#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

RHS-elements function as type II toxin-antitoxin modules that regulate intra-macrophage replication of Salmonella Typhimurium


Autoři: Magnus Stårsta aff001;  Disa L. Hammarlöf aff001;  Marcus Wäneskog aff001;  Susan Schlegel aff001;  Feifei Xu aff001;  Arvid Heden Gynnå aff001;  Malin Borg aff001;  Sten Herschend aff001;  Sanna Koskiniemi aff001
Působiště autorů: Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden aff001
Vyšlo v časopise: RHS-elements function as type II toxin-antitoxin modules that regulate intra-macrophage replication of Salmonella Typhimurium. PLoS Genet 16(2): e32767. doi:10.1371/journal.pgen.1008607
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008607

Souhrn

RHS elements are components of conserved toxin-delivery systems, wide-spread within the bacterial kingdom and some of the most positively selected genes known. However, very little is known about how Rhs toxins affect bacterial biology. Salmonella Typhimurium contains a full-length rhs gene and an adjacent orphan rhs gene, which lacks the conserved delivery part of the Rhs protein. Here we show that, in addition to the conventional delivery, Rhs toxin-antitoxin pairs encode for functional type-II toxin-antitoxin (TA) loci that regulate S. Typhimurium proliferation within macrophages. Mutant S. Typhimurium cells lacking both Rhs toxins proliferate 2-times better within macrophages, mainly because of an increased growth rate. Thus, in addition to providing strong positive selection for the rhs loci under conditions when there is little or no toxin delivery, internal expression of the toxin-antitoxin system regulates growth in the stressful environment found inside macrophages.

Klíčová slova:

Antitoxins – Arabinose – Cell-mediated immunity – Macrophages – Proteases – Salmonella – Salmonella typhimurium – Toxins


Zdroje

1. Helaine S, Cheverton AM, Watson KG, Faure LM, Matthews SA, Holden DW. Internalization of Salmonella by macrophages induces formation of nonreplicating persisters. Science. 2014;343(6167):204–8. Epub 2014/01/11. doi: 10.1126/science.1244705 24408438.

2. Korch SB, Contreras H, Clark-Curtiss JE. Three Mycobacterium tuberculosis Rel toxin-antitoxin modules inhibit mycobacterial growth and are expressed in infected human macrophages. J Bacteriol. 2009;191(5):1618–30. Epub 2008/12/31. doi: 10.1128/JB.01318-08 19114484; PubMed Central PMCID: PMC2648211.

3. Page R, Peti W. Toxin-antitoxin systems in bacterial growth arrest and persistence. Nat Chem Biol. 2016;12(4):208–14. Epub 2016/03/19. doi: 10.1038/nchembio.2044 26991085.

4. Muthuramalingam M, White JC, Bourne CR. Toxin-Antitoxin Modules Are Pliable Switches Activated by Multiple Protease Pathways. Toxins (Basel). 2016;8(7). Epub 2016/07/15. doi: 10.3390/toxins8070214 27409636; PubMed Central PMCID: PMC4963847.

5. Wilbaux M, Mine N, Guerout AM, Mazel D, Van Melderen L. Functional interactions between coexisting toxin-antitoxin systems of the ccd family in Escherichia coli O157:H7. J Bacteriol. 2007;189(7):2712–9. Epub 2007/01/30. doi: 10.1128/JB.01679-06 17259320; PubMed Central PMCID: PMC1855815.

6. Keren I, Shah D, Spoering A, Kaldalu N, Lewis K. Specialized persister cells and the mechanism of multidrug tolerance in Escherichia coli. J Bacteriol. 2004;186(24):8172–80. Epub 2004/12/04. doi: 10.1128/JB.186.24.8172-8180.2004 15576765; PubMed Central PMCID: PMC532439.

7. Vazquez-Laslop N, Lee H, Neyfakh AA. Increased persistence in Escherichia coli caused by controlled expression of toxins or other unrelated proteins. J Bacteriol. 2006;188(10):3494–7. Epub 2006/05/05. doi: 10.1128/JB.188.10.3494-3497.2006 16672603; PubMed Central PMCID: PMC1482871.

8. Ogura T, Hiraga S. Mini-F plasmid genes that couple host cell division to plasmid proliferation. Proc Natl Acad Sci U S A. 1983;80(15):4784–8. Epub 1983/08/01. doi: 10.1073/pnas.80.15.4784 6308648; PubMed Central PMCID: PMC384129.

9. Gerdes K, Bech FW, Jorgensen ST, Lobner-Olesen A, Rasmussen PB, Atlung T, et al. Mechanism of postsegregational killing by the hok gene product of the parB system of plasmid R1 and its homology with the relF gene product of the E. coli relB operon. EMBO J. 1986;5(8):2023–9. Epub 1986/08/01. 3019679; PubMed Central PMCID: PMC1167073.

10. Gerdes K, Rasmussen PB, Molin S. Unique type of plasmid maintenance function: postsegregational killing of plasmid-free cells. Proc Natl Acad Sci U S A. 1986;83(10):3116–20. Epub 1986/05/01. doi: 10.1073/pnas.83.10.3116 3517851; PubMed Central PMCID: PMC323463.

11. Norton JP, Mulvey MA. Toxin-antitoxin systems are important for niche-specific colonization and stress resistance of uropathogenic Escherichia coli. PLoS Pathog. 2012;8(10):e1002954. Epub 2012/10/12. doi: 10.1371/journal.ppat.1002954 23055930; PubMed Central PMCID: PMC3464220.

12. Stewart GR, Patel J, Robertson BD, Rae A, Young DB. Mycobacterial mutants with defective control of phagosomal acidification. PLoS Pathog. 2005;1(3):269–78. Epub 2005/12/03. doi: 10.1371/journal.ppat.0010033 16322769; PubMed Central PMCID: PMC1291353.

13. Bukowski M, Lyzen R, Helbin WM, Bonar E, Szalewska-Palasz A, Wegrzyn G, et al. A regulatory role for Staphylococcus aureus toxin-antitoxin system PemIKSa. Nat Commun. 2013;4:2012. Epub 2013/06/19. doi: 10.1038/ncomms3012 23774061.

14. De la Cruz MA, Zhao W, Farenc C, Gimenez G, Raoult D, Cambillau C, et al. A toxin-antitoxin module of Salmonella promotes virulence in mice. PLoS Pathog. 2013;9(12):e1003827. Epub 2014/01/05. doi: 10.1371/journal.ppat.1003827 24385907; PubMed Central PMCID: PMC3868539.

15. Haraga A, Ohlson MB, Miller SI. Salmonellae interplay with host cells. Nat Rev Microbiol. 2008;6(1):53–66. Epub 2007/11/21. doi: 10.1038/nrmicro1788 18026123.

16. Haselbeck AH, Panzner U, Im J, Baker S, Meyer CG, Marks F. Current perspectives on invasive nontyphoidal Salmonella disease. Curr Opin Infect Dis. 2017;30(5):498–503. Epub 2017/07/22. doi: 10.1097/QCO.0000000000000398 28731899.

17. Linehan SA, Holden DW. The interplay between Salmonella typhimurium and its macrophage host—what can it teach us about innate immunity? Immunol Lett. 2003;85(2):183–92. Epub 2003/01/16. doi: 10.1016/s0165-2478(02)00227-4 12527226.

18. Tucker RP, Beckmann J, Leachman NT, Scholer J, Chiquet-Ehrismann R. Phylogenetic analysis of the teneurins: conserved features and premetazoan ancestry. Molecular biology and evolution. 2012;29(3):1019–29. Epub 2011/11/03. doi: 10.1093/molbev/msr271 22045996; PubMed Central PMCID: PMC3278476.

19. Foster SJ. Molecular analysis of three major wall-associated proteins of Bacillus subtilis 168: evidence for processing of the product of a gene encoding a 258 kDa precursor two-domain ligand-binding protein. Molecular microbiology. 1993;8(2):299–310. Epub 1993/04/01. doi: 10.1111/j.1365-2958.1993.tb01574.x 8316082.

20. Koskiniemi S, Lamoureux JG, Nikolakakis KC, T'Kint de Roodenbeke C, Kaplan MD, Low DA, et al. Rhs proteins from diverse bacteria mediate intercellular competition. Proceedings of the National Academy of Sciences of the United States of America. 2013;110(17):7032–7. Epub 2013/04/11. doi: 10.1073/pnas.1300627110 23572593; PubMed Central PMCID: PMC3637788.

21. Whitney JC, Beck CM, Goo YA, Russell AB, Harding BN, De Leon JA, et al. Genetically distinct pathways guide effector export through the type VI secretion system. Mol Microbiol. 2014;92(3):529–42. doi: 10.1111/mmi.12571 24589350.

22. Alcoforado Diniz J, Coulthurst SJ. Intraspecies Competition in Serratia marcescens Is Mediated by Type VI-Secreted Rhs Effectors and a Conserved Effector-Associated Accessory Protein. Journal of bacteriology. 2015;197(14):2350–60. Epub 2015/05/06. doi: 10.1128/JB.00199-15 25939831; PubMed Central PMCID: PMC4524185.

23. Hood RD, Singh P, Hsu F, Guvener T, Carl MA, Trinidad RR, et al. A type VI secretion system of Pseudomonas aeruginosa targets a toxin to bacteria. Cell Host Microbe. 2010;7(1):25–37. Epub 2010/02/02. doi: 10.1016/j.chom.2009.12.007 20114026; PubMed Central PMCID: PMC2831478.

24. Ma AT, Mekalanos JJ. In vivo actin cross-linking induced by Vibrio cholerae type VI secretion system is associated with intestinal inflammation. Proc Natl Acad Sci U S A. 2010;107(9):4365–70. Epub 2010/02/13. doi: 10.1073/pnas.0915156107 20150509; PubMed Central PMCID: PMC2840160.

25. Russell AB, Peterson SB, Mougous JD. Type VI secretion system effectors: poisons with a purpose. Nat Rev Microbiol. 2014;12(2):137–48. Epub 2014/01/05. doi: 10.1038/nrmicro3185 24384601.

26. Shneider MM, Buth SA, Ho BT, Basler M, Mekalanos JJ, Leiman PG. PAAR-repeat proteins sharpen and diversify the type VI secretion system spike. Nature. 2013;500(7462):350–3. Epub 2013/08/09. doi: 10.1038/nature12453 23925114; PubMed Central PMCID: PMC3792578.

27. Jackson AP, Thomas GH, Parkhill J, Thomson NR. Evolutionary diversification of an ancient gene family (rhs) through C-terminal displacement. BMC genomics. 2009;10:584. Epub 2009/12/09. doi: 10.1186/1471-2164-10-584 PubMed Central PMCID: PMC2935791. 19968874

28. Busby JN, Panjikar S, Landsberg MJ, Hurst MR, Lott JS. The BC component of ABC toxins is an RHS-repeat-containing protein encapsulation device. Nature. 2013;501(7468):547–50. Epub 2013/08/06. doi: 10.1038/nature12465 23913273.

29. Aoki SK, Pamma R, Hernday AD, Bickham JE, Braaten BA, Low DA. Contact-dependent inhibition of growth in Escherichia coli. Science. 2005;309(5738):1245–8. Epub 2005/08/20. doi: 10.1126/science.1115109 16109881.

30. Aoki SK, Diner EJ, de Roodenbeke CT, Burgess BR, Poole SJ, Braaten BA, et al. A widespread family of polymorphic contact-dependent toxin delivery systems in bacteria. Nature. 2010;468(7322):439–42. Epub 2010/11/19. doi: 10.1038/nature09490 21085179; PubMed Central PMCID: PMC3058911.

31. Ting SY, Bosch DE, Mangiameli SM, Radey MC, Huang S, Park YJ, et al. Bifunctional Immunity Proteins Protect Bacteria against FtsZ-Targeting ADP-Ribosylating Toxins. Cell. 2018. Epub 2018/10/23. doi: 10.1016/j.cell.2018.09.037 30343895.

32. Sana TG, Flaugnatti N, Lugo KA, Lam LH, Jacobson A, Baylot V, et al. Salmonella Typhimurium utilizes a T6SS-mediated antibacterial weapon to establish in the host gut. Proc Natl Acad Sci U S A. 2016;113(34):E5044–51. Epub 2016/08/10. doi: 10.1073/pnas.1608858113 27503894; PubMed Central PMCID: PMC5003274.

33. Mulder DT, Cooper CA, Coombes BK. Type VI secretion system-associated gene clusters contribute to pathogenesis of Salmonella enterica serovar Typhimurium. Infection and immunity. 2012;80(6):1996–2007. Epub 2012/04/12. doi: 10.1128/IAI.06205-11 22493086; PubMed Central PMCID: PMC3370595.

34. Koskiniemi S, Garza-Sanchez F, Sandegren L, Webb JS, Braaten BA, Poole SJ, et al. Selection of Orphan Rhs Toxin Expression in Evolved Salmonella enterica Serovar Typhimurium. PLoS Genet. 2014;10(3):e1004255. Epub 2014/03/29. doi: 10.1371/journal.pgen.1004255 24675981.

