Expression of a novel class of bacterial Ig-like proteins is required for IncHI plasmid conjugation
Autoři:
Mário Hüttener aff001; Alejandro Prieto aff001; Sonia Aznar aff001; Manuel Bernabeu aff001; Estibaliz Glaría aff002; Annabel F. Valledor aff002; Sonia Paytubi aff001; Susana Merino aff001; Joan Tomás aff001; Antonio Juárez aff001
Působiště autorů:
Department of Genetics, Microbiology and Statistics, University of Barcelona, Barcelona, Spain
aff001; Department of Cell Biology, Physiology and Immunology, University of Barcelona, Barcelona, Spain
aff002; Institute for Bioengineering of Catalonia, The Barcelona Institute of Science and Technology, Barcelona, Spain
aff003
Vyšlo v časopise:
Expression of a novel class of bacterial Ig-like proteins is required for IncHI plasmid conjugation. PLoS Genet 15(9): e32767. doi:10.1371/journal.pgen.1008399
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1008399
Souhrn
Antimicrobial resistance (AMR) is currently one of the most important challenges to the treatment of bacterial infections. A critical issue to combat AMR is to restrict its spread. In several instances, bacterial plasmids are involved in the global spread of AMR. Plasmids belonging to the incompatibility group (Inc)HI are widespread in Enterobacteriaceae and most of them express multiple antibiotic resistance determinants. They play a relevant role in the recent spread of colistin resistance. We present in this report novel findings regarding IncHI plasmid conjugation. Conjugative transfer in liquid medium of an IncHI plasmid requires expression of a plasmid-encoded, large-molecular-mass protein that contains an Ig-like domain. The protein, termed RSP, is encoded by a gene (ORF R0009) that maps in the Tra2 region of the IncHI1 R27 plasmid. The RSP protein is exported outside the cell by using the plasmid-encoded type IV secretion system that is also used for its transmission to new cells. Expression of the protein reduces cell motility and enables plasmid conjugation. Flagella are one of the cellular targets of the RSP protein. The RSP protein is required for a high rate of plasmid transfer in both flagellated and nonflagellated Salmonella cells. This effect suggests that RSP interacts with other cellular structures as well as with flagella. These unidentified interactions must facilitate mating pair formation and, hence, facilitate IncHI plasmid conjugation. Due to its location on the outer surfaces of the bacterial cell, targeting the RSP protein could be a means of controlling IncHI plasmid conjugation in natural environments or of combatting infections caused by AMR enterobacteria that harbor IncHI plasmids.
Klíčová slova:
Biology and life sciences – Genetics – DNA – Plasmids – Genetic elements – Genomics – Mobile genetic elements – Biochemistry – Nucleic acids – Forms of DNA – Cell biology – Cellular structures and organelles – Flagella – Cellular types – Animal cells – Blood cells – White blood cells – Macrophages – Immune cells – Microbiology – Medical microbiology – Microbial pathogens – Bacterial pathogens – Salmonella – Microbial control – Organisms – Bacteria – Enterobacteriaceae – Molecular biology – Molecular biology techniques – DNA construction – Plasmid construction – Medicine and health sciences – Pathology and laboratory medicine – Pathogens – Virulence factors – Pathogen motility – Infectious diseases – Bacterial diseases – Pharmacology – Antimicrobial resistance – Antibiotic resistance – Immunology – Research and analysis methods – Database and informatics methods – Biological databases – Bioinformatics – Sequence analysis – Sequence databases
