Journal of Veterinary Science

The Korean Society of Veterinary Science (대한수의학회)
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Pathophysiology of enteropathogenic Escherichia coli during a host infection

  • Lee, Jun Bong (College of Veterinary Medicine & Institute of Veterinary Science, Kangwon National University) ;
  • Kim, Se Kye (College of Veterinary Medicine & Institute of Veterinary Science, Kangwon National University) ;
  • Yoon, Jang Won (College of Veterinary Medicine & Institute of Veterinary Science, Kangwon National University)
  • Received : 2021.06.01
  • Accepted : 2021.12.07
  • Published : 2022.03.31
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Abstract

Enteropathogenic Escherichia coli (EPEC) is a major cause of infantile diarrhea in developing countries. However, sporadic outbreaks caused by this microorganism in developed countries are frequently reported recently. As an important zoonotic pathogen, EPEC is being monitored annually in several countries. Hallmark of EPEC infection is formation of attaching and effacing (A/E) lesions on the small intestine. To establish A/E lesions during a gastrointestinal tract (GIT) infeciton, EPEC must thrive in diverse GIT environments. A variety of stress responses by EPEC have been reported. These responses play significant roles in helping E. coli pass through GIT environments and establishing E. coli infection. Stringent response is one of those responses. It is mediated by guanosine tetraphosphate. Interestingly, previous studies have demonstrated that stringent response is a universal virulence regulatory mechanism present in many bacterial pathogens including EPEC. However, biological signficance of a bacterial stringent response in both EPEC and its interaction with the host during a GIT infection is unclear. It needs to be elucidated to broaden our insight to EPEC pathogenesis. In this review, diverse responses, including stringent response, of EPEC during a GIT infection are discussed to provide a new insight into EPEC pathophysiology in the GIT.

Keywords

Acknowledgement

This study was supported in parts by grants from National Research Foundation (NRF2017R1A2B4013056) and from the Animal & Plant Quarantine Agency (Z-1543081-2021-23-01), Ministry of Agriculture, Food, and Rural Affairs, Republic of Korea.

