The Multiple Interactions between Salmonella and Phagocytes

Jessica A. Thompson; David W. Holden

doi:10.1128/9781555816650.ch23

Chapter 23 : The Multiple Interactions between Salmonella and Phagocytes

Authors: Jessica A. Thompson¹, David W. Holden²

VIEW AFFILIATIONS HIDE AFFILIATIONS

Affiliations: 1: Department of Microbiology, Imperial College London, London, United Kingdom; 2: Department of Microbiology, Imperial College London, London, United Kingdom

Content Type: Monograph

Publication Year: 2009

Category: Microbial Genetics and Molecular Biology; Bacterial Pathogenesis

Book DOI: 10.1128/9781555816650

Chapter DOI: 10.1128/9781555816650.ch23

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:

The Multiple Interactions between Salmonella and Phagocytes, Page 1 of 2

< Previous page | Next page > /docserver/preview/fulltext/10.1128/9781555816650/9781555814014_Chap23-1.gif /docserver/preview/fulltext/10.1128/9781555816650/9781555814014_Chap23-2.gif

Abstract:

This chapter outlines the current understanding of host-pathogen interactions, illustrating the close evolutionary relationship between Salmonella and phagocytic cells. After oral ingestion, a proportion of Salmonella is able to withstand the acidic pH of the stomach and colonize the small intestine. Tumor necrosis factor alpha (TNF-α) also contributes toward the stimulation of oxidative responses by phagocytes and is crucial to the development of organized granulomas that contain bacteria within discrete foci in infected tissues. Extracellular and intracellular conditions that normally contribute to elimination of pathogens thus facilitate the adaptation of Salmonella to a physiological state that enables it to colonize macrophages and cause systemic disease. The subepithelial dome (SED) contains large numbers of phagocytes, many of which are CD11c+ dendritic cells (DCs); these are likely to be the first phagocytic cell type that Salmonella encounters following its translocation across the epithelial cell layer. Caspase-1- mediated apoptosis antagonizes clearance of the pathogen from the SED, and is important for colonization of the Peyer’s patches and bacterial dissemination to the lymph nodes and spleen. Antimicrobial activity is found in the cytosol of macrophages and the granules of neutrophils; delivery of these to Salmonella-containing vacuoles (SCVs) and the extracellular environment targets both intra- and extracellular Salmonella. Early vacuole maturation is characterized by delivery of vacuolar ATPase to the SCV and its subsequent acidification.

Citation: Thompson J, Holden D. 2009. The Multiple Interactions between Salmonella and Phagocytes, p 381-392. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch23

Highlighted Text: Show | Hide

Full text loading...

Figures

The Multiple Interactions between Salmonella and Phagocytes

[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/10.1128/9781555816650.ch23-1,webId=/content/author/10.1128/9781555816650.ch23-1,properties={foaf_givenname=Jessica A., foaf_name=Jessica A. Thompson, foaf_surname=Thompson, pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/10.1128/9781555816650.ch23-aff1]]}], com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/10.1128/9781555816650.ch23-2,webId=/content/author/10.1128/9781555816650.ch23-2,properties={foaf_givenname=David W., foaf_name=David W. Holden, foaf_surname=Holden, pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/10.1128/9781555816650.ch23-aff2]]}]]

/content/10.1128/9781555816650.ch23.ch23fig01

FIGURE 1

Interactions between Salmonella and phagocytes at the intestinal epithelium. Salmonella access the SED through invasion of M cells, enterocytes, and phagocytosis by CD18+ DCs. Flagellin binding to TLR5 elicits IL-8 signaling that recruits neutrophils from the circulation. Interaction between SipA and epithelial cells leads to secretion of PEEC and neutrophil migration to the gut lumen. Epithelial cells secrete IL-6, which activates the antibacterial activities of neutrophils. Phagocytosis of Salmonella by DCs and macrophages leads to SipB-dependent cytotoxicity or migration and maturation of infected cells.