Zdroje
1. Morens DM, Folkers GK, Fauci AS. The challenge of emerging and re-emerging infectious diseases. Nature. 2004;430: 242–249. doi: 10.1038/nature02759 15241422
2. Meyer E, Schwab F, Schroeren-Boersch B, Gastmeier P. Dramatic increase of third-generation cephalosporin-resistant E. coli in German intensive care units: secular trends in antibiotic drug use and bacterial resistance, 2001 to 2008. Crit Care. 2010;14: R113. doi: 10.1186/cc9062 20546564
3. Rossolini GM, Mantengoli E, Docquier J-D, Musmanno RA, Coratza G. Epidemiology of infections caused by multiresistant gram-negatives: ESBLs, MBLs, panresistant strains. New Microbiol. 2007;30: 332–339. 17802921
4. Spellberg B, Guidos R, Gilbert D, Bradley J, Boucher HW, Scheld WM, et al. The epidemic of antibiotic-resistant infections: a call to action for the medical community from the Infectious Diseases Society of America. Clin Infect Dis. 2008;46: 155–164. doi: 10.1086/524891 18171244
5. Carattoli A. Plasmids and the spread of resistance. Int J Med Microbiol. 2013;303: 298–304. doi: 10.1016/j.ijmm.2013.02.001 23499304
6. Wang J, Stephan R, Zurfluh K, Hächler H, Fanning S. Characterization of the genetic environment of bla ESBL genes, integrons and toxin-antitoxin systems identified on large transferrable plasmids in multi-drug resistant Escherichia coli. Front Microbiol. 2014;5: 716. doi: 10.3389/fmicb.2014.00716 25610429
7. Lopatkin AJ, Meredith HR, Srimani JK, Pfeiffer C, Durrett R, You L. Persistence and reversal of plasmid-mediated antibiotic resistance. Nat Commun. 2017;8: 1689. doi: 10.1038/s41467-017-01532-1 29162798
8. Phan M-D, Wain J. IncHI plasmids, a dynamic link between resistance and pathogenicity. J Infect Dev Ctries. 2008;2: 272–278. 19741288
9. Whiteley M, Taylor DE. Identification of DNA homologies among H incompatibility group plasmids by restriction enzyme digestion and Southern transfer hybridization. Antimicrob Agents Chemother. 1983;24: 194–200. doi: 10.1128/aac.24.2.194 6314885
10. Liang Q, Yin Z, Zhao Y, Liang L, Feng J, Zhan Z, et al. Sequencing and comparative genomics analysis of the IncHI2 plasmids pT5282-mphA and p112298-catA and the IncHI5 plasmid pYNKP001-dfrA. Int J Antimicrob Agents. 2017;49: 709–718. doi: 10.1016/j.ijantimicag.2017.01.021 28390961
11. Maher D, Sherburne R, Taylor DE. H-pilus assembly kinetics determined by electron microscopy. J Bacteriol. 1993;175: 2175–2183. doi: 10.1128/jb.175.8.2175-2183.1993 8096837
12. Parry CM, Ho VA, Phuong LT, Bay PVB, Lanh MN, Tung LT, et al. Randomized controlled comparison of ofloxacin, azithromycin, and an ofloxacin-azithromycin combination for treatment of multidrug-resistant and nalidixic acid-resistant typhoid fever. Antimicrob Agents Chemother. 2007;51: 819–825. doi: 10.1128/AAC.00447-06 17145784
13. Holt KE, Phan M-D, Baker S, Duy PT, Nga TVT, Nair S, et al. Emergence of a globally dominant IncHI1 plasmid type associated with multiple drug resistant typhoid. PLoS Negl Trop Dis. 2011;5: e1245. doi: 10.1371/journal.pntd.0001245 21811646
14. Chen W, Fang T, Zhou X, Zhang D, Shi X, Shi C. IncHI2 Plasmids Are Predominant in Antibiotic-Resistant Salmonella Isolates. Front Microbiol. 2016;7: 1566. doi: 10.3389/fmicb.2016.01566 27746775
15. Villa L, Poirel L, Nordmann P, Carta C, Carattoli A. Complete sequencing of an IncH plasmid carrying the blaNDM-1, blaCTX-M-15 and qnrB1 genes. J Antimicrob Chemother. 2012;67: 1645–1650. doi: 10.1093/jac/dks114 22511638
16. Dolejska M, Villa L, Poirel L, Nordmann P, Carattoli A. Complete sequencing of an IncHI1 plasmid encoding the carbapenemase NDM-1, the ArmA 16S RNA methylase and a resistance-nodulation-cell division/multidrug efflux pump. J Antimicrob Chemother. 2013;68: 34–39. doi: 10.1093/jac/dks357 22969080