References

  1. Ochoa TJ, Contreras CA. Enteropathogenic Escherichia coli infection in children. Curr Opin Infect Dis. 2011;24(5):478-483. https://doi.org/10.1097/QCO.0b013e32834a8b8b
  2. Chen HD, Frankel G. Enteropathogenic Escherichia coli: unravelling pathogenesis. FEMS Microbiol Rev. 2005;29(1):83-98. https://doi.org/10.1016/j.femsre.2004.07.002
  3. Trabulsi LR, Keller R, Tardelli Gomes TA. Typical and atypical enteropathogenic Escherichia coli. Emerg Infect Dis. 2002;8(5):508-513. https://doi.org/10.3201/eid0805.010385
  4. Kinnula S, Hemminki K, Kotilainen H, Ruotsalainen E, Tarkka E, Salmenlinna S, et al. Outbreak of multiple strains of non-O157 Shiga toxin-producing and enteropathogenic Escherichia coli associated with rocket salad, Finland, autumn 2016. Euro Surveill. 2018;23(35):23.
  5. Lim MA, Kim JY, Acharya D, Bajgain BB, Park JH, Yoo SJ, et al. A diarrhoeagenic Enteropathogenic Escherichia coli (EPEC) infection outbreak that occurred among elementary school children in Gyeongsangbuk-Do province of South Korea was associated with consumption of water-contaminated food items. Int J Environ Res Public Health. 2020;17(9):3149. https://doi.org/10.3390/ijerph17093149
  6. Clarke SC, Haigh RD, Freestone PP, Williams PH. Virulence of enteropathogenic Escherichia coli, a global pathogen. Clin Microbiol Rev. 2003;16(3):365-378. https://doi.org/10.1128/CMR.16.3.365-378.2003
  7. Cantas L, Suer K. Review: the important bacterial zoonoses in "one health" concept. Front Public Health. 2014;2:144. https://doi.org/10.3389/fpubh.2014.00144
  8. Rhouma M, Fairbrother JM, Beaudry F, Letellier A. Post weaning diarrhea in pigs: risk factors and noncolistin-based control strategies. Acta Vet Scand. 2017;59(1):31. https://doi.org/10.1186/s13028-017-0299-7
  9. Gansheroff LJ, O'Brien AD. Escherichia coli O157:H7 in beef cattle presented for slaughter in the U.S.: higher prevalence rates than previously estimated. Proc Natl Acad Sci U S A. 2000;97(7):2959-2961. https://doi.org/10.1073/pnas.97.7.2959
  10. Jeamsripong S, Chase JA, Jay-Russell MT, Buchanan RL, Atwill ER. Experimental in-field transfer and survival of Escherichia coli from animal feces to romaine lettuce in Salinas Valley, California. Microorganisms. 2019;7(10):408. https://doi.org/10.3390/microorganisms7100408
  11. Fairbrother JM, Nadeau E. Escherichia coli: on-farm contamination of animals. Rev Sci Tech. 2006;25(2):555-569. https://doi.org/10.20506/rst.25.2.1682
  12. Tenaillon O, Skurnik D, Picard B, Denamur E. The population genetics of commensal Escherichia coli. Nat Rev Microbiol. 2010;8(3):207-217. https://doi.org/10.1038/nrmicro2298
  13. Kaper JB, Nataro JP, Mobley HL. Pathogenic Escherichia coli. Nat Rev Microbiol. 2004;2(2):123-140. https://doi.org/10.1038/nrmicro818
  14. Yoon JW, Hovde CJ. All blood, no stool: enterohemorrhagic Escherichia coli O157:H7 infection. J Vet Sci. 2008;9(3):219-231. https://doi.org/10.4142/jvs.2008.9.3.219
  15. Bray J. Isolation of antigenically homogeneous strains of Bact. coli neapolitanum from summer diarrhoea of infants. J Pathol Bacteriol. 1945;57(2):239-247. https://doi.org/10.1002/path.1700570210
  16. Robins-Browne RM. Traditional enteropathogenic Escherichia coli of infantile diarrhea. Rev Infect Dis. 1987;9(1):28-53. https://doi.org/10.1093/clinids/9.1.28
  17. Ochoa TJ, Barletta F, Contreras C, Mercado E. New insights into the epidemiology of enteropathogenic Escherichia coli infection. Trans R Soc Trop Med Hyg. 2008;102(9):852-856. https://doi.org/10.1016/j.trstmh.2008.03.017
  18. Berdal JE, Follin-Arbelet B, Bjornholt JV. Experiences from multiplex PCR diagnostics of faeces in hospitalised patients: clinical significance of Enteropathogenic Escherichia coli (EPEC) and culture negative campylobacter. BMC Infect Dis. 2019;19(1):630. https://doi.org/10.1186/s12879-019-4271-1
  19. Staples M, Doyle CJ, Graham RM, Jennison AV. Molecular epidemiological typing of enteropathogenic Escherichia coli strains from Australian patients. Diagn Microbiol Infect Dis. 2013;75(3):320-324. https://doi.org/10.1016/j.diagmicrobio.2012.11.010
  20. Thomas RR, Brooks HJ, O'Brien R. Prevalence of Shiga toxin-producing and enteropathogenic Escherichia coli marker genes in diarrhoeic stools in a New Zealand catchment area. J Clin Pathol. 2017;70(1):81-84. https://doi.org/10.1136/jclinpath-2016-203882
  21. Lee DW, Gwack J, Youn SK. Enteropathogenic Escherichia coli outbreak and its incubation period: is it short or long? Osong Public Health Res Perspect. 2012;3(1):43-47. https://doi.org/10.1016/j.phrp.2012.01.007
