. 31.
    Zusman T, Yerushalmi G, Segal G (2003) Functional similarities between the icm/dot pathogenesis systems of Coxiella burnetii and Legionella pneumophila. Infect Immun 71(7): 3714–3723PubMedGoogle Scholar
  32. 32.
    Feldman M, Zusman T, Hagag S, Segal G (2005) Coevolution between nonhomologous but functionally similar proteins and their conserved partners in the Legionella pathogenesis system. Proc Natl Acad Sci USA 102(34): 12206–12211PubMedGoogle Scholar
  33. 33.
    Segal G, Feldman M, Zusman T (2005) The Icm/Dot type-IV secretion systems of Legionella pneumophila and Coxiella burnetii. FEMS Microbiol Rev 29(1): 65–81Google Scholar
  34. 34.
    Fields BS (1996) The molecular ecology of legionellae. Trends Microbiol 4: 286–290PubMedGoogle Scholar
  35. 35.
    Shadrach WS, Rydzewski K, Laube U, Holland G, Ozel M, Kiderlen AF, Flieger A (2005) Balamuthia mandrillaris, free-living ameba and opportunistic agent of encephalitis, is a potential host for Legionella pneumophila bacteria. Appl Environ Microbiol 71(5): 2244–2249PubMedGoogle Scholar
  36. 36.
    Harb OS, Gao L-Y, Abu Kwaik Y (2000) From protozoa to mammalian cells: A new paradigm in the life cycle of intracellular bacterial pathogens. Environ Microbiol 2: 251–265PubMedGoogle Scholar
  37. 37.
    Fliermans CB (1996) Ecology of Legionella: From data to knowledge with a little wisdom. Microb Ecol 32(2): 203–228PubMedGoogle Scholar
  38. 38.
    Fields BS, Benson RF, Besser RE (2002) Legionella and Legionnaires’ disease: 25 years of investigation. Clin Microbiol Rev 15(3): 506–526PubMedGoogle Scholar
  39. 39.
    Molmeret M, Bitar DM, Han L, Kwaik YA (2004) Cell biology of the intracellular infection by Legionella pneumophila. Microbes Infect 6(1): 129–139PubMedGoogle Scholar
  40. 40.
    Rowbotham TJ (1983) Isolation of Legionella pneumophila from clinical specimens via amoebae, and the interaction of those and other isolates with amoebae. J Clin Pathol 36: 978–986PubMedGoogle Scholar
  41. 41.
    Adeleke A, Pruckler J, Benson R, Rowbotham T, Halablab M, Fields BS (1996) Legionella-like amoebal pathogens-phylogenetic status and possible role in respiratory disease. Emerg Infect Dis 2: 225–229PubMedGoogle Scholar
  42. 42.
    Marrie TJ, Raoult D, La Scola B, Birtles RJ, de Carolis E (2001) Legionella-like and other amoebal pathogens as agents of community-acquired pneumonia. Emerg Infect Dis 7(6): 1026–1029PubMedGoogle Scholar
  43. 43.
    Birtles RJ, Rowbotham TJ, Raoult D, Harrison TG (1996) Phylogenetic diversity of intra-amoebal legionellae as revealed by 16S rRNA gene sequence comparison. Microbiology 142 (Pt 12): 3525–3530PubMedGoogle Scholar
  44. 44.
    Muraca P, Stout JE, Yu VL (1987) Comparative assessment of chlorine, heat, ozone, and UV light for killing Legionella pneumophila within a model plumbing system. Appl Environ Microbiol 53: 447–453PubMedGoogle Scholar
  45. 45.
    Kool JL, Carpenter JC, Fields BS (1999) Effect of monochloramine disinfection of municipal drinking water on risk of nosocomial Legionnaires’ disease. Lancet 353(9149): 272–7PubMedGoogle Scholar
  46. 46.
    Biurrun A, Caballero L, Pelaz C, Leon E, Gago A (1999) Treatment of a Legionella pneumophila-colonized water distribution system using coppersilver ionization and continuous chlorination. Infect Control Hosp Epidemiol 20(6): 426–8PubMedGoogle Scholar
  47. 47.
    Yamamoto H, Ezaki T, Ikedo M, Yabuuchi E (1991) Effects of biocidal treatments to inhibit the growth of legionellae and other microorganisms in cooling towers. Microbiol Immunol 35: 795–802PubMedGoogle Scholar
  48. 48.
    Kusnetsov J, Iivanainen E, Elomaa N, Zacheus O, Martikainen PJ (2001) Copper and silver ions more effective against legionellae than against mycobacteria in a hospital warm water system. Water Res 35(17): 4217–4225PubMedGoogle Scholar
  49. 49.
    Darelid J, Lofgren S, Malmvall BE (2002) Control of nosocomial Legionnaires’ disease by keeping the circulating hot water temperature above 55 degrees C: experience from a 10-year surveillance programme in a district general hospital. J Hosp Infect 50(3): 213–219PubMedGoogle Scholar
  50. 50.
    Hoebe CJ, Kool JL (2000) Control of Legionella in drinking-water systems. Lancet 355(9221): 2093–2094PubMedGoogle Scholar
  51. 51.
    Barker J, Brown MRW, Collier PJ, Farrell I, Gilbert P (1992) Relationships between Legionella pneumophila and Acanthamoebae polyphaga: physiologi cal status and susceptibility to chemical inactivation. Appl Environ Microbiol 58: 2420–2425PubMedGoogle Scholar
  52. 52.
    Abu Kwaik Y, Gao L-Y, Harb OS, Stone BJ (1997) Transcriptional regulation of the macrophage-induced gene (gspA) of Legionella pneumophila and phenotypic characterization of a null mutant. Mol Microbiol 24: 629–642PubMedGoogle Scholar
  53. 53.
    Berk SG, Ting RS, Turner GW, Ashburn RJ (1998) Production of respirable vesicles containing live Legionella pneumophila cells by two Acanthamoeba spp. Appl Environ Microbiol 64: 279–286PubMedGoogle Scholar
  54. 54.
    Barker J, Scaife H, Brown MRW (1995) Intraphagocytic growth induces an antibiotic-resistant phenotype of Legionella pneumophila. Antimicrob Agents Chemother 39: 2684–2688PubMedGoogle Scholar
  55. 55.
    Abu Kwaik Y, Gao L-Y, Stone BJ, Venkataraman C, Harb OS (1998) Invasion of protozoa by Legionella pneumophila and its role in bacterial ecology and pathogenesis. Appl Environ Microbiol 64: 3127–3133PubMedGoogle Scholar
  56. 56.
    Fields BS, Nerad TA, Sawyer TK, King CH, Barbaree JM, Martin WT, Morrill WE, Sanden GN (1990) Characterization of an axenic strain of Hartmannella vermiformis obtained from an investigation of nosocomial legionellosis. J Protozool 37: 581–583PubMedGoogle Scholar
  57. 57.
    Byrne B, Swanson MS (1998) Expression of Legionella pneumophila virulence traits in response to growth conditions. Infect Immun 66: 3029–3034PubMedGoogle Scholar
  58. 58.
    Hammer BK, Swanson MS (1999) Co-ordination of Legionella pneumophila virulence with entry into stationary phase by ppGpp. Mol Microbiol 33(4): 721–731PubMedGoogle Scholar
  59. 59.
    Hammer BK, Tateda ES, Swanson MS (2002) A two-component regulator induces the transmission phenotype of stationary-phase Legionella pneumophila. Mol Microbiol 44(1): 107–118PubMedGoogle Scholar
  60. 60.
    Barker J, Lambert PA, Brown MRW (1993) Influence of intra-amoebic and other growth conditions on the surface properties of Legionella pneumophila. Infect Immun 61: 3503–3510PubMedGoogle Scholar
  61. 61.
    Cirillo JD, Tompkins LS, Falkow S (1994) Growth of Legionella pneumophila in Acanthamoeba castellanii enhances invasion. Infect Immun 62: 3254–3261PubMedGoogle Scholar
  62. 62.
    Brieland JK, Fantone JC, Remick DG, LeGendre M, McClain M, Engleberg NC (1997) The role of Legionella pneumophila-infected Hartmanella vermiformisas an infectious particle in a murine model of Legionnaires’ disease. Infect Immun 65: 4892–4896PubMedGoogle Scholar
  63. 63.
    O’Brien SJ, Bhopal RS (1993) Legionnaires’ disease: the infective dose paradox. Lancet 342: 5–6PubMedGoogle Scholar
  64. 64.
    Steinert M, Emody L, Amann R, Hacker J (1997) Resuscitation of viable but nonculturable Legionella pneumophila Philadelphia JR32 by Acanthamoeba castellanii. Appl Environ Microbiol 63: 2047–2053PubMedGoogle Scholar
  65. 65.
    Venkataraman C, Haack BJ, Bondada S, Abu Kwaik Y (1997) Identification of a Gal/GalNAc lectin in the protozoan Hartmannella vermiformis as a potential receptor for attachment and invasion by the Legionnaires’ disease bacterium, Legionella pneumophila. J Exp Med 186: 537–547PubMedGoogle Scholar
  66. 66.
    Harb OS, Venkataraman C, Haack BJ, Gao L-Y, Abu Kwaik Y (1998) Heterogeneity in the attachment and uptake mechanisms of the Legionnaires’ disease bacterium, Legionella pneumophila, by protozoan hosts. Appl Environ Microbiol 64: 126–132PubMedGoogle Scholar
  67. 67.
    Mann BJ, Torian BE, Vedvick TS, Petri WAJ (1991) Sequence of a cysteine-rich galactose-specific lectin of Entamoeba histolytica. Proc Natl Acad Sci USA 88: 3248–3252PubMedGoogle Scholar
  68. 68.
    Venkataraman C, Gao L-Y, Bondada S, Abu Kwaik Y (1998) Identification of putative cytoskeletal protein homologues in the protozoan Hartmannella vermiformis as substrates for induced tyrosine phosphatase activity upon attachment to the Legionnaires’ disease bacterium, Legionella pneumophila. J Exp Med 188: 505–514PubMedGoogle Scholar
  69. 69.
    Abu Kwaik Y, Venkataraman C, Gao L-Y, Harb OS (1998) Signal transduction in the protozoan host Hartmannella vermiformis upon attachment and invasion by its bacterial parasite, the Legionnaires’ disease agent, Legionella micdadei. Appl Environ Microbiol 64: 3134–3139PubMedGoogle Scholar
  70. 70.
    Abu Kwaik Y, Fields BS, Engleberg NC (1994) Protein expression by the protozoan Hartmannella vermiformis upon contact with its bacterial parasite Legionella pneumophila. Infect Immun 62: 1860–1866PubMedGoogle Scholar
  71. 71.
    Horwitz MA (1984) Phagocytosis of the Legionnaires’ disease bacterium (Legionella pneumophila) occurs by a novel mechanism: engulfment within a pseudopod coil. Cell 36: 27–33PubMedGoogle Scholar
  72. 72.
    Hilbi H, Segal G, Shuman HA (2001) Icm/dot-dependent upregulation of phagocytosis by Legionella pneumophila. Mol Microbiol 42(3): 603–617PubMedGoogle Scholar
  73. 73.
    Horwitz MA, Silverstein SC (1981) 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: 398–406PubMedGoogle Scholar
  74. 74.
    Payne NR, Horwitz MA (1987) Phagocytosis of Legionella pneumophila is mediated by human monocyte complement receptors. J Exp Med 166: 1377–1389PubMedGoogle Scholar
  75. 75.
    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
  76. 76.
    Cirillo JD, Cirillo SL, Yan L, Bermudez LE, Falkow S, Tompkins LS (1999) Intracellular growth in Acanthamoeba castellanii affects monocyte entry mechanisms and enhances virulence of Legionella pneumophila. Infect Immun 67(9): 4427–4434PubMedGoogle Scholar
  77. 77.
    Watarai M, Derre I, Kirby J, Growney JD, Dietrich WF, Isberg RR (2001) Legionella pneumophila is internalized by a macropinocytotic uptake pathway controlled by the Dot/Icm system and the mouse Lgn1 locus. J Exp Med 194(8): 1081–1096PubMedGoogle Scholar
  78. 78.
    Bandyopadhyay P, Xiao H, Coleman HA, Price-Whelan A, Steinman HM (2004) Icm/dot-independent entry of Legionella pneumophila into amoeba and macrophage hosts. Infect Immun 72(8): 4541–4551PubMedGoogle Scholar
  79. 79.
    Cirillo SL, Lum J, Cirillo JD (2000) Identification of novel loci involved in entry by Legionella pneumophila. Microbiology 146(Pt 6): 1345–1359PubMedGoogle Scholar
  80. 80.
    Cirillo SL, Bermudez LE, El-Etr SH, Duhamel GE, Cirillo JD (2001) Legionella pneumophila entry gene rtxA is involved in virulence. Infect Immun 69(1): 508–17PubMedGoogle Scholar
  81. 81.
    Abu Kwaik Y (1998) Fatal attraction of mammalian cells to Legionella pneumophila. Mol Microbiol 30: 689–696Google Scholar
  82. 82.
    Elliott JA, Winn WC Jr (1986) Treatment of alveolar macrophages with cytochalasin D inhibits uptake and subsequent growth of Legionella pneumophila. Infect Immun 51: 31–36PubMedGoogle Scholar
  83. 83.
    Rechnitzer C, Blom J (1989) Engulfment of the Philadelphia strain of Legionella pneumophila within pseudopod coils in human phagocytes. Comparison with the other Legionella strains and species. Acta Pathol Microbiol Immunol Scand [B] 97: 105–114Google Scholar
  84. 84.
    Weinbaum DL, Benner RR, Dowling JN, Alpern A, Pasculle AW, Donowitz GR (1984) Interaction of Legionella micdadei with human monocytes. Infect Immun 46: 68–73PubMedGoogle Scholar
  85. 85.
    Dowling JN, Saha AK, Glew RH (1992) Virulence factors of the family Legionellaceae. Microbiol Rev 56: 32–60PubMedGoogle Scholar
  86. 86.
    Yamamoto Y, Klein TW, Friedman H (1992) Genetic control of macrophage susceptibility to infection by Legionella pneumophila. FEMS Microbiol Immunol 89: 137–146Google Scholar
  87. 87.
    Beckers MC, Yoshida S, Morgan K, Skamene E, Gros P (1995) Natural resistance to infection with Legionella pneumophila: chromosomal localization of the Lgn1 susceptibility gene. Mamm Genome 6(8): 540–545PubMedGoogle Scholar
  88. 88.
    Beckers MC, Ernst E, Diez E, Morissette C, Gervais F, Hunter K, Housman D, Yoshida S, Skamene E, Gros P (1997) High-resolution linkage map of mouse chromosome 13 in the vicinity of the host resistance locus Lgn1. Genomics 39(3): 254–263PubMedGoogle Scholar
  89. 89.
    Dietrich WF, Damron DM, Isberg RR, Lander ES, Swanson MS (1995) Lgn1, a gene that determines susceptibility to Legionella pneumophila, maps to mouse chromosome 13. Genomics 26(3): 443–50PubMedGoogle Scholar
  90. 90.
    Miyamoto H, Maruta K, Ogawa M, Beckers MC, Gros P, Yoshida S (1996) Spectrum of Legionella species whose intracellular multiplication in murine macrophages is genetically controlled by Lgn1. Infect Immun 64(5): 1842–5PubMedGoogle Scholar
  91. 91.
    Maier JK, Lahoua Z, Gendron NH, Fetni R, Johnston A, Davoodi J, Rasper D, Roy S, Slack RS, Nicholson DW et al (2002) The neuronal apoptosis inhibitory protein is a direct inhibitor of caspases 3 and 7. J Neurosci 22(6): 2035–2043PubMedGoogle Scholar
  92. 92.
    Wright EK, Goodart SA, Growney JD, Hadinoto V, Endrizzi MG, Long EM, Sadigh K, Abney AL, Bernstein-Hanley I, Dietrich WF (2003) Naip5 affects host susceptibility to the intracellular pathogen Legionella pneumophila. Curr Biol 13(1): 27–36PubMedGoogle Scholar
  93. 93.
    Diez E, Lee SH, Gauthier S, Yaraghi Z, Tremblay M, Vidal S, Gros P (2003) Birc1e is the gene within the Lgn1 locus associated with resistance to Legionella pneumophila. Nat Genet 33(1): 55–60PubMedGoogle Scholar
  94. 94.
    Kirby JE, Isberg RR (1998) Legionnaires’ disease: the pore macrophage and the legion of terror within. Trends Microbiol 6: 256–258PubMedGoogle Scholar
  95. 95.
    Kirby JE, Vogel JP, Andrews HL, Isberg RR (1998) Evidence for pore-forming ability by Legionella pneumophila. Mol Microbiol 27: 323–336PubMedGoogle Scholar
  96. 96.
    Coers J, Monahan C, Roy CR (1999) Modulation of phagosome biogenesis by Legionella pneumophila creates an organelle permissive for intracellular growth. Nat Cell Biol 1(7): 451–453PubMedGoogle Scholar
  97. 97.
    Katz SM, Hashemi S (1982) Electron microscopic examination of the inflammatory response to Legionella pneumophila in guinea pigs. Lab Invest 46: 24–32PubMedGoogle Scholar
  98. 98.
    Horwitz MA (1983) Formation of a novel phagosome by the Legionnaires’ disease bacterium (Legionella pneumophila) in human monocytes. J Exp Med 158: 1319–1331PubMedGoogle Scholar
  99. 99.
    Tilney LG, Harb OS, Connelly PS, Robinson CG, Roy CR (2001) How the parasitic bacterium Legionella pneumophila modifies its phagosome and transforms it into rough ER: implications for conversion of plasma membrane to the ER membrane. J Cell Sci 114 (Pt 24): 4637–4650PubMedGoogle Scholar
  100. 100.
    Swanson MS, Isberg RR (1995) Formation of the Legionella pneumophila replicative phagosome. Infect Agents Dis 2: 269–271Google Scholar
  101. 101.
    Horwitz MA (1983) The Legionnaires’ disease bacterium (Legionella pneumophila) inhibits phagosome-lysosome fusion in human monocytes. J Exp Med 158: 2108–2126PubMedGoogle Scholar
  102. 102.
    Horwitz MA, Maxfield FR (1984) Legionella pneumophila inhibits acidification of its phagosome in human monocytes. J Cell Biol 99: 1936–1943PubMedGoogle Scholar
  103. 103.
    Gao L-Y, Susa M, Ticac B, Abu Kwaik Y (1999) Heterogeneity in intracellular replication and cytopathogenicity of Legionella pneumophila and Legionella micdadei in mammalian and protozoan cells. Microb Pathog 27: 273–287PubMedGoogle Scholar
  104. 104.
    Roy CR, Tilney LG (2002) The road less traveled: transport of Legionella to the endoplasmic reticulum. J Cell Biol 158(3): 415–419PubMedGoogle Scholar
  105. 105.
    Swanson MS, Isberg RR (1995) Association of Legionella pneumophila with the macrophage endoplasmic reticulum. Infect Immun 63: 3609–3620PubMedGoogle Scholar
  106. 106.
    Kagan JC, Roy CR (2002) Legionella phagosomes intercept vesicular traffic from endoplasmic reticulum exit sites. Nat Cell Biol 4(12): 945–54PubMedGoogle Scholar
  107. 107.
    Kagan JC, Stein MP, Pypaert M, Roy CR (2004) Legionella subvert the functions of Rab1 and Sec22b to create a replicative organelle. J Exp Med 199(9): 1201–1211PubMedGoogle Scholar
  108. 108.
    Derre I, Isberg RR (2004) Legionella pneumophila replication vacuole formation involves rapid recruitment of proteins of the early secretory system. Infect Immun 72(5): 3048–3053PubMedGoogle Scholar
  109. 109.
    Abu Kwaik Y (1998) Induced expression of the Legionella pneumophila gene encoding a 20-kilodalton protein during intracellular infection. Infect Immun 66: 203–212PubMedGoogle Scholar
  110. 110.
    Hagele S, Kohler R, Merkert H, Schleicher M, Hacker J, Steinert M (2000) Dictyostelium discoideum: a new host model system for intracellular pathogens of the genus Legionella. Cell Microbiol 2(2): 165–171PubMedGoogle Scholar
  111. 111.
    Solomon JM, Isberg RR (2000) Growth of Legionella pneumophila in Dictyostelium discoideum: a novel system for genetic analysis of host-pathogen interactions. i 8(10): 478–480Google Scholar
  112. 112.
    Li Z, Solomon JM, Isberg RR (2005) Dictyostelium discoideum strains lacking the RtoA protein are defective for maturation of the Legionella pneumophila replication vacuole. Cell Microbiol 7(3): 431–442PubMedGoogle Scholar
  113. 113.
    Fajardo M, Schleicher M, Noegel A, Bozzaro S, Killinger S, Heuner K, Hacker J, Steinert M (2004) Calnexin, calreticulin and cytoskeleton-associated proteins modulate uptake and growth of Legionella pneumophila in Dictyostelium discoideum. Microbiology 150(Pt 9): 2825–2835PubMedGoogle Scholar
  114. 114.
    Otto GP, Wu MY, Clarke M, Lu H, Anderson OR, Hilbi H, Shuman HA, Kessin RH (2004) Macroautophagy is dispensable for intracellular replication of Legionella pneumophila in Dictyostelium discoideum. Mol Microbiol 51(1): 63–72PubMedGoogle Scholar
  115. 115.
    Alli OA, Zink S, von Lackum NK, Abu-Kwaik Y (2003) Comparative assessment of virulence traits in Legionella spp. Microbiology 149(Pt 3): 631–641PubMedGoogle Scholar
  116. 116.
    Gao L-Y, Harb OS, Abu Kwaik Y (1998) Identification of macrophage-specific infectivity loci (mil) of Legionella pneumophila that are not required for infectivity of protozoa. Infect Immun 66: 883–892PubMedGoogle Scholar
  117. 117.
    Cianciotto NP, Fields BS (1992) Legionella pneumophila mip gene potentiates intracellular infection of protozoa and human macrophages. Proc Natl Acad Sci USA 89: 5188–5191PubMedGoogle Scholar
  118. 118.
    Stone BJ, Brier A, Kwaik YA (1999) The Legionella pneumophila prp locus; required during infection of macrophages and amoebae. Microb Pathog 27(6): 369–376PubMedGoogle Scholar
  119. 119.
    Solomon JM, Rupper A, Cardelli JA, Isberg RR (2000) Intracellular growth of Legionella pneumophila in Dictyostelium discoideum, a system for genetic analysis of host-pathogen interactions. Infect Immun 68(5): 2939–2947PubMedGoogle Scholar
  120. 120.
    Nagai H, Cambronne ED, Kagan JC, Amor JC, Kahn RA, Roy CR (2005) A C-terminal translocation signal required for Dot/Icm-dependent delivery of the Legionella RalF protein to host cells. Proc Natl Acad Sci USA 102(3): 826–831PubMedGoogle Scholar
  121. 121.
    Coers J, Kagan JC, Matthews M, Nagai H, Zuckman DM, Roy CR (2000) Identification of icm protein complexes that play distinct roles in the biogenesis of an organelle permissive for Legionella pneumophila intracellular growth. Mol Microbiol 38(4): 719–736PubMedGoogle Scholar
  122. 122.
    Feldman MF, Cornelis GR (2003) The multitalented type III chaperones: all you can do with 15 kDa. FEMS Microbiol Lett 219(2): 151–158PubMedGoogle Scholar
  123. 123.
    Bardill JP, Miller JL, Vogel JP (2005) IcmS-dependent translocation of SdeA into macrophages by the Legionella pneumophila type IV secretion system. Mol Microbiol 56(1): 90–103PubMedGoogle Scholar
  124. 124.
    Ninio S, Zuckman-Cholon DM, Cambronne ED, Roy CR (2005) The Legionella IcmS-IcmW protein complex is important for Dot/Icm-mediated protein translocation. Mol Microbiol 55(3): 912–926PubMedGoogle Scholar
  125. 125.
    Bachman MA, Swanson MS (2001) RpoS co-operates with other factors to induce Legionella pneumophila virulence in the stationary phase. Mol Microbiol 40(5): 1201–1214PubMedGoogle Scholar
  126. 126.
    Hales LM, Shuman HA (1999) The Legionella pneumophila rpoS gene is required for growth within Acanthamoeba castellanii. J Bacteriol 181(16): 4879–4889PubMedGoogle Scholar
  127. 127.
    Samrakandi MM, Cirillo SL, Ridenour DA, Bermudez LE, Cirillo JD (2002) Genetic and phenotypic differences between Legionella pneumophila strains. J Clin Microbiol 40(4): 1352–1362PubMedGoogle Scholar
  128. 128.
    Zusman T, Gal-Mor O, Segal G (2002) Characterization of a Legionella pneumophila relA insertion mutant and toles of RelA and RpoS in virulence gene expression. J Bacteriol 184(1): 67–75PubMedGoogle Scholar
  129. 129.
    Fettes PS, Forsbach-Birk V, Lynch D, Marre R (2001) Overexpresssion of a Legionella pneumophila homologue of the E. coli regulator csrA affects cell size, flagellation, and pigmentation. Int J Med Microbiol 291(5): 353–360PubMedGoogle Scholar
  130. 130.
    Lynch D, Fieser N, Gloggler K, Forsbach-Birk V, Marre R (2003) The response regulator LetA regulates the stationary-phase stress response in Legionella pneumophila and is required for efficient infection of Acanthamoeba castellanii. FEMS Microbiol Lett 219(2): 241–248PubMedGoogle Scholar
  131. 131.
    Gal-Mor O, Segal G (2003) The Legionella pneumophila GacA homolog (LetA) is involved in the regulation of icm virulence genes and is required for intracellular multiplication in Acanthamoeba castellanii. Microb Pathog 34(4): 187–194PubMedGoogle Scholar
  132. 132.
    Cohen JJ (1993) Overview: Mechanisms of apoptosis. Immunol Today 14: 126–130PubMedGoogle Scholar
  133. 133.
    Gao L-Y, Abu Kwaik Y (1999) Apoptosis in macrophages and alveolar epithelial cells during early stages of infection by Legionella pneumophila and its role in cytopathogenicity. Infect Immun 67: 862–870PubMedGoogle Scholar
  134. 134.
    Gao L-Y, Abu Kwaik Y (1999) Activation of caspase-3 in Legionella pneumophila-induced apoptosis in macrophages. Infect Immun 67(9): 4886–4894PubMedGoogle Scholar
  135. 135.
    Hagele S, Hacker J, Brand BC (1998) Legionella pneumophila kills human phagocytes but not protozoan host cells by inducing apoptotic cell death. FEMS Microbiol Lett 169(1): 51–58PubMedGoogle Scholar
  136. 136.
    Molmeret M, Zink SD, Han L, Abu-Zant A, Asari R, Bitar DM, Abu Kwaik Y (2004) Activation of caspase-3 by the Dot/Icm virulence system is essential for arrested biogenesis of the Legionella-containing phagosome. Cell Microbiol 6(1): 33–48PubMedGoogle Scholar
  137. 137.
    Zink SD, Pedersen L, Cianciotto NP, Abu-Kwaik Y (2002) The Dot/Icm type IV secretion system of Legionella pneumophila is essential for the induction of apoptosis in human macrophages. Infect Immun 70(3): 1657–1663PubMedGoogle Scholar
  138. 138.
    Alli OAT, Gao L-Y, Pedersen LL, Zink S, Radulic M, Doric M, Abu Kwaik Y (2000) Temporal pore formation-mediated egress from macrophages and alveolar epithelial cells by Legionella pneumophila. Infect Immun 68: 6431–6440PubMedGoogle Scholar
  139. 139.
    Molmeret M, Alli OA, Zink S, Flieger A, Cianciotto NP, Kwaik YA (2002) icmT is essential for pore formation-mediated egress of Legionella pneumophila from mammalian and protozoan cells. Infect Immun 70(1): 69–78PubMedGoogle Scholar
  140. 140.
    Molmeret M, Bitar DM, Han L, Kwaik YA (2004) Disruption of the phagosomal membrane and egress of Legionella pneumophila into the cytoplasm during the last stages of intracellular infection of macrophages and Acanthamoeba polyphaga. Infect Immun 72(7): 4040–4051PubMedGoogle Scholar
  141. 141.
    Arnoult D, Tatischeff I, Estaquier J, Girard M, Sureau F, Tissier JP, Grodet A, Dellinger M, Traincard F, Kahn A et al (2001) On the evolutionary conservation of the cell death pathway: mitochondrial release of an apoptosis-inducing factor during Dictyostelium discoideum cell death. Mol Biol Cell 12(10): 3016–3030PubMedGoogle Scholar
  142. 142.
    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(1): 352–361PubMedGoogle Scholar
  143. 143.
    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(3): 401–403PubMedGoogle Scholar
  144. 144.
    Tateda K, Moore TA, Deng JC, Newstead MW, Zeng X, Matsukawa A, Swanson MS, Yamaguchi K, Standiford TJ (2001) Early recruitment of neutrophils determines subsequent T1/T2 host responses in a murine model of Legionella pneumophila pneumonia. J Immunol 166(5): 3355–3361PubMedGoogle Scholar
  145. 145.
    Gao L-Y, Stone BJ, Brieland JK, Abu Kwaik Y (1998) Different fates of Legionella pneumophila pmi and mil mutants within human-derived macrophages and alveolar epithelial cells. Microb Pathog 25: 291–306PubMedGoogle Scholar
  146. 146.
    Brieland JK, Jackson C, Hurst S, Loebenberg D, Muchamuel T, Debets R, Kastelein R, Churakova T, Abrams J, Hare R, O’Garra A (2000) Immunomodulatory role of endogenous interleukin-18 in gamma interferonmediated resolution of replicative Legionella pneumophila lung infection. Infect Immun 68(12): 6567–6573PubMedGoogle Scholar
  147. 147.
    Santic M, Molmeret M, Abu Kwaik Y (2005) Maturation of the Legionella pneumophila-containing phagosome into a phagolysosome within gamma interferon-activated macrophages. Infect Immun 73(5): 3166–3171PubMedGoogle Scholar
  148. 148.
    Skerrett SJ, Bagby GJ, Schmidt RA, Nelson S (1997) Antibody-mediated depletion of tumor necrosis factor-alpha impairs pulmonary host defenses to Legionella pneumophila. J Infect Dis 176(4): 1019–1028PubMedGoogle Scholar
  149. 149.
    Brieland JK, Remick DG, Freeman PT, Hurley MC, Fantone JC, Engleberg NC (1995) In vivo regulation of replicative Legionella pneumophila lung infection by endogenous tumor necrosis factor alpha and nitric oxide. Infect Immun 63: 3253–3258PubMedGoogle Scholar
  150. 150.
    Brieland J, Freeman P, kunkel R, Chrisp C, Hurley M, Fantone J, Engleberg NC (1994) Replicative Legionella pneumophila lung infection in intratracheally inoculated A/J mice: A murine model of human Legionnaires’ disease. Am J Pathol 145: 1537–1546PubMedGoogle Scholar
  151. 151.
    Brieland J, McClain M, Heath L, Chrisp C, Huffnagle G, LeGendre M, Hurley M, Fantone J, Engleberg C (1996) Coinoculation with Hartmannella vermiformis enhances replicative Legionella pneumophila lung infection in a murine model of Legionnaires’ disease. Infect Immun 64(7): 2449–2456PubMedGoogle Scholar
  152. 152.
    Nash TW, Libby DM, Horwitz MA (1988) IFN-gamma-activated human alveolar macrophages inhibit the intracellular multiplication of Legionella pneumophila. J Immunol 140: 3978–3981PubMedGoogle Scholar
  153. 153.
    Byrd TF, Horwitz MA (1989) Interferon gamma-activated human monocytes downregulate transferrin receptors and inhibit the intracellular multiplication of Legionella pneumophila by limiting the availability of iron. J Clin Invest 83: 1457–1465PubMedGoogle Scholar
  154. 154.
    Neild AL, Shin S, Roy CR (2005) Activated macrophages infected with Legionella inhibit T cells by means of MyD88-dependent production of prostaglandins. J Immunol 175(12): 8181–8190PubMedGoogle Scholar
  155. 155.
    Gebran SJ, Yamamoto Y, Newton C, Klein TW, 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(8): 3197–3205PubMedGoogle Scholar
  156. 156.
    Yamamoto Y, Klein TW, Friedman H (1996) Immunoregulatory role of nitric oxide in Legionella pneumophila-infected macrophages. Cell Immunol 171(2): 231–9PubMedGoogle Scholar
  157. 157.
    Yamamoto Y, Klein TW, Newton CA, Widen R, Friedman H (1988) Growth of Legionella pneumophila in thioglycolate-elicited peritoneal macrophages from A/J mice. Infect Immun 56: 370–375PubMedGoogle Scholar
  158. 158.
    Breiman RF, Horwitz MA (1987) Guinea pigs sublethally infected with aerosolized Legionella pneumophila develop humoral and cell-mediated immune responses and are protected against lethal aerosol challenge. A model for studying host defense against lung infections caused by intracellular pathogens. J Exp Med 165: 799–811PubMedGoogle Scholar
  159. 159.
    Horwitz MA, Silverstein SC (1981) 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: 386–397PubMedGoogle Scholar
  160. 160.
    Susa M, Ticac T, Rukavina T, Doric M, Marre R (1998) Legionella pneumophila infection in intratracheally inoculated T cell depleted or non-depleted A/J mice. J Immunol 160: 316–321PubMedGoogle Scholar
  161. 161.
    Neild AL, Roy CR (2003) Legionella reveal dendritic cell functions that facilitate selection of antigens for MHC class II presentation. Immunity 18(6): 813–823PubMedGoogle Scholar
  162. 162.
    Neild AL, Roy CR (2004) Immunity to vacuolar pathogens: what can we learn from Legionella? Cell Microbiol 6(11): 1011–1018PubMedGoogle Scholar
  163. 163.
    Neild A, Murata T, Roy CR (2005) Processing and major histocompatibility complex class II presentation of Legionella pneumophila antigens by infected macrophages. Infect Immun 73(4): 2336–2343PubMedGoogle Scholar

Copyright information

© Birkhäuser Verlag Basel/Switzerland 2007

Authors and Affiliations

  • Dina M. Bitar
    • 1
  • Marina Santic
    • 2
  • Yousef Abu Kwaik
    • 3
  • Maëlle Molmeret
    • 3
  1. 1.Department of Microbiology and Department of Medical Microbiology and Immunology, Faculty of MedicineAl-Quds UniversityJerusalemIsrael
  2. 2.Department of Microbiology and Parasitology, Medical FacultyUniversity of RijekaCroatia
  3. 3.Department of Microbiology and Immunology, Room MS-410University of LouisvilleLouisvilleUSA

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