17. Lim LM, Ly N, Anderson D, Yang JC, Macander L, Jarkowski A, et al. Resurgence of colistin: a review of resistance, toxicity, pharmacodynamics, and dosing. Pharmacotherapy. 2010;30: 1279–1291. doi: 10.1592/phco.30.12.1279 21114395
18. Catry B, Cavaleri M, Baptiste K, Grave K, Grein K, Holm A, et al. Use of colistin-containing products within the European Union and European Economic Area (EU/EEA): development of resistance in animals and possible impact on human and animal health. Int J Antimicrob Agents. 2015;46: 297–306. doi: 10.1016/j.ijantimicag.2015.06.005 26215780
19. Olaitan AO, Morand S, Rolain J-M. Mechanisms of polymyxin resistance: acquired and intrinsic resistance in bacteria. Front Microbiol. 2014;5: 643. doi: 10.3389/fmicb.2014.00643 25505462
20. Liu Y-Y, Wang Y, Walsh TR, Yi L-X, Zhang R, Spencer J, et al. Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect Dis. 2016;16: 161–168. doi: 10.1016/S1473-3099(15)00424-7 26603172
21. Gao R, Hu Y, Li Z, Sun J, Wang Q, Lin J, et al. Dissemination and Mechanism for the MCR-1 Colistin Resistance. PLoS Pathog. 2016;12: e1005957. doi: 10.1371/journal.ppat.1005957 27893854
22. Xavier BB, Lammens C, Ruhal R, Kumar-Singh S, Butaye P, Goossens H, et al. Identification of a novel plasmid-mediated colistin-resistance gene, mcr-2, in Escherichia coli, Belgium, June 2016. Euro Surveill. 2016;21. doi: 10.2807/1560-7917.ES.2016.21.27.30280 27416987
23. Borowiak M, Fischer J, Hammerl JA, Hendriksen RS, Szabo I, Malorny B. Identification of a novel transposon-associated phosphoethanolamine transferase gene, mcr-5, conferring colistin resistance in d-tartrate fermenting Salmonella enterica subsp. enterica serovar Paratyphi B. J Antimicrob Chemother. 2017;72: 3317–3324. doi: 10.1093/jac/dkx327 28962028
24. Carattoli A, Villa L, Feudi C, Curcio L, Orsini S, Luppi A, et al. Novel plasmid-mediated colistin resistance mcr-4 gene in Salmonella and Escherichia coli, Italy 2013, Spain and Belgium, 2015 to 2016. Euro Surveill. 2017;22. doi: 10.2807/1560-7917.ES.2017.22.31.30589 28797329
25. Yin W, Li H, Shen Y, Liu Z, Wang S, Shen Z, et al. Novel Plasmid-Mediated Colistin Resistance Gene mcr-3 in Escherichia coli. MBio. 2017;8. doi: 10.1128/mBio.00543-17 28655818
26. Matamoros S, van Hattem JM, Arcilla MS, Willemse N, Melles DC, Penders J, et al. Global phylogenetic analysis of Escherichia coli and plasmids carrying the mcr-1 gene indicates bacterial diversity but plasmid restriction. Sci Rep. 2017;7: 15364. doi: 10.1038/s41598-017-15539-7 29127343
27. Wong MH-Y, Chan EW-C, Xie L, Li R, Chen S. IncHI2 Plasmids Are the Key Vectors Responsible for oqxAB Transmission among Salmonella Species. Antimicrob Agents Chemother. 2016;60: 6911–6915. doi: 10.1128/AAC.01555-16 27572409
28. Wang Y, Tian G-B, Zhang R, Shen Y, Tyrrell JM, Huang X, et al. Prevalence, risk factors, outcomes, and molecular epidemiology of mcr-1-positive Enterobacteriaceae in patients and healthy adults from China: an epidemiological and clinical study. Lancet Infect Dis. 2017;17: 390–399. doi: 10.1016/S1473-3099(16)30527-8 28139431
29. Zheng B, Dong H, Xu H, Lv J, Zhang J, Jiang X, et al. Coexistence of MCR-1 and NDM-1 in Clinical Escherichia coli Isolates. Clin Infect Dis. 2016;63: 1393–1395. doi: 10.1093/cid/ciw553 27506685
30. Forde BM, Zowawi HM, Harris PNA, Roberts L, Ibrahim E, Shaikh N, et al. Discovery of mcr-1-Mediated Colistin Resistance in a Highly Virulent Escherichia coli Lineage. mSphere. 2018;3. doi: 10.1128/mSphere.00486-18 30305321
31. Lawley TD, Gilmour MW, Gunton JE, Standeven LJ, Taylor DE. Functional and mutational analysis of conjugative transfer region 1 (Tra1) from the IncHI1 plasmid R27. J Bacteriol. 2002;184: 2173–2180. doi: 10.1128/JB.184.8.2173-2180.2002 11914349
32. Lawley TD, Gilmour MW, Gunton JE, Tracz DM, Taylor DE. Functional and mutational analysis of conjugative transfer region 2 (Tra2) from the IncHI1 plasmid R27. J Bacteriol. 2003;185: 581–591. doi: 10.1128/JB.185.2.581-591.2003 12511505
33. Alonso G, Baptista K, Ngo T, Taylor DE. Transcriptional organization of the temperature-sensitive transfer system from the IncHI1 plasmid R27. Microbiology (Reading, Engl). 2005;151: 3563–3573. doi: 10.1099/mic.0.28256–0
34. Sherburne CK, Lawley TD, Gilmour MW, Blattner FR, Burland V, Grotbeck E, et al. The complete DNA sequence and analysis of R27, a large IncHI plasmid from Salmonella typhi that is temperature sensitive for transfer. Nucleic Acids Res. 2000;28: 2177–2186. doi: 10.1093/nar/28.10.2177 10773089
35. Gilmour MW, Thomson NR, Sanders M, Parkhill J, Taylor DE. The complete nucleotide sequence of the resistance plasmid R478: defining the backbone components of incompatibility group H conjugative plasmids through comparative genomics. Plasmid. 2004;52: 182–202. doi: 10.1016/j.plasmid.2004.06.006 15518875
36. Halaby DM, Mornon JP. The immunoglobulin superfamily: an insight on its tissular, species, and functional diversity. J Mol Evol. 1998;46: 389–400. doi: 10.1007/pl00006318 9541533
37. Bodelón G, Palomino C, Fernández LÁ. Immunoglobulin domains in Escherichia coli and other enterobacteria: from pathogenesis to applications in antibody technologies. FEMS Microbiol Rev. 2013;37: 204–250. doi: 10.1111/j.1574-6976.2012.00347.x 22724448
38. Hüttener M, Prieto A, Aznar S, Dietrich M, Paytubi S, Juárez A. Tetracycline alters gene expression in Salmonella strains that harbor the Tn10 transposon. Environ Microbiol Rep. 2018;10: 202–209. doi: 10.1111/1758-2229.12621 29393572
39. Yang Y-H, Jiang Y-L, Zhang J, Wang L, Bai X-H, Zhang S-J, et al. Structural insights into SraP-mediated Staphylococcus aureus adhesion to host cells. PLoS Pathog. 2014;10: e1004169. doi: 10.1371/journal.ppat.1004169 24901708
40. Wagner C, Polke M, Gerlach RG, Linke D, Stierhof Y-D, Schwarz H, et al. Functional dissection of SiiE, a giant non-fimbrial adhesin of Salmonella enterica. Cell Microbiol. 2011;13: 1286–1301. doi: 10.1111/j.1462-5822.2011.01621.x 21729227
41. Rooker MM, Sherburne C, Lawley TD, Taylor DE. Characterization of the Tra2 region of the IncHI1 plasmid R27. Plasmid. 1999;41: 226–239. doi: 10.1006/plas.1999.1396 10366528
42. Paytubi S, Aznar S, Madrid C, Balsalobre C, Dillon SC, Dorman CJ, et al. A novel role for antibiotic resistance plasmids in facilitating Salmonella adaptation to non-host environments. Environ Microbiol. 2014;16: 950–962. doi: 10.1111/1462-2920.12244 24024872
43. Taylor DE, Newnham PJ, Sherburne C, Lawley TD, Rooker MM. Sequencing and characterization of Salmonella typhi plasmid R27 (incompatibility group HI1) trhC, a transfer gene encoding a potential nucleoside triphosphate-binding domain. Plasmid. 1999;41: 207–218. doi: 10.1006/plas.1999.1394 10366526
44. Forns N, Baños RC, Balsalobre C, Juárez A, Madrid C. Temperature-dependent conjugative transfer of R27: role of chromosome- and plasmid-encoded Hha and H-NS proteins. J Bacteriol. 2005;187: 3950–3959. doi: 10.1128/JB.187.12.3950-3959.2005 15937157
45. Taylor DE, Levine JG. Studies of temperature-sensitive transfer and maintenance of H incompatibility group plasmids. J Gen Microbiol. 1980;116: 475–484. doi: 10.1099/00221287-116-2-475 6989956
46. Maher D, Taylor DE. Host range and transfer efficiency of incompatibility group HI plasmids. Can J Microbiol. 1993;39: 581–587. doi: 10.1139/m93-084 8358670
47. Vogel JP, Andrews HL, Wong SK, Isberg RR. Conjugative transfer by the virulence system of Legionella pneumophila. Science. 1998;279: 873–876. doi: 10.1126/science.279.5352.873 9452389
48. Hong PC, Tsolis RM, Ficht TA. Identification of genes required for chronic persistence of Brucella abortus in mice. Infect Immun. 2000;68: 4102–4107. doi: 10.1128/iai.68.7.4102-4107.2000 10858227
49. Fernández-González E, de Paz HD, Alperi A, Agúndez L, Faustmann M, Sangari FJ, et al. Transfer of R388 derivatives by a pathogenesis-associated type IV secretion system into both bacteria and human cells. J Bacteriol. 2011;193: 6257–6265. doi: 10.1128/JB.05905-11 21908662
50. Schröder G, Schuelein R, Quebatte M, Dehio C. Conjugative DNA transfer into human cells by the VirB/VirD4 type IV secretion system of the bacterial pathogen Bartonella henselae. Proceedings of the National Academy of Sciences. 2011;108: 14643–14648. doi: 10.1073/pnas.1019074108 21844337
51. Christie PJ. The Mosaic Type IV Secretion Systems. EcoSal Plus. 2016;7. doi: 10.1128/ecosalplus.ESP-0020-2015 27735785
52. Cascales E, Christie PJ. The versatile bacterial type IV secretion systems. Nat Rev Microbiol. 2003;1: 137–149. doi: 10.1038/nrmicro753 15035043
53. Luque A, Paytubi S, Sánchez-Montejo J, Gibert M, Balsalobre C, Madrid C. Crosstalk between bacterial conjugation and motility is mediated by plasmid-borne regulators. Environ Microbiol Rep. 2019. doi: 10.1111/1758-2229.12784 31309702
54. Siboo IR, Chambers HF, Sullam PM. Role of SraP, a Serine-Rich Surface Protein of Staphylococcus aureus, in binding to human platelets. Infect Immun. 2005;73: 2273–2280. doi: 10.1128/IAI.73.4.2273-2280.2005 15784571
55. Li X, Bleumink-Pluym NMC, Luijkx YMCA, Wubbolts RW, van Putten JPM, Strijbis K. MUC1 is a receptor for the Salmonella SiiE adhesin that enables apical invasion into enterocytes. PLoS Pathog. 2019;15: e1007566. doi: 10.1371/journal.ppat.1007566 30716138
56. Walsh PM, McKay LL. Recombinant plasmid associated cell aggregation and high-frequency conjugation of Streptococcus lactis ML3. J Bacteriol. 1981;146: 937–944. 6787018
57. Luo H, Wan K, Wang HH. High-frequency conjugation system facilitates biofilm formation and pAMbeta1 transmission by Lactococcus lactis. Appl Environ Microbiol. 2005;71: 2970–2978. doi: 10.1128/AEM.71.6.2970-2978.2005 15932992
58. Tremblay C-L, Archambault M. Interference in pheromone-responsive conjugation of a high-level bacitracin resistant Enterococcus faecalis plasmid of poultry origin. Int J Environ Res Public Health. 2013;10: 4245–4260. doi: 10.3390/ijerph10094245 24030654
59. Tietgen M, Semmler T, Riedel-Christ S, Kempf VAJ, Molinaro A, Ewers C, et al. Impact of the colistin resistance gene mcr-1 on bacterial fitness. Int J Antimicrob Agents. 2018;51: 554–561. doi: 10.1016/j.ijantimicag.2017.11.011 29180279
60. Arcilla MS, van Hattem JM, Matamoros S, Melles DC, Penders J, de Jong MD, et al. Dissemination of the mcr-1 colistin resistance gene. Lancet Infect Dis. 2016;16: 147–149. doi: 10.1016/S1473-3099(15)00541-1
61. Baquero F, Coque TM, la Cruz de F. Ecology and evolution as targets: the need for novel eco-evo drugs and strategies to fight antibiotic resistance. Antimicrob Agents Chemother. 2011;55: 3649–3660. doi: 10.1128/AAC.00013-11 21576439
62. Lipsitch M, Siber GR. How Can Vaccines Contribute to Solving the Antimicrobial Resistance Problem? MBio. 2016;7. doi: 10.1128/mBio.00428-16 27273824
63. Miller JH. A Short Course in Bacterial Genetics. CSHL Press; 1992.
64. Datsenko KA, Wanner BL. One-step inactivation of chromosomal genes in Escherichia coli K-12 using PCR products. Proc Natl Acad Sci USA. 2000;97: 6640–6645. doi: 10.1073/pnas.120163297 10829079
65. Cherepanov PP, Wackernagel W. Gene disruption in Escherichia coli: TcR and KmR cassettes with the option of Flp-catalyzed excision of the antibiotic-resistance determinant. Gene. 1995;158: 9–14. doi: 10.1016/0378-1119(95)00193-a 7789817
66. Ellermeier CD, Janakiraman A, Slauch JM. Construction of targeted single copy lac fusions using lambda Red and FLP-mediated site-specific recombination in bacteria. Gene. 2002;290: 153–161. doi: 10.1016/s0378-1119(02)00551-6 12062810
67. Uzzau S, Figueroa-Bossi N, Rubino S, Bossi L. Epitope tagging of chromosomal genes in Salmonella. Proc Natl Acad Sci USA. 2001;98: 15264–15269. doi: 10.1073/pnas.261348198 11742086
68. Sambrook J, Russell DW. Molecular Cloning. CSHL Press; 2001. doi: 10.1089/152045501300189286
69. Wai SN, Westermark M, Oscarsson J, Jass J, Maier E, Benz R, et al. Characterization of dominantly negative mutant ClyA cytotoxin proteins in Escherichia coli. J Bacteriol. 2003;185: 5491–5499. doi: 10.1128/JB.185.18.5491-5499.2003 12949101
70. 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: 402–408. doi: 10.1006/meth.2001.1262 11846609
71. Kelley LA, Mezulis S, Yates CM, Wass MN, Sternberg MJE. The Phyre2 web portal for protein modeling, prediction and analysis. Nat Protoc. 2015;10: 845–858. doi: 10.1038/nprot.2015.053 25950237
72. Jones DT. Protein secondary structure prediction based on position-specific scoring matrices. J Mol Biol. 1999;292: 195–202. doi: 10.1006/jmbi.1999.3091 10493868
73. Valledor AF, Comalada M, Xaus J, Celada A. The differential time-course of extracellular-regulated kinase activity correlates with the macrophage response toward proliferation or activation. J Biol Chem. 2000;275: 7403–7409. doi: 10.1074/jbc.275.10.7403 10702314
74. Birmingham CL, Smith AC, Bakowski MA, Yoshimori T, Brumell JH. Autophagy controls Salmonella infection in response to damage to the Salmonella-containing vacuole. J Biol Chem. 2006;281: 11374–11383. doi: 10.1074/jbc.M509157200 16495224
75. Matalonga J, Glaria E, Bresque M, Escande C, Carbó JM, Kiefer K, et al. The Nuclear Receptor LXR Limits Bacterial Infection of Host Macrophages through a Mechanism that Impacts Cellular NAD Metabolism. Cell Rep. 2017;18: 1241–1255. doi: 10.1016/j.celrep.2017.01.007 28147278
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