  22. Wang L, Zhang S, Zheng D, Fujihara S, Wakabayashi A, Okahata K, et al. Prevalence of diarrheagenic Escherichia coli in foods and fecal specimens obtained from cattle, pigs, chickens, asymptomatic carriers, and patients in Osaka and Hyogo, Japan. Jpn J Infect Dis. 2017;70(4):464-469. https://doi.org/10.7883/yoken.JJID.2016.486
  23. Bardiau M, Szalo M, Mainil JG. Initial adherence of EPEC, EHEC and VTEC to host cells. Vet Res. 2010;41(5):57. https://doi.org/10.1051/vetres/2010029
  24. Thiry D, Saulmont M, Takaki S, De Rauw K, Duprez JN, Iguchi A, et al. Enteropathogenic Escherichia coli O80:H2 in young calves with diarrhea, Belgium. Emerg Infect Dis. 2017;23(12):2093-2095. https://doi.org/10.3201/eid2312.170450
  25. De Rauw K, Thiry D, Caljon B, Saulmont M, Mainil J, Pierard D. Characteristics of Shiga toxin producingand enteropathogenic Escherichia coli of the emerging serotype O80:H2 isolated from humans and diarrhoeic calves in Belgium. Clin Microbiol Infect. 2019;25(1):111.e5-111.e8. https://doi.org/10.1016/j.cmi.2018.07.023
  26. Garcia-Menino I, Garcia V, Mora A, Diaz-Jimenez D, Flament-Simon SC, Alonso MP, et al. Swine enteric colibacillosis in Spain: pathogenic potential of mcr-1 ST10 and ST131 E. coli isolates. Front Microbiol. 2018;9:2659. https://doi.org/10.3389/fmicb.2018.02659
  27. Kjaergaard AB, Carr AP, Gaunt MC. Enteropathogenic Escherichia coli (EPEC) infection in association with acute gastroenteritis in 7 dogs from Saskatchewan. Can Vet J 2016;57(9):964-968.
  28. Watson VE, Jacob ME, Flowers JR, Strong SJ, DebRoy C, Gookin JL. Association of atypical enteropathogenic Escherichia coli with diarrhea and related mortality in kittens. J Clin Microbiol. 2017;55(9):2719-2735. https://doi.org/10.1128/JCM.00403-17
  29. Arais LR, Barbosa AV, Andrade JR, Gomes TA, Asensi MD, Aires CA, et al. Zoonotic potential of atypical enteropathogenic Escherichia coli (aEPEC) isolated from puppies with diarrhoea in Brazil. Vet Microbiol. 2018;227:45-51. https://doi.org/10.1016/j.vetmic.2018.10.023
  30. Moon HW, Whipp SC, Argenzio RA, Levine MM, Giannella RA. Attaching and effacing activities of rabbit and human enteropathogenic Escherichia coli in pig and rabbit intestines. Infect Immun. 1983;41(3):1340-1351. https://doi.org/10.1128/iai.41.3.1340-1351.1983
  31. Nataro JP, Kaper JB. Diarrheagenic Escherichia coli. Clin Microbiol Rev. 1998;11(1):142-201. https://doi.org/10.1128/cmr.11.1.142
  32. Ramboarina S, Fernandes PJ, Daniell S, Islam S, Simpson P, Frankel G, et al. Structure of the bundleforming pilus from enteropathogenic Escherichia coli. J Biol Chem. 2005;280(48):40252-40260. https://doi.org/10.1074/jbc.M508099200
  33. Giron JA, Ho AS, Schoolnik GK. An inducible bundle-forming pilus of enteropathogenic Escherichia coli. Science. 1991;254(5032):710-713. https://doi.org/10.1126/science.1683004
  34. Scaletsky IC, Silva ML, Trabulsi LR. Distinctive patterns of adherence of enteropathogenic Escherichia coli to HeLa cells. Infect Immun. 1984;45(2):534-536. https://doi.org/10.1128/iai.45.2.534-536.1984
  35. Stone KD, Zhang HZ, Carlson LK, Donnenberg MS. A cluster of fourteen genes from enteropathogenic Escherichia coli is sufficient for the biogenesis of a type IV pilus. Mol Microbiol. 1996;20(2):325-337. https://doi.org/10.1111/j.1365-2958.1996.tb02620.x
  36. Baldini MM, Kaper JB, Levine MM, Candy DC, Moon HW. Plasmid-mediated adhesion in enteropathogenic Escherichia coli. J Pediatr Gastroenterol Nutr. 1983;2(3):534-538. https://doi.org/10.1097/00005176-198302030-00023
  37. Bieber D, Ramer SW, Wu CY, Murray WJ, Tobe T, Fernandez R, et al. Type IV pili, transient bacterial aggregates, and virulence of enteropathogenic Escherichia coli. Science. 1998;280(5372):2114-2118. https://doi.org/10.1126/science.280.5372.2114
  38. Zhang HZ, Lory S, Donnenberg MS. A plasmid-encoded prepilin peptidase gene from enteropathogenic Escherichia coli. J Bacteriol. 1994;176(22):6885-6891. https://doi.org/10.1128/jb.176.22.6885-6891.1994
  39. Anantha RP, Stone KD, Donnenberg MS. Effects of bfp mutations on biogenesis of functional enteropathogenic Escherichia coli type IV pili. J Bacteriol. 2000;182(9):2498-2506. https://doi.org/10.1128/JB.182.9.2498-2506.2000
  40. Anantha RP, Stone KD, Donnenberg MS. Role of BfpF, a member of the PilT family of putative nucleotide-binding proteins, in type IV pilus biogenesis and in interactions between enteropathogenic Escherichia coli and host cells. Infect Immun. 1998;66(1):122-131. https://doi.org/10.1128/iai.66.1.122-131.1998
