1887

Abstract

The pathogenicity island 2 (SPI-2)-encoded type III secretion system (injectisome) is assembled following uptake of bacteria into vacuoles in mammalian cells. The injectisome translocates virulence proteins (effectors) into infected cells. Numerous studies have established the requirement for a functional SPI-2 injectisome for growth of Typhimurium in mouse macrophages, but the results of similar studies involving Typhi and human-derived macrophages are not consistent. It is important to clarify the functions of the . Typhi SPI-2 injectisome, not least because an inactivated SPI-2 injectisome forms the basis for live attenuated . Typhi vaccines that have undergone extensive trials in humans. Intracellular expression of injectisome genes and effector delivery take longer in the . Typhi/human macrophage model than for . Typhimurium and we propose that this could explain the conflicting results. Furthermore, strains of both . Typhimurium and . Typhi contain intact genes for several ‘core’ effectors. In . Typhimurium these cooperate to regulate the vacuole membrane and contribute to intracellular bacterial replication; similar functions are therefore likely in . Typhi.

Funding
This study was supported by the:
  • BBSRC (Award BB/R011834/1)
    • Principle Award Recipient: TeresaLM Thurston
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License. This article was made open access via a Publish and Read agreement between the Microbiology Society and the corresponding author’s institution.
Loading

Article metrics loading...

/content/journal/micro/10.1099/mic.0.001405
2023-10-20
2024-05-22
Loading full text...

Full text loading...

/deliver/fulltext/micro/169/10/mic001405.html?itemId=/content/journal/micro/10.1099/mic.0.001405&mimeType=html&fmt=ahah

References

  1. Richter-Dahlfors A, Buchan AMJ, Finlay BB. Murine salmonellosis studied by confocal microscopy: Salmonella typhimurium resides intracellularly inside macrophages and exerts a cytotoxic effect on phagocytes in vivo. J Exp Med 1997; 186:569–580 [View Article] [PubMed]
    [Google Scholar]
  2. Salcedo SP, Noursadeghi M, Cohen J, Holden DW. Intracellular replication of Salmonella typhimurium strains in specific subsets of splenic macrophages in vivo. Cell Microbiol 2001; 3:587–597 [View Article] [PubMed]
    [Google Scholar]
  3. Santos RL, Zhang S, Tsolis RM, Kingsley RA, Adams LG et al. Animal models of Salmonella infections: enteritis versus typhoid fever. Microbes Infect 2001; 3:1335–1344 [View Article] [PubMed]
    [Google Scholar]
  4. Watson KG, Holden DW. Dynamics of growth and dissemination of Salmonella in vivo. Cell Microbiol 2010; 12:1389–1397 [View Article] [PubMed]
    [Google Scholar]
  5. Pickard D, Wain J, Baker S, Line A, Chohan S et al. Composition, acquisition, and distribution of the Vi exopolysaccharide-encoding Salmonella enterica pathogenicity island SPI-7. J Bacteriol 2003; 185:5055–5065 [View Article] [PubMed]
    [Google Scholar]
  6. Galán JE. Typhoid toxin provides a window into typhoid fever and the biology of Salmonella Typhi. Proc Natl Acad Sci U S A 2016; 113:6338–6344 [View Article] [PubMed]
    [Google Scholar]
  7. Hensel M, Shea JE, Waterman SR, Mundy R, Nikolaus T 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; 30:163–174 [View Article] [PubMed]
    [Google Scholar]
  8. Coombes BK, Wickham ME, Lowden MJ, Brown NF, Finlay BB. Negative regulation of Salmonella pathogenicity island 2 is required for contextual control of virulence during typhoid. Proc Natl Acad Sci U S A 2005; 102:17460–17465 [View Article] [PubMed]
    [Google Scholar]
  9. Hensel M, Shea JE, Raupach B, Monack D, Falkow S et al. Functional analysis of ssaJ and the ssaK/U operon, 13 genes encoding components of the type III secretion apparatus of Salmonella pathogenicity island 2. Mol Microbiol 1997; 24:155–167 [View Article] [PubMed]
    [Google Scholar]
  10. Jennings E, Thurston TLM, Holden DW. Salmonella SPI-2 type III secretion system effectors: molecular mechanisms and physiological consequences. Cell Host Microbe 2017; 22:217–231 [View Article] [PubMed]
    [Google Scholar]
  11. Figueira R, Holden DW. Functions of the Salmonella pathogenicity island 2 (SPI-2) type III secretion system effectors. Microbiology 2012; 158:1147–1161 [View Article] [PubMed]
    [Google Scholar]
  12. Figueira R, Watson KG, Holden DW, Helaine S. Identification of Salmonella pathogenicity island-2 type III secretion system effectors involved in intramacrophage replication of S. enterica serovar typhimurium: implications for rational vaccine design. mBio 2013; 4:e00065 [View Article] [PubMed]
    [Google Scholar]
  13. Reuter T, Scharte F, Franzkoch R, Liss V, Hensel M. Single cell analyses reveal distinct adaptation of typhoidal and non-typhoidal Salmonella enterica serovars to intracellular lifestyle. PLoS Pathog 2021; 17:e1009319 [View Article] [PubMed]
    [Google Scholar]
  14. Khan SA, Stratford R, Wu T, Mckelvie N, Bellaby T et al. Salmonella typhi and S typhimurium derivatives harbouring deletions in aromatic biosynthesis and Salmonella pathogenicity island-2 (SPI-2) genes as vaccines and vectors. Vaccine 2003; 21:538–548 [View Article] [PubMed]
    [Google Scholar]
  15. Hamblin M, Schade R, Narasimhan R, Monack DM. Salmonella enterica serovar Typhi uses two type 3 secretion systems to replicate in human macrophages and colonize humanized mice. mBio 2023; 14:e0113723 [View Article] [PubMed]
    [Google Scholar]
  16. Stratford R, McKelvie ND, Hughes NJ, Aldred E, Wiseman C et al. Optimization of Salmonella enterica serovar Typhi DeltaaroC DeltassaV derivatives as vehicles for delivering heterologous antigens by chromosomal integration and in vivo inducible promoters. Infect Immun 2005; 73:362–368 [View Article] [PubMed]
    [Google Scholar]
  17. Forest CG, Ferraro E, Sabbagh SC, Daigle F. Intracellular survival of Salmonella enterica serovar Typhi in human macrophages is independent of Salmonella pathogenicity island (SPI)-2. Microbiology 2010; 156:3689–3698 [View Article] [PubMed]
    [Google Scholar]
  18. Sabbagh SC, Lepage C, McClelland M, Daigle F. Selection of Salmonella enterica serovar Typhi genes involved during interaction with human macrophages by screening of a transposon mutant library. PLoS One 2012; 7:e36643 [View Article] [PubMed]
    [Google Scholar]
  19. Kirkpatrick BD, Tenney KM, Larsson CJ, O’Neill JP, Ventrone C et al. The novel oral typhoid vaccine M01ZH09 is well tolerated and highly immunogenic in 2 vaccine presentations. J Infect Dis 2005; 192:360–366 [View Article]
    [Google Scholar]
  20. Kirkpatrick BD, McKenzie R, O’Neill JP, Larsson CJ, Bourgeois AL et al. Evaluation of Salmonella enterica serovar Typhi (Ty2 aroC-ssaV-) M01ZH09, with a defined mutation in the Salmonella pathogenicity island 2, as a live, oral typhoid vaccine in human volunteers. Vaccine 2006; 24:116–123 [View Article] [PubMed]
    [Google Scholar]
  21. Tran TH, Nguyen TD, Nguyen TT, Ninh TTV, Tran NBC et al. A randomised trial evaluating the safety and immunogenicity of the novel single oral dose typhoid vaccine M01ZH09 in healthy Vietnamese children. PLoS One 2010; 5:e11778 [View Article] [PubMed]
    [Google Scholar]
  22. Hindle Z, Chatfield SN, Phillimore J, Bentley M, Johnson J et al. Characterization of Salmonella enterica derivatives harboring defined aroC and Salmonella pathogenicity island 2 type III secretion system (ssaV) mutations by immunization of healthy volunteers. Infect Immun 2002; 70:3457–3467 [View Article] [PubMed]
    [Google Scholar]
  23. Yoshida Y, Miki T, Ono S, Haneda T, Ito M et al. Functional characterization of the type III secretion ATPase SsaN encoded by Salmonella pathogenicity island 2. PLoS One 2014; 9:e94347 [View Article] [PubMed]
    [Google Scholar]
  24. Yu XJ, Grabe GJ, Liu M, Mota LJ, Holden DW. SsaV interacts with SsaL to control the translocon-to-effector switch in the Salmonella SPI-2 type three secretion system. mBio 2018; 9:e01149-18 [View Article] [PubMed]
    [Google Scholar]
  25. Karlinsey JE, Stepien TA, Mayho M, Singletary LA, Bingham-Ramos LK et al. Genome-wide analysis of Salmonella enterica serovar typhi in humanized mice reveals key virulence features. Cell Host Microbe 2019; 26:426–434 [View Article] [PubMed]
    [Google Scholar]
  26. Song J, Willinger T, Rongvaux A, Eynon EE, Stevens S et al. A mouse model for the human pathogen Salmonella typhi. Cell Host Microbe 2010; 8:369–376 [View Article] [PubMed]
    [Google Scholar]
  27. Rytkönen A, Poh J, Garmendia J, Boyle C, Thompson A et al. SseL, a Salmonella deubiquitinase required for macrophage killing and virulence. Proc Natl Acad Sci U S A 2007; 104:3502–3507 [View Article] [PubMed]
    [Google Scholar]
  28. Parkhill J, Dougan G, James KD, Thomson NR, Pickard D et al. Complete genome sequence of a multiple drug resistant Salmonella enterica serovar Typhi CT18. Nature 2001; 413:848–852 [View Article] [PubMed]
    [Google Scholar]
  29. McClelland M, Sanderson KE, Clifton SW, Latreille P, Porwollik S et al. Comparison of genome degradation in Paratyphi A and Typhi, human-restricted serovars of Salmonella enterica that cause typhoid. Nat Genet 2004; 36:1268–1274 [View Article] [PubMed]
    [Google Scholar]
  30. Nuccio SP, Bäumler AJ. Comparative analysis of Salmonella genomes identifies a metabolic network for escalating growth in the inflamed gut. mBio 2014; 5:e00929–14 [View Article] [PubMed]
    [Google Scholar]
  31. McQuate SE, Young AM, Silva-Herzog E, Bunker E, Hernandez M et al. Long-term live-cell imaging reveals new roles for Salmonella effector proteins SseG and SteA. Cell Microbiol 2017; 19: [View Article] [PubMed]
    [Google Scholar]
  32. Beuzón CR, Méresse S, Unsworth KE, Ruíz-Albert J, Garvis S et al. Salmonella maintains the integrity of its intracellular vacuole through the action of SifA. EMBO J 2000; 19:3235–3249 [View Article] [PubMed]
    [Google Scholar]
  33. Brumell JH, Rosenberger CM, Gotto GT, Marcus SL, Finlay BB. SifA permits survival and replication of Salmonella typhimurium in murine macrophages. Cell Microbiol 2001; 3:75–84 [View Article] [PubMed]
    [Google Scholar]
  34. Salcedo SP, Holden DW. SseG, a virulence protein that targets Salmonella to the Golgi network. EMBO J 2003; 22:5003–5014 [View Article] [PubMed]
    [Google Scholar]
  35. Abrahams GL, Müller P, Hensel M. Functional dissection of SseF, a type III effector protein involved in positioning the Salmonella-containing vacuole. Traffic 2006; 7:950–965 [View Article] [PubMed]
    [Google Scholar]
  36. Yu X-J, Liu M, Holden DW. Salmonella effectors SseF and SseG interact with mammalian protein ACBD3 (GCP60) to anchor Salmonella -containing vacuoles at the Golgi network. mBio 2016; 7: [View Article]
    [Google Scholar]
  37. Mota LJ, Ramsden AE, Liu M, Castle JD, Holden DW. SCAMP3 is a component of the Salmonella-induced tubular network and reveals an interaction between bacterial effectors and post-Golgi trafficking. Cell Microbiol 2009; 11:1236–1253 [View Article] [PubMed]
    [Google Scholar]
  38. Reinicke AT, Hutchinson JL, Magee AI, Mastroeni P, Trowsdale J et al. A Salmonella typhimurium effector protein SifA is modified by host cell prenylation and S-acylation machinery. J Biol Chem 2005; 280:14620–14627 [View Article] [PubMed]
    [Google Scholar]
  39. McGourty K, Thurston TL, Matthews SA, Pinaud L, Mota LJ et al. Salmonella inhibits retrograde trafficking of mannose-6-phosphate receptors and lysosome function. Science 2012; 338:963–967 [View Article] [PubMed]
    [Google Scholar]
  40. Röder J, Felgner P, Hensel M. Comprehensive single cell analyses of the nutritional environment of intracellular Salmonella enterica. Front Cell Infect Microbiol 2021; 11:624650 [View Article] [PubMed]
    [Google Scholar]
  41. Hagar JA, Powell DA, Aachoui Y, Ernst RK, Miao EA. Cytoplasmic LPS activates caspase-11: implications in TLR4-independent endotoxic shock. Science 2013; 341:1250–1253 [View Article] [PubMed]
    [Google Scholar]
  42. Thurston TLM, Matthews SA, Jennings E, Alix E, Shao F et al. Growth inhibition of cytosolic Salmonella by caspase-1 and caspase-11 precedes host cell death. Nat Commun 2016; 7:13292 [View Article] [PubMed]
    [Google Scholar]
  43. Shi J, Zhao Y, Wang Y, Gao W, Ding J et al. Inflammatory caspases are innate immune receptors for intracellular LPS. Nature 2014; 514:187–192 [View Article] [PubMed]
    [Google Scholar]
  44. Broz P, Ruby T, Belhocine K, Bouley DM, Kayagaki N et al. Caspase-11 increases susceptibility to Salmonella infection in the absence of caspase-1. Nature 2012; 490:288–291 [View Article] [PubMed]
    [Google Scholar]
  45. Ruiz-Albert J, Yu X-J, Beuzón CR, Blakey AN, Galyov EE et al. Complementary activities of SseJ and SifA regulate dynamics of the Salmonella typhimurium vacuolar membrane. Mol Microbiol 2002; 44:645–661 [View Article] [PubMed]
    [Google Scholar]
  46. Schroeder N, Henry T, de Chastellier C, Zhao W, Guilhon A-A et al. The virulence protein SopD2 regulates membrane dynamics of Salmonella-containing vacuoles. PLoS Pathog 2010; 6:e1001002 [View Article] [PubMed]
    [Google Scholar]
  47. Domingues L, Ismail A, Charro N, Rodríguez-Escudero I, Holden DW et al. The Salmonella effector SteA binds phosphatidylinositol 4-phosphate for subcellular targeting within host cells. Cell Microbiol 2016; 18:949–969 [View Article] [PubMed]
    [Google Scholar]
  48. Henry T, Couillault C, Rockenfeller P, Boucrot E, Dumont A et al. The Salmonella effector protein PipB2 is a linker for kinesin-1. Proc Natl Acad Sci U S A 2006; 103:13497–13502 [View Article] [PubMed]
    [Google Scholar]
  49. Alberdi L, Vergnes A, Manneville J-B, Tembo DL, Fang Z et al. Regulation of kinesin-1 activity by the Salmonella enterica effectors PipB2 and SifA. J Cell Sci 2020; 133:jcs239863 [View Article] [PubMed]
    [Google Scholar]
  50. Raffatellu M, Chessa D, Wilson RP, Dusold R, Rubino S et al. The Vi capsular antigen of Salmonella enterica serotype Typhi reduces toll-like receptor-dependent interleukin-8 expression in the intestinal mucosa. Infect Immun 2005; 73:3367–3374 [View Article] [PubMed]
    [Google Scholar]
  51. Dougan G, Baker S. Salmonella enterica serovar Typhi and the pathogenesis of typhoid fever. Annu Rev Microbiol 2014; 68:317–336 [View Article] [PubMed]
    [Google Scholar]
  52. Cerny O, Godlee C, Tocci R, Cross NE, Shi H et al. CD97 stabilises the immunological synapse between dendritic cells and T cells and is targeted for degradation by the Salmonella effector SteD. PLoS Pathog 2021; 17:e1009771 [View Article] [PubMed]
    [Google Scholar]
  53. Alix E, Godlee C, Cerny O, Blundell S, Tocci R et al. The tumour suppressor TMEM127 is a Nedd4-family E3 ligase adaptor required by Salmonella SteD to ubiquitinate and degrade MHC class II molecules. Cell Host Microbe 2020; 28:54–68 [View Article] [PubMed]
    [Google Scholar]
  54. Dougan G, John V, Palmer S, Mastroeni P. Immunity to salmonellosis. Immunol Rev 2011; 240:196–210 [View Article] [PubMed]
    [Google Scholar]
  55. Dunstan SJ, Hue NT, Han B, Li Z, Tram TTB et al. Variation at HLA-DRB1 is associated with resistance to enteric fever. Nat Genet 2014; 46:1333–1336 [View Article] [PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/micro/10.1099/mic.0.001405
Loading
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error