35. Kung VL, Khare S, Stehlik C, Bacon EM, Hughes AJ, Hauser AR. An rhs gene of Pseudomonas aeruginosa encodes a virulence protein that activates the inflammasome. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(4):1275–80. Epub 2012/01/11. doi: 10.1073/pnas.1109285109 22232685; PubMed Central PMCID: PMC3268321.

36. Chaudhuri RR, Morgan E, Peters SE, Pleasance SJ, Hudson DL, Davies HM, et al. Comprehensive assignment of roles for Salmonella typhimurium genes in intestinal colonization of food-producing animals. PLoS genetics. 2013;9(4):e1003456. Epub 2013/05/03. doi: 10.1371/journal.pgen.1003456 23637626; PubMed Central PMCID: PMC3630085.

37. Kroger C, Colgan A, Srikumar S, Handler K, Sivasankaran SK, Hammarlof DL, et al. An infection-relevant transcriptomic compendium for Salmonella enterica Serovar Typhimurium. Cell Host Microbe. 2013;14(6):683–95. Epub 2013/12/18. doi: 10.1016/j.chom.2013.11.010 24331466.

38. Morse RP, Nikolakakis KC, Willett JL, Gerrick E, Low DA, Hayes CS, et al. Structural basis of toxicity and immunity in contact-dependent growth inhibition (CDI) systems. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(52):21480–5. Epub 2012/12/14. doi: 10.1073/pnas.1216238110 23236156; PubMed Central PMCID: PMC3535622.

39. Helaine S, Thompson JA, Watson KG, Liu M, Boyle C, Holden DW. Dynamics of intracellular bacterial replication at the single cell level. Proc Natl Acad Sci U S A. 2010;107(8):3746–51. Epub 2010/02/06. doi: 10.1073/pnas.1000041107 20133586; PubMed Central PMCID: PMC2840444.

40. Harms A, Brodersen DE, Mitarai N, Gerdes K. Toxins, Targets, and Triggers: An Overview of Toxin-Antitoxin Biology. Mol Cell. 2018;70(5):768–84. Epub 2018/02/06. doi: 10.1016/j.molcel.2018.01.003 29398446.

41. Ghosh A, Baltekin O, Waneskog M, Elkhalifa D, Hammarlof DL, Elf J, et al. Contact-dependent growth inhibition induces high levels of antibiotic-tolerant persister cells in clonal bacterial populations. EMBO J. 2018. Epub 2018/03/25. doi: 10.15252/embj.201798026 29572241.

42. Takaya A, Tomoyasu T, Tokumitsu A, Morioka M, Yamamoto T. The ATP-dependent lon protease of Salmonella enterica serovar Typhimurium regulates invasion and expression of genes carried on Salmonella pathogenicity island 1. J Bacteriol. 2002;184(1):224–32. Epub 2001/12/14. doi: 10.1128/JB.184.1.224-232.2002 11741864; PubMed Central PMCID: PMC134781.

43. Lovett ST, Hurley RL, Sutera VA Jr., Aubuchon RH, Lebedeva MA. Crossing over between regions of limited homology in Escherichia coli. RecA-dependent and RecA-independent pathways. Genetics. 2002;160(3):851–9. Epub 2002/03/20. 11901106; PubMed Central PMCID: PMC1462031.

44. Petersen L, Bollback JP, Dimmic M, Hubisz M, Nielsen R. Genes under positive selection in Escherichia coli. Genome research. 2007;17(9):1336–43. Epub 2007/08/07. doi: 10.1101/gr.6254707 17675366; PubMed Central PMCID: PMC1950902.

45. Werren JH. Selfish genetic elements, genetic conflict, and evolutionary innovation. Proc Natl Acad Sci U S A. 2011;108 Suppl 2:10863–70. Epub 2011/06/22. doi: 10.1073/pnas.1102343108 21690392; PubMed Central PMCID: PMC3131821.

46. Brunet YR, Khodr A, Logger L, Aussel L, Mignot T, Rimsky S, et al. H-NS Silencing of the Salmonella Pathogenicity Island 6-Encoded Type VI Secretion System Limits Salmonella enterica Serovar Typhimurium Interbacterial Killing. Infect Immun. 2015;83(7):2738–50. Epub 2015/04/29. doi: 10.1128/IAI.00198-15 25916986; PubMed Central PMCID: PMC4468533.

47. 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. Epub 1999/11/05. doi: 10.1038/44593 10548107.

48. Virtanen P, Waneskog M, Koskiniemi S. Class II contact-dependent growth inhibition (CDI) systems allow for broad-range cross-species toxin delivery within the Enterobacteriaceae family. Mol Microbiol. 2019. Epub 2019/02/03. doi: 10.1111/mmi.14214 30710431.

49. Ma J, Sun M, Dong W, Pan Z, Lu C, Yao H. PAAR-Rhs proteins harbor various C-terminal toxins to diversify the antibacterial pathways of type VI secretion systems. Environ Microbiol. 2017;19(1):345–60. Epub 2016/11/22. doi: 10.1111/1462-2920.13621 27871130.

50. Kuroda A. A polyphosphate-lon protease complex in the adaptation of Escherichia coli to amino acid starvation. Biosci Biotechnol Biochem. 2006;70(2):325–31. Epub 2006/02/24. doi: 10.1271/bbb.70.325 16495646.

51. Nomura K, Kato J, Takiguchi N, Ohtake H, Kuroda A. Effects of inorganic polyphosphate on the proteolytic and DNA-binding activities of Lon in Escherichia coli. J Biol Chem. 2004;279(33):34406–10. Epub 2004/06/10. doi: 10.1074/jbc.M404725200 15187082.

52. Takaya A, Suzuki M, Matsui H, Tomoyasu T, Sashinami H, Nakane A, et al. Lon, a stress-induced ATP-dependent protease, is critically important for systemic Salmonella enterica serovar typhimurium infection of mice. Infect Immun. 2003;71(2):690–6. Epub 2003/01/24. doi: 10.1128/IAI.71.2.690-696.2003 12540547; PubMed Central PMCID: PMC145356.

53. Zhang D, de Souza RF, Anantharaman V, Iyer LM, Aravind L. Polymorphic toxin systems: Comprehensive characterization of trafficking modes, processing, mechanisms of action, immunity and ecology using comparative genomics. Biology direct. 2012;7:18. Epub 2012/06/27. doi: 10.1186/1745-6150-7-18 22731697; PubMed Central PMCID: PMC3482391.

54. Poole SJ, Diner EJ, Aoki SK, Braaten BA, t'Kint de Roodenbeke C, Low DA, et al. Identification of functional toxin/immunity genes linked to contact-dependent growth inhibition (CDI) and rearrangement hotspot (Rhs) systems. PLoS genetics. 2011;7(8):e1002217. Epub 2011/08/11. doi: 10.1371/journal.pgen.1002217 21829394; PubMed Central PMCID: PMC3150448.

55. Datsenko KA, Wanner BL. One-step inactivation of chromosomal genes in Escherichia coli K-12 using PCR products. Proceedings of the National Academy of Sciences of the United States of America. 2000;97(12):6640–5. Epub 2000/06/01. doi: 10.1073/pnas.120163297 10829079; PubMed Central PMCID: PMC18686.

56. B B. Curing bacterial cells of lysogenic viruses by using UCB indicator plates. BioTechniques. 1984;2:234–40.

57. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25(4):402–8. Epub 2002/02/16. doi: 10.1006/meth.2001.1262 11846609.

58. Katoh K, Standley DM. MAFFT multiple sequence alignment software version 7: improvements in performance and usability. Mol Biol Evol. 2013;30(4):772–80. Epub 2013/01/19. doi: 10.1093/molbev/mst010 23329690; PubMed Central PMCID: PMC3603318.


Článek vyšel v časopise

PLOS Genetics


2020 Číslo 2
Nejčtenější tento týden
Nejčtenější v tomto čísle
Kurzy

Zvyšte si kvalifikaci online z pohodlí domova

plice
INSIGHTS from European Respiratory Congress
nový kurz

Současné pohledy na riziko v parodontologii
Autoři: MUDr. Ladislav Korábek, CSc., MBA

Svět praktické medicíny 3/2024 (znalostní test z časopisu)

Kardiologické projevy hypereozinofilií
Autoři: prof. MUDr. Petr Němec, Ph.D.

Střevní příprava před kolonoskopií
Autoři: MUDr. Klára Kmochová, Ph.D.

Všechny kurzy
Kurzy Podcasty Doporučená témata Časopisy
Přihlášení
Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.

Přihlášení

Nemáte účet?  Registrujte se

#ADS_BOTTOM_SCRIPTS#