  41. Zahavi EE, Lieberman JA, Donnenberg MS, Nitzan M, Baruch K, Rosenshine I, et al. Bundle-forming pilus retraction enhances enteropathogenic Escherichia coli infectivity. Mol Biol Cell. 2011;22(14):2436-2447. https://doi.org/10.1091/mbc.E11-01-0001
  42. Croxen MA, Finlay BB. Molecular mechanisms of Escherichia coli pathogenicity. Nat Rev Microbiol. 2010;8(1):26-38. https://doi.org/10.1038/nrmicro2265
  43. Perna NT, Mayhew GF, Posfai G, Elliott S, Donnenberg MS, Kaper JB, et al. Molecular evolution of a pathogenicity island from enterohemorrhagic Escherichia coli O157:H7. Infect Immun. 1998;66(8):3810-3817. https://doi.org/10.1128/iai.66.8.3810-3817.1998
  44. Deng W, Puente JL, Gruenheid S, Li Y, Vallance BA, Vazquez A, et al. Dissecting virulence: systematic and functional analyses of a pathogenicity island. Proc Natl Acad Sci U S A. 2004;101(10):3597-3602. https://doi.org/10.1073/pnas.0400326101
  45. Costa TR, Felisberto-Rodrigues C, Meir A, Prevost MS, Redzej A, Trokter M, et al. Secretion systems in Gram-negative bacteria: structural and mechanistic insights. Nat Rev Microbiol. 2015;13(6):343-359. https://doi.org/10.1038/nrmicro3456
  46. Gaytan MO, Martinez-Santos VI, Soto E, Gonzalez-Pedrajo B. Type three secretion system in attaching and effacing pathogens. Front Cell Infect Microbiol. 2016;6:129. https://doi.org/10.3389/fcimb.2016.00129
  47. Sekiya K, Ohishi M, Ogino T, Tamano K, Sasakawa C, Abe A. Supermolecular structure of the enteropathogenic Escherichia coli type III secretion system and its direct interaction with the EspA-sheath-like structure. Proc Natl Acad Sci U S A. 2001;98(20):11638-11643. https://doi.org/10.1073/pnas.191378598
  48. Croxen MA, Law RJ, Scholz R, Keeney KM, Wlodarska M, Finlay BB. Recent advances in understanding enteric pathogenic Escherichia coli. Clin Microbiol Rev. 2013;26(4):822-880. https://doi.org/10.1128/CMR.00022-13
  49. Iizumi Y, Sagara H, Kabe Y, Azuma M, Kume K, Ogawa M, et al. The enteropathogenic E. coli effector EspB facilitates microvillus effacing and antiphagocytosis by inhibiting myosin function. Cell Host Microbe. 2007;2(6):383-392. https://doi.org/10.1016/j.chom.2007.09.012
  50. Kenny B, DeVinney R, Stein M, Reinscheid DJ, Frey EA, Finlay BB. Enteropathogenic E. coli (EPEC) transfers its receptor for intimate adherence into mammalian cells. Cell. 1997;91(4):511-520. https://doi.org/10.1016/S0092-8674(00)80437-7
  51. Bhatt S, Romeo T, Kalman D. Honing the message: post-transcriptional and post-translational control in attaching and effacing pathogens. Trends Microbiol. 2011;19(5):217-224. https://doi.org/10.1016/j.tim.2011.01.004
  52. Kenny B. Phosphorylation of tyrosine 474 of the enteropathogenic Escherichia coli (EPEC) Tir receptor molecule is essential for actin nucleating activity and is preceded by additional host modifications. Mol Microbiol. 1999;31(4):1229-1241. https://doi.org/10.1046/j.1365-2958.1999.01265.x
  53. Gruenheid S, DeVinney R, Bladt F, Goosney D, Gelkop S, Gish GD, et al. Enteropathogenic E. coli Tir binds Nck to initiate actin pedestal formation in host cells. Nat Cell Biol. 2001;3(9):856-859. https://doi.org/10.1038/ncb0901-856
  54. Kalman D, Weiner OD, Goosney DL, Sedat JW, Finlay BB, Abo A, et al. Enteropathogenic E. coli acts through WASP and Arp2/3 complex to form actin pedestals. Nat Cell Biol. 1999;1(6):389-391. https://doi.org/10.1038/14087
  55. Martins FH, Kumar A, Abe CM, Carvalho E, Nishiyama-Jr M, Xing C, et al. EspFu-mediated actin assembly enhances enteropathogenic Escherichia coli adherence and activates host cell inflammatory signaling pathways. MBio. 2020;11(2):11.
  56. Mekalanos JJ. Environmental signals controlling expression of virulence determinants in bacteria. J Bacteriol. 1992;174(1):1-7. https://doi.org/10.1128/jb.174.1.1-7.1992
  57. Pienaar JA, Singh A, Barnard TG. Acid-happy: survival and recovery of enteropathogenic Escherichia coli (EPEC) in simulated gastric fluid. Microb Pathog. 2019;128:396-404. https://doi.org/10.1016/j.micpath.2019.01.022
  58. Lin J, Smith MP, Chapin KC, Baik HS, Bennett GN, Foster JW. Mechanisms of acid resistance in enterohemorrhagic Escherichia coli. Appl Environ Microbiol. 1996;62(9):3094-3100. https://doi.org/10.1128/aem.62.9.3094-3100.1996
  59. Castanie-Cornet MP, Penfound TA, Smith D, Elliott JF, Foster JW. Control of acid resