The Salmonella type III effector SpvC triggers the reverse transmigration of infected cells into the bloodstream


Autoři: Adarsh Gopinath aff001;  Taylor A. Allen aff001;  Caleb J. Bridgwater aff001;  Corey M. Young aff001;  Micah J. Worley aff001
Působiště autorů: Department of Biology, University of Louisville, Louisville, Kentucky, United States of America aff001;  Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky, United States of America aff002
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: 10.1371/journal.pone.0226126

Souhrn

Salmonella can appear in the bloodstream within CD18 expressing phagocytes following oral ingestion in as little as 15 minutes. Here, we provide evidence that the process underlying this phenomenon is reverse transmigration. Reverse transmigration is a normal host process in which dendritic cells can reenter the bloodstream by traversing endothelium in the basal to apical direction. We have developed an in vitro reverse transmigration assay in which dendritic cells are given the opportunity to cross endothelial monolayers in the basal to apical direction grown on membranes with small pores, modeling how such cells can penetrate the bloodstream. We demonstrate that exposing dendritic cells to microbial components negatively regulates reverse transmigration. We propose that microbial components normally cause the host to toggle between positively and negatively regulating reverse transmigration, balancing the need to resolve inflammation with inhibiting the spread of microbes. We show that Salmonella in part overcomes this negative regulation of reverse transmigration with the Salmonella pathogenicity island-2 encoded type III secretion system, which increases reverse transmigration by over an order of magnitude. The SPI-2 type III secretion system does this in part, but not entirely by injecting the type III effector SpvC into infected cells. We further demonstrate that SpvC greatly promotes early extra-intestinal dissemination in mice. This result combined with the previous observation that the spv operon is conserved amongst strains of non-typhoidal Salmonella capable of causing bacteremia in humans suggests that this pathway to the bloodstream could be important for understanding human infections.

Klíčová slova:

Bloodstream infections – Dendritic cells – Endothelial cells – Pathogenesis – Salmonella – Salmonella typhi – Salmonella typhimurium – Salmonellosis


Zdroje

1. Voedisch S, Koenecke C, David S, Herbrand H, Forster R, Rhen M, et al. Mesenteric lymph nodes confine dendritic cell-mediated dissemination of Salmonella enterica serovar Typhimurium and limit systemic disease in mice. Infect Immun. 2009;77(8):3170–80. doi: 10.1128/IAI.00272-09 19506012

2. Barnes PD, Bergman MA, Mecsas J, Isberg RR. Yersinia pseudotuberculosis disseminates directly from a replicating bacterial pool in the intestine. J Exp Med. 2006;203(6):1591–601. doi: 10.1084/jem.20060905 16754724.

3. Coburn B, Li Y, Owen D, Vallance BA, Finlay BB. Salmonella enterica serovar Typhimurium pathogenicity island 2 is necessary for complete virulence in a mouse model of infectious enterocolitis. Infect Immun. 2005;73(6):3219–27. Epub 2005/05/24. 15908346

4. Spadoni I, Zagato E, Bertocchi A, Paolinelli R, Hot E, Di Sabatino A, et al. A gut-vascular barrier controls the systemic dissemination of bacteria. Science. 2015;350(6262):830–4. doi: 10.1126/science.aad0135 26564856.

5. Rescigno M, Rotta G, Valzasina B, Ricciardi-Castagnoli P. Dendritic cells shuttle microbes across gut epithelial monolayers. Immunobiology. 2001;204(5):572–81. doi: 10.1078/0171-2985-00094 11846220.

6. Vazquez-Torres A, Fang FC. Cellular routes of invasion by enteropathogens. Curr Opin Microbiol. 2000;3(1):54–9. doi: 10.1016/s1369-5274(99)00051-x 10679413.

7. Vazquez-Torres A, Jones-Carson J, Baumler AJ, Falkow S, Valdivia R, Brown W, et al. Extraintestinal dissemination of Salmonella by CD18-expressing phagocytes. Nature. 1999;401(6755):804–8. doi: 10.1038/44593 10548107.

8. Worley MJ, Nieman GS, Geddes K, Heffron F. Salmonella typhimurium disseminates within its host by manipulating the motility of infected cells. Proc Natl Acad Sci U S A. 2006;103(47):17915–20. doi: 10.1073/pnas.0604054103 17095609

9. Thornbrough JM, Worley MJ. A naturally occurring single nucleotide polymorphism in the Salmonella SPI-2 type III effector srfH/sseI controls early extraintestinal dissemination. PLoS One. 2012;7(9):e45245. doi: 10.1371/journal.pone.0045245 23028876

10. Pang T, Bhutta ZA, Finlay BB, Altwegg M. Typhoid fever and other salmonellosis: a continuing challenge. Trends Microbiol. 1995;3(7):253–5. doi: 10.1016/s0966-842x(00)88937-4 7551636.

11. Groisman EA, Ochman H. Cognate gene clusters govern invasion of host epithelial cells by Salmonella typhimurium and Shigella flexneri. Embo J. 1993;12(10):3779–87. 8404849

12. Galyov EE, Wood MW, Rosqvist R, Mullan PB, Watson PR, Hedges S, et al. A secreted effector protein of Salmonella dublin is translocated into eukaryotic cells and mediates inflammation and fluid secretion in infected ileal mucosa. Mol Microbiol. 1997;25(5):903–12. doi: 10.1111/j.1365-2958.1997.mmi525.x 9364916

13. Hobbie S, Chen LM, Davis RJ, Galan JE. Involvement of mitogen-activated protein kinase pathways in the nuclear responses and cytokine production induced by Salmonella typhimurium in cultured intestinal epithelial cells. J Immunol. 1997;159(11):5550–9. 9548496

14. van der Velden AW, Velasquez M, Starnbach MN. Salmonella rapidly kill dendritic cells via a caspase-1-dependent mechanism. J Immunol. 2003;171(12):6742–9. Epub 2003/12/10. doi: 10.4049/jimmunol.171.12.6742 14662878.

15. Cirillo DM, Valdivia RH, Monack DM, Falkow S. Macrophage-dependent induction of the Salmonella pathogenicity island 2 type III secretion system and its role in intracellular survival. Mol Microbiol. 1998;30(1):175–88. doi: 10.1046/j.1365-2958.1998.01048.x 9786194

16. Hensel M, Shea JE, Waterman SR, Mundy R, Nikolaus T, Banks G, et al. Genes encoding putative effector proteins of the type III secretion system of Salmonella pathogenicity island 2 are required for bacterial virulence and proliferation in macrophages. Mol Microbiol. 1998;30(1):163–74. doi: 10.1046/j.1365-2958.1998.01047.x 9786193

17. Ochman H, Soncini FC, Solomon F, Groisman EA. Identification of a pathogenicity island required for Salmonella survival in host cells. Proceedings of the National Academy of Sciences of the United States of America. 1996;93(15):7800–4. doi: 10.1073/pnas.93.15.7800 8755556

18. Boyd EF, Hartl DL. Salmonella virulence plasmid. Modular acquisition of the spv virulence region by an F-plasmid in Salmonella enterica subspecies I and insertion into the chromosome of subspecies II, IIIa, IV and VII isolates. Genetics. 1998;149(3):1183–90. Epub 1998/07/03. 9649513

19. Montenegro MA, Morelli G, Helmuth R. Heteroduplex analysis of Salmonella virulence plasmids and their prevalence in isolates of defined sources. Microb Pathog. 1991;11(6):391–7. Epub 1991/12/01. doi: 10.1016/0882-4010(91)90035-9 1795629.

20. Fierer J, Krause M, Tauxe R, Guiney D. Salmonella typhimurium bacteremia: association with the virulence plasmid. J Infect Dis. 1992;166(3):639–42. doi: 10.1093/infdis/166.3.639 1500749.

21. Mazurkiewicz P, Thomas J, Thompson JA, Liu M, Arbibe L, Sansonetti P, et al. SpvC is a Salmonella effector with phosphothreonine lyase activity on host mitogen-activated protein kinases. Mol Microbiol. 2008;67(6):1371–83. Epub 2008/02/21. doi: 10.1111/j.1365-2958.2008.06134.x 18284579

22. Li H, Xu H, Zhou Y, Zhang J, Long C, Li S, et al. The phosphothreonine lyase activity of a bacterial type III effector family. Science. 2007;315(5814):1000–3. Epub 2007/02/17. doi: 10.1126/science.1138960 17303758.

23. Bianchi G, D’Amico G, Sozzani S, Mantovani A, Allavena P. Transendothelial migration and reverse transmigration of in vitro cultured human dendritic cells. Methods Mol Med. 2001;64:325–30. doi: 10.1385/1-59259-150-7:325 21374272.

24. D’Amico G, Bianchi G, Bernasconi S, Bersani L, Piemonti L, Sozzani S, et al. Adhesion, transendothelial migration, and reverse transmigration of in vitro cultured dendritic cells. Blood. 1998;92(1):207–14. Epub 1998/06/25. 9639518.

25. Brown NF, Vallance BA, Coombes BK, Valdez Y, Coburn BA, Finlay BB. Salmonella pathogenicity island 2 is expressed prior to penetrating the intestine. PLoS Pathog. 2005;1(3):e32. Epub 2005/11/24. doi: 10.1371/journal.ppat.0010032 16304611

26. Lesnick ML, Reiner NE, Fierer J, Guiney DG. The Salmonella spvB virulence gene encodes an enzyme that ADP-ribosylates actin and destabilizes the cytoskeleton of eukaryotic cells. Mol Microbiol. 2001;39(6):1464–70. Epub 2001/03/22. doi: 10.1046/j.1365-2958.2001.02360.x 11260464.

27. Otto H, Tezcan-Merdol D, Girisch R, Haag F, Rhen M, Koch-Nolte F. The spvB gene-product of the Salmonella enterica virulence plasmid is a mono(ADP-ribosyl)transferase. Mol Microbiol. 2000;37(5):1106–15. Epub 2000/09/06. doi: 10.1046/j.1365-2958.2000.02064.x 10972829.

28. Tezcan-Merdol D, Nyman T, Lindberg U, Haag F, Koch-Nolte F, Rhen M. Actin is ADP-ribosylated by the Salmonella enterica virulence-associated protein SpvB. Mol Microbiol. 2001;39(3):606–19. Epub 2001/02/13. doi: 10.1046/j.1365-2958.2001.02258.x 11169102.

29. Kawakami K, Koguchi Y, Qureshi MH, Zhang T, Kinjo Y, Yara S, et al. Anti-CD11 b monoclonal antibody suppresses brain dissemination of Cryptococcus neoformans in mice. Microbiol Immunol. 2002;46(3):181–6. doi: 10.1111/j.1348-0421.2002.tb02684.x 12008927.

30. Zeituni AE, Carrion J, Cutler CW. Porphyromonas gingivalis-dendritic cell interactions: consequences for coronary artery disease. Journal of oral microbiology. 2010;2. doi: 10.3402/jom.v2i0.5782 21523219

31. Levine MM, Black RE, Lanata C. Precise estimation of the numbers of chronic carriers of Salmonella typhi in Santiago, Chile, an endemic area. J Infect Dis. 1982;146(6):724–6. Epub 1982/12/01. doi: 10.1093/infdis/146.6.724 7142746.

32. Vogelsang TM, Boe J. Temporary and chronic carriers of Salmonella typhi and Salmonella paratyphi B. J Hyg (Lond). 1948;46(3):252–61. Epub 1948/09/01. doi: 10.1017/s0022172400036378 18122185.

33. Brooks J. The sad and tragic life of Typhoid Mary. Cmaj. 1996;154(6):915–6. 8634973.

34. Marr JS. Typhoid Mary. Lancet. 1999;353(9165):1714. doi: 10.1016/S0140-6736(05)77031-8 10335825.

35. MacPherson GG, Jenkins CD, Stein MJ, Edwards C. Endotoxin-mediated dendritic cell release from the intestine. Characterization of released dendritic cells and TNF dependence. J Immunol. 1995;154(3):1317–22. 7822800.

36. Westermann J, Puskas Z, Pabst R. Blood transit and recirculation kinetics of lymphocyte subsets in normal rats. Scand J Immunol. 1988;28(2):203–10. doi: 10.1111/j.1365-3083.1988.tb02432.x 3137655.

37. Yamauchi J, Miyamoto Y, Kokubu H, Nishii H, Okamoto M, Sugawara Y, et al. Endothelin suppresses cell migration via the JNK signaling pathway in a manner dependent upon Src kinase, Rac1, and Cdc42. FEBS Lett. 2002;527(1–3):284–8. Epub 2002/09/11. doi: 10.1016/s0014-5793(02)03231-3 12220675.

38. Kedzierski RM, Yanagisawa M. Endothelin system: the double-edged sword in health and disease. Annu Rev Pharmacol Toxicol. 2001;41:851–76. Epub 2001/03/27. doi: 10.1146/annurev.pharmtox.41.1.851 11264479.

39. Christiansen JH, Coles EG, Wilkinson DG. Molecular control of neural crest formation, migration and differentiation. Curr Opin Cell Biol. 2000;12(6):719–24. Epub 2000/11/07. doi: 10.1016/s0955-0674(00)00158-7 11063938.

40. Marim FM, Silveira TN, Lima DS Jr., Zamboni DS. A method for generation of bone marrow-derived macrophages from cryopreserved mouse bone marrow cells. PLoS One. 2010;5(12):e15263. doi: 10.1371/journal.pone.0015263 21179419

41. Randolph GJ, Sanchez-Schmitz G, Liebman RM, Schakel K. The CD16(+) (FcgammaRIII(+)) subset of human monocytes preferentially becomes migratory dendritic cells in a model tissue setting. J Exp Med. 2002;196(4):517–27. doi: 10.1084/jem.20011608 12186843

42. Kidwai AS, Mushamiri I, Niemann GS, Brown RN, Adkins JN, Heffron F. Diverse secreted effectors are required for Salmonella persistence in a mouse infection model. PLoS One. 2013;8(8):e70753. doi: 10.1371/journal.pone.0070753 23950998

43. Worley MJ, Ching KH, Heffron F. Salmonella SsrB activates a global regulon of horizontally acquired genes. Mol Microbiol. 2000;36(3):749–61. doi: 10.1046/j.1365-2958.2000.01902.x 10844662.

44. Geddes K, Worley M, Niemann G, Heffron F. Identification of new secreted effectors in Salmonella enterica serovar Typhimurium. Infect Immun. 2005;73(10):6260–71. doi: 10.1128/IAI.73.10.6260-6271.2005 16177297

45. Maloy SR, Stewart VJ, Taylor RK. Genetic Analysis of Pathogenic Bacteria. Cold Spring Harbor: Cold Spring Harbor Laboratory Press; 1996.


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