10.1128/9781555816650/f0382-01_thmb.gif

10.1128/9781555816650/f0382-01.gif

FIGURE 1

/content/10.1128/9781555816650.ch23.ch23fig02

FIGURE 2

Salmonella virulence proteins modify macrophage behavior. (A) Salmonella is phagocytosed by macrophages and resides within the SCV, which selectively interacts with the endocytic pathway. pag gene products of the PhoP/Q regulon modify LPS and enable resistance to AMPs. PhoP/Q activity also blocks fusion between the maturing SCV and lysosomes. (B) The SPI-2 T3SS is activated and bacteria begin to replicate. (C) PipB2 binds kinesin on the SCV while SifA interaction with SKIP prevents excessive kinesin recruitment, loss of the vacuole membrane, and cytosolic killing of bacteria. SseJ contributes to membrane stability. (D) SseI binds TRIP6 and increases cell motility. (E) Unknown SPI-2 effector(s) inhibit MHC-II antigen presentation, and (F) at late stages of infection SseL deubiquitinates host protein(s) and induces host cell death.

10.1128/9781555816650/f0388-01_thmb.gif

10.1128/9781555816650/f0388-01.gif

FIGURE 2

References

/content/book/10.1128/9781555816650.ch23

1. Alpuche Aranda, C. M.,, J. A. Swanson,, W. P. Loomis, and, S. I. Miller. 1992. Salmonella Typhimurium activates virulence gene transcription within acidified macrophage phagosomes. Proc. Natl. Acad. Sci. USA 89: 10079– 10083.

2. Bader, M. W.,, S. Sanowar,, M. E. Daley,, A. R. Schneider,, U. Cho,, W. Xu,, R. E. Klevit,, H. Le Moual, and, S. I. Miller. 2005. Recognition of antimicrobial peptides by a bacterial sensor kinase. Cell 122: 461– 472.

3. Beuzon, C. R.,, S. Meresse,, K. E. Unsworth,, J. Ruiz-Albert,, S. Garvis,, S. R. Waterman,, T. A. Ryder,, E. Boucrot, and, D. W. Holden. 2000. Salmonella maintains the integrity of its intracellular vacuole through the action of SifA. EMBO J. 19: 3235– 3249.

4. Beuzon, C. R.,, S. P. Salcedo, and, D. W. Holden. 2002. Growth and killing of a Salmonella enterica serovar Typhimurium sifA mutant strain in the cytosol of different host cell lines. Microbiology 148: 2705– 2715.

5. Biedzka-Sarek, M.,, and M. Skurnik. 2006. How to outwit the enemy: dendritic cells face Salmonella. APMIS 114: 589– 600.

6. Bishop, R. E.,, H. S. Gibbons,, T. Guina,, M. S. Trent,, S. I. Miller, and, C. R. Raetz. 2000. Transfer of palmitate from phospholipids to lipid A in outer membranes of Gram-negative bacteria. EMBO J. 19: 5071– 5080.

7. Boucrot, E.,, T. Henry,, J. P. Borg,, J. P. Gorvel, and, S. Meresse. 2005. The intracellular fate of Salmonella depends on the recruitment of kinesin. Science 308: 1174– 1178.

8. Brodsky, I. E.,, N. Ghori,, S. Falkow, and, D. Monack. 2005. Mig-14 is an inner membrane-associated protein that promotes Salmonella typhimurium resistance to CRAMP, survival within activated macrophages and persistent infection. Mol. Microbiol. 55: 954– 972.

9. Carter, P. B.,, and F. M. Collins. 1974. The route of enteric infection in normal mice. J. Exp. Med. 139: 1189– 1203.

10. Catron, D. M.,, M. D. Sylvester,, Y. Lange,, M. Kadekoppala,, B. D. Jones,, D. M. Monack,, S. Falkow, and, K. Haldar. 2002. The Salmonella-containing vacuole is a major site of intracellular cholesterol accumulation and recruits the GPI-anchored protein CD55. Cell. Microbiol. 4: 315– 328.

11. Chakravortty, D.,, I. Hansen-Wester, and, M. Hensel. 2002. Salmonella pathogenicity island 2 mediates protection of intracellular Salmonella from reactive nitrogen intermediates. J. Exp. Med. 195: 1155– 1166.

12. Cheminay, C.,, A. Mohlenbrink, and, M. Hensel. 2005. Intracellular Salmonella inhibit antigen presentation by dendritic cells. J. Immunol. 174: 2892– 2899.

13. Cheminay, C.,, M. Schoen,, M. Hensel,, A. Wandersee Steinhaäuser,, U. Ritter,, H. Körner,, M. Röllinghoff, and, J. Hein. 2002. Migration of Salmonella Typhimuriumharbouring bone marrow-derived dendritic cells towards the chemokines CCL-19 and CCL-21. Microb. Pathog. 32: 207– 218.

14. Cirillo, D. M.,, R. H. Valdivia,, D. M. Monack, and, S. Falkow. 1998. Macrophage-dependent induction of the Salmonella pathogenicity island 2 type III secretion system and its role in intracellular survival. Mol. Microbiol. 30: 175– 188.

15. Clark, M. A.,, M. A. Jepson,, N. L. Simmons, and, B. H. Hirst. 1994. Preferential interaction of Salmonella Typhimurium with mouse Peyer’s patch M cells. Res. Microbiol. 145: 543– 552.

16. Clark, M. A.,, K. A. Reed,, J. Lodge,, J. Stephen,, B. H. Hirst, and, M. A. Jepson. 1996. Invasion of murine intestinal M cells by Salmonella Typhimurium inv mutants severely deficient for invasion of cultured cells. Infect. Immun. 64: 4363– 4368.

17. Conlan, J. W. 1997. Critical roles of neutrophils in host defense against experimental systemic infections of mice by Listeria monocytogenes, Salmonella Typhimurium, and Yersinia enterocolitica. Infect. Immun. 65: 630– 635.

18. Detweiler, C. S.,, D. M. Monack,, I. E. Brodsky,, H. Mathew, and, S. Falkow. 2003. virK, somA and rcsC are important for systemic Salmonella enterica serovar Typhimurium infection and cationic peptide resistance. Mol. Microbiol. 48: 385– 400.

19. Dreher, D.,, M. Kok,, C. Obregon,, S. G. Kiama,, P. Gehr, and, L. P. Nicod. 2002. Salmonella virulence factor SipB induces activation and release of IL-18 in human dendritic cells. J. Leukoc. Biol. 72: 743– 751.

20. Dunlap, N. E.,, W. H. Benjamin,, A. K. Berry,, J. H. Eldridge, and, D. E. Briles. 1992. A “safe-site” for Salmonella Typhimurium is within splenic polymorphonuclear cells. Microb. Pathog. 13: 181– 190.

21. Fields, P. I.,, E. A. Groisman, and, F. Heffron. 1989. A Salmonella locus that controls resistance to microbicidal proteins from phagocytic cells. Science 243: 1059– 1062.

22. Fields, P. I.,, R. V. Swanson,, C. G. Haidaris, and, F. Heffron. 1986. Mutants of Salmonella Typhimurium that cannot survive within the macrophage are avirulent. Proc. Natl. Acad. Sci. USA 83: 5189– 5193.

23. Freeman, J. A.,, C. Rappl,, V. Kuhle,, M. Hensel, and, S. I. Miller. 2002. SpiC is required for translocation of Salmonella pathogenicity island 2 effectors and secretion of translocon proteins SseB and SseC. J. Bacteriol. 184: 4971– 4980.

24. Garvis, S. G.,, C. R. Beuzon, and, D. W. Holden. 2001. A role for the PhoP/Q regulon in inhibition of fusion between lysosomes and Salmonella-containing vacuoles in macrophages. Cell. Microbiol. 3: 731– 744.

25. Groisman, E. A.,, E. Chiao,, C. J. Lipps, and, F. Heffron. 1989. Salmonella Typhimurium phoP virulence gene is a transcriptional regulator. Proc. Natl. Acad. Sci. USA 86: 7077– 7781.

26. Gunn, J. S.,, K. B. Lim,, J. Krueger,, K. Kim,, L. Guo,, M. Hackett, and, S. I. Miller. 1998. PmrA-PmrB-regulated genes necessary for 4-aminoarabinose lipid A modification and polymyxin resistance. Mol. Microbiol. 27: 1171– 1182.

27. Gunn, J. S.,, and S. I. Miller. 1996. PhoP-PhoQ activates transcription of pmrAB, encoding a two-component regulatory system involved in Salmonella Typhimurium antimicrobial peptide resistance. J. Bacteriol. 178: 6857– 6864.

28. Gunn, J. S.,, S. S. Ryan,, J. C. Van Velkingurgh,, R. K. Ernst, and, S. I. Miller. 2000. Genetic and functional analysis of a PmrA-PmrB-regulated locus necessary for lipopolysaccharide modification, antimicrobial peptide resistance, and oral virulence of Salmonella enterica serovar Typhimurium. Infect. Immun. 69: 6139– 6146.

29. Henry, T.,, C. Couillault,, P. Rockenfeller,, E. Boucrot,, A. Dumont,, N. Schroeder,, A. Hermant,, L. A. Knodler,, P. Lecine,, O. Steele-Mortimer,, J. P. Borg,, J. P. Gorvel, and, S. Meresse. 2005. The Salmonella effector protein PipB2 is a linker for kinesin-1. Proc. Natl. Acad. Sci. USA 103: 13497– 13502.

30. Hernandez, L. D.,, M. Pypaert,, R. A. Flavell, and, J. E. Galan. 2003. A Salmonella protein causes macrophage cell death by inducing autophagy. J. Cell Biol. 163: 1123– 1131.

31. Hersh, D.,, D. M. Monack,, M. R. Smith,, N. Ghori,, S. Falkow, and, A. Zychlinsky. 1999. The Salmonella invasin SipB induces macrophage apoptosis by binding to caspase-1. Proc. Natl. Acad. Sci. USA 96: 2396– 2401.

32. Hopkins, S. A.,, F. Niedergang,, I. E. Corthesy-Theulaz, and, J. P. Kraehenbuhl. 2000. A recombinant Salmonella Typhimurium vaccine strain is taken up and survives within murine Peyer’s patch dendritic cells. Cell. Microbiol. 2: 59– 68.

33. Hueck, C. J. 1998. Type III protein secretion systems in bacterial pathogens of animals and plants. Microbiol. Mol. Biol. Rev. 62: 379– 433.

34. Iwasaki, A.,, and B. L. Kelsall. 2000. Localization of distinct Peyer’s patch dendritic cell subsets and their recruitment by chemokines macrophage inflammatory protein (MIP)-3α, MIP-3β, and secondary lymphoid organ chemokine. J. Exp. Med. 191: 1381– 1394.

35. Jantsch, J.,, C. Cheminay,, D. Chakravortty,, T. Lindig,, J. Hein, and, M. Hensel. 2003. Intracellular activities of Salmonella enterica in murine dendritic cells. Cell. Microbiol. 5: 933– 945.

36. Johansson, C.,, and M. J. Wick. 2004. Liver dendritic cells present bacterial antigens and produce cytokines upon Salmonella encounter. J. Immunol. 172: 2496– 2503.

37. Jones, B. D.,, N. Ghori, and, S. Falkow. 1994. Salmonella Typhimurium initiates murine infection by penetrating and destroying the specialized epithelial M cells of the Peyer’s patches. J. Exp. Med. 180: 15– 23.

38. Kawasaki, K.,, R. K. Ernst, and, S. I. Miller. 2004. Deacylation and palmitoylation of lipid A by Salmonellae outer membrane enzymes modulate host signaling through Toll-like receptor 4. J. Endotoxin Res. 10: 439– 444.

39. Kelsall, B. L.,, and W. Strober. 1996. Distinct populations of dendritic cells are present in the subepithelial dome and T cell regions of the murine Peyer’s patch. J. Exp. Med. 183: 237– 247.

40. Kossack, R. E.,, R. L. Guerrant,, P. Densen,, J. Schadelin, and, G. L. Mandell. 1981. Diminished neutrophil oxidative metabolism after phagocytosis of virulent Salmonella Typhi. Infect. Immun. 31: 674– 678.

41. Kurita, A.,, H. Gotoh,, M. Eguchi,, N. Okada,, S. Matsuura,, H. Matsui,, H. Danbara, and, Y. Kikuchi. 2003. Intracellular expression of the Salmonella plasmid virulence protein, SpvB, causes apoptotic cell death in eukaryotic cells. Microb. Pathog. 35: 43– 48.

42. Lee, C. A.,, M. Silva,, A. M. Siber,, A. J. Kelly,, E. Galyov, and, B. A. McCormick. 2000. A secreted Salmonella protein induces a proinflammatory response in epithelial cells, which promotes neutrophil migration. Proc. Natl. Acad. Sci. USA 97: 12283– 12288.

43. Marriot, I.,, T. G. Hammond,, E. K. Thomas, and, K. L. Bost. 1999. Salmonella efficiently enter and survive within cultured CD11c + dendritic cells initiating cytokine secretion. Eur. J. Immunol. 29: 1107– 1115.

44. Martin-Orozco, N.,, N. Touret,, M. L. Zaharik,, E. Park,, R. Kopelman,, S. Miller,, B. B. Finlay,, P. Gros, and, S. Grinstein. 2006. Visualization of vacuolar acidification-induced transcription of genes of pathogens inside macrophages. Mol. Biol. Cell. 17: 498– 510.

45. Mastroeni, P. 2002. Immunity to systemic Salmonella infections. Curr. Mol. Med. 2: 393– 406.

46. Mastroeni, P.,, and M. Sheppard. 2004. Salmonella infections in the mouse model: host resistance factors and in vivo dynamics of bacterial spread and distribution in the tissues. Microbes Infect. 6: 398– 405.

47. Mastroeni, P.,, A. Vazquez-Torres,, F. C. Fang,, Y. Xu,, S. Khan,, C. E. Hormaeche, and, G. Dougan. 2000. Antimicrobial actions of the NADPH phagocyte oxidase and inducible nitric oxide synthase in experimental salmonellosis. II. Effects on microbial proliferation and host survival in vivo. J. Exp. Med. 192 : 237– 248.

48. Matsui, H.,, M. Eguchi, and, Y. Kikuchi. 2000. Use of confocal microscopy to detect Salmonella Typhimurium within host cells associated with Spv-mediated intracellular proliferation. Microb. Pathog. 29: 53– 59

49. Mazurkiewicz, P.,, J. Thomas,, J. A. Thompson,, M. Liu,, L. Arbibe,, P. Sansonetti, and, D. W. Holden. 2008. SpvC is a Salmonella effector with phosphothreonine lyase activity on host mitogen-activated protein kinases. Mol. Microbiol. 67: 1371– 1383.

50. Meresse, S.,, K. E. Unsworth,, A. Habermann,, G Griffiths,, F. Fang,, M. J. Martinez-Lorenzo,, S. R. Waterman,, J. P. Gorvel, and, D. W. Holden. 2001. Remodelling of the actin cytoskeleton is essential for replication of intravacuolar Salmonella. Cell. Microbiol. 3: 567– 577.

51. Miller, S. I.,, A. M. Kukral, and, J. J. Mekalanos. 1989. A two-component regulatory system (phoP phoQ) controls Salmonella Typhimurium virulence. Proc. Natl. Acad. Sci. USA 86: 5054– 5058.

52. Mitchell, E. K.,, P. Mastroeni,, A. P. Kelly, and, J. Trowsdale. 2004. Inhibition of cell surface MHC class II expression by Salmonella. Eur. J. Immunol. 34: 2559– 2567.

53. Nadeau, W. J.,, T. G. Pistole, and, B. A. McCormick. 2002. Polymorphonuclear leukocyte migration across model intestinal epithelia enhances Salmonella Typhimurium killing via the epithelial derived cytokine, IL-6. Microb. Infect. 4: 1379– 1387.

54. Nawabi, P.,, D. M. Catron, and, K. Haldar. 2008. Esterification of cholesterol by a type III secretion effector during intracellular Salmonella infection. Mol. Microbiol. 68: 173– 185.

55. Niedergang, F.,, J. Sirard,, C. T. Blanc, and, J. Kraehenbuhl. 2000. Entry and survival of Salmonella Typhimurium in dendritic cells and presentation of recombinant antigens do not require macrophage-specific virulence factors. Proc. Natl. Acad. Sci. USA 97: 14650– 14655.

56. Niess, J. H.,, S. Brand,, X. Gu,, L. Landsman,, S. Jung,, B. A. McCormick,, J. M. Vyas,, M. Boes,, H. L. Ploegh,, F. G. Fox,, D. R. Littman, and, H. Reinecker. 2005. CX 3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science 307: 254– 258.

57. Norris, F. A.,, M. P. Wilson,, T. S. Wallis,, E. E. Galyov, and, P. W. Majerus. 1998. SopB, a protein required for virulence of Salmonella Dublin, is an inositol phosphate phosphatase. Proc. Natl. Acad. Sci. USA 95: 14057– 14059.

58. Parkhill, J.,, G. Dougan,, K. D. James,, N. R. Thomson,, D. Pickard,, J. Wain,, C. Churcher,, K. L. Mungall,, S. D. Bentley,, M. T. Holden,, M. Sebaihia,, S. Baker,, D. Basham,, K. Brooks,, T. Chillingworth,, P. Connerton,, A. Cronin,, P. Davis,, R. M. Davies,, L. Dowd,, N. White,, J. Farrar,, T. Felt-well,, N. Hamlin,, A. Haque,, T. T. Hien,, S. Holroyd,, K. Jagels,, A. Krogh,, T. S. Larsen,, S. Leather,, S. Moule,, P. O’Gaora,, C. Parry,, M. Quail,, K. Rutherford,, M. Simmonds,, J. Skelton,, K. Stevens,, S. Whitehead, and, B. G. Barrell. 2001. Complete genome sequence of a multiple drug resistant Salmonella enterica serovar Typhi CT18. Nature 413: 848– 852.

59. Peschel, A. 2002. How do bacteria resist human antimicrobial peptides? Trends Microbiol. 10: 179– 186.

60. Prost, L. R.,, M. E. Daley,, V. Le Sage,, M. W. Bader,, H. Le Moual,, R. E. Klevit, and, S. I. Miller. 2007. Activation of the bacterial sensor kinase PhoQ by acidic pH. Mol. Cell 26: 165– 174.

61. Raffatellu, M.,, D. Chessa,, R. P. Wilson,, R. Dusold,, S. Rubino, and, A. J. Baumler. 2005. The Vi capsular antigen of Salmonella enterica serotype Typhi reduces Toll-like receptor-dependent interleukin-8 expression in the intestinal mucosa. Infect Immun. 73: 3367– 3374.

62. Rathman, M.,, L. P. Barker, and, S. Falkow. 1997. The unique trafficking pattern of Salmonella Typhimurium-containing phagosomes in murine macrophages is independent of the mechanism of bacterial entry. Infect. Immun. 65: 1475– 1485.

63. Rathman, M.,, M. D. Sjaastad, and, S. Falkow. 1996. Acidification of phagosomes containing Salmonella Typhimurium in murine macrophages. Infect. Immun. 64: 2765– 2773.

64. Reinicke, A. T.,, J. L. Hutchinson,, A. I. Magee,, P. Mastroeni,, J. Trowsdale, and, A. P. Kelly. 2005. A Salmonella Typhimurium effector protein SifA is modified by host cell prenylation and S-acylation machinery. J. Biol. Chem. 280: 14620– 14627.

65. Rescigno, M.,, M. Urbano,, B. Valzasina,, M. Francolini,, G. Rotta,, R. Bonasio,, F. Granucci,, J. Kraehenbuhl, and, P. Ricciardi-Castagnoli. 2001. Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nat. Immunol. 2: 361– 367.

66. Richter-Dahlfors, A.,, A. M. Buchan, and, B. B. Finlay. 1997. Murine salmonellosis studied by confocal microscopy: Salmonella Typhimurium resides intracellularly inside macrophages and exerts a cytotoxic effect on phagocytes in vivo. J. Exp. Med. 186: 569– 580.

67. Ruiz-Albert, J.,, X. J. Yu,, C. R. Beuzon,, A. N. Blakey,, E. E. Galyov, and, D. W. Holden. 2002. Complementary activities of SseJ and SifA regulate dynamics of the Salmonella Typhimurium vacuolar membrane. Mol. Microbiol. 44: 645– 661.

68. Rytkönen, A.,, J. Poh,, J. Garmendia,, C. Boyle,, A. Thompson,, M. Liu,, P. Freemont,, J. C. Hinton, and, D. W. Holden. 2007. SseL, a Salmonella deubiquitinase required for macrophage killing and virulence. Proc. Natl. Acad. Sci. USA 104: 3502– 3507.

69. Salcedo, S. P.,, M. Noursadeghi,, J. Cohen, and, D. W. Holden. 2001. Intracellular replication of Salmonella Typhimurium strains in specific subsets of splenic macrophages in vivo. Cell Microbiol. 3: 587– 597.

70. Shea, J. E.,, C. R. Beuzon,, C. Gleeson,, R. Mundy, and, D. W. Holden. 1999. Influence of the Salmonella Typhimurium pathogenicity island 2 type III secretion system on bacterial growth in the mouse. Infect. Immun. 67: 213– 219.

71. Sheppard, M.,, C. Webb,, F. Heath,, V. Mallows,, R. Emilianus,, D. Maskell, and, P. Mastroeni. 2003. Dynamics of bacterial growth and distribution within the liver during Salmonella infection. Cell Microbiol. 5: 593– 600.

72. Sundquist, M.,, and M. J. Wick. 2005. TNF-alpha-dependent and -independent maturation of dendritic cells and recruited CD11c(int)CD11b+ Cells during oral Salmonella infection. J. Immunol. 175: 3287– 3298.

73. Tobar, J. A.,, L. J. Carreno,, S. M. Bueno,, P. A. Gonzalez,, J. E. Mora,, S. A. Quezada, and, A. M. Kalergis. 2006. Virulent Salmonella enterica serovar Typhimurium evades adaptive immunity by preventing dendritic cells from activating T cells. Infect. Immun. 74: 6438– 6448.

74. Tobar, J. A.,, P. A. Gonzalez, and, A. M. Kalergis. 2004. Salmonella escape from antigen presentation can be overcome by targeting bacteria to Fc gamma receptors on dendritic cells. J. Immunol. 173: 4058– 4065.

75. Trent, M. S.,, W. Pabich,, C. R. Raetz, and, S. I. Miller. 2001. A PhoP/PhoQ-induced lipase (PagL) that catalyzes 3-O-deacylation of lipid A precursors in membranes of Salmonella Typhimurium. J. Biol. Chem. 276: 9083– 9092.

76. Uchiya, K.,, M. A. Barbieri,, K. Funato,, A. H. Shah,, P. D. Stahl, and, E. A. Groisman. 1999. A Salmonella virulence protein that inhibits cellular trafficking. EMBO J. 18: 3924– 3933.

77. Van der Velden, A. W.,, M. K. Copass, and, M. N. Starnbach. 2005. Salmonella inhibit T cell proliferation by a direct, contact-dependent immunosuppressive effect. Proc. Natl. Acad. Sci. USA 102: 17769– 17774.

78. Vazquez-Torres, A.,, J. Jones-Carson,, A. J. Baäumler,, S. Falkow,, R. Valdivia,, W. Brown,, M. Le,, R. Berggren,, W. T. Parks, and, F. C. Fang. 1999. Extraintestinal dissemination of Salmonella by CD18-expressing phagocytes. Nature 401: 804– 808.

79. Vazquez-Torres, A.,, Y. Xu,, J. Jones-Carson,, D. W. Holden,, S. M. Lucia,, M. C. Dinauer,, P. Mastroeni, and, F. C. Fang. 2000. Salmonella pathogenicity island 2-dependent evasion of the phagocyte NADPH oxidase. Science 287: 1655– 1658.

80. Waterman, S. R.,, and D. W. Holden. 2003. Functions and effectors of the Salmonella pathogenicity island 2 type III secretion system. Cell. Microbiol. 5: 501– 511.

81. Worley, M. J.,, G. S. Nieman,, K. Geddes, and, F. Heffron. 2006. Salmonella Typhimurium disseminates within its host by manipulating the motility of infected cells. Proc. Natl. Acad. Sci. USA 103: 17915– 17920.

82. Yrlid, U.,, M. Svensson,, A. Kirby, and, M. J. Wick. 2001. Antigen-presenting cells and anti- Salmonella immunity. Microb. Infect. 3: 1239– 1248.

83. Yrlid, U.,, and M. J. Wick. 2002. Antigen presentation capacity and cytokine production by murine splenic dendritic cell subsets upon Salmonella encounter. J. Immunol. 169: 108– 116.

84. Yu, X. J.,, M. Liu, and, D. W. Holden. 2004. SsaM and SpiC interact and regulate secretion of Salmonella pathogenicity island 2 type III secretion system effectors and translocators. Mol. Microbiol. 54: 604– 819.

85. Zhao, C.,, M. W. Wood,, E. E. Galyov,, U. E. Hopken,, M. Lipp,, H. C. Bodmer,, D. F. Tough, and, R. W. Carter. 2006. Salmonella Typhimurium infection triggers dendritic cells and macrophages to adopt distinct migration patterns in vivo. Eur. J. Immunol. 36: 2939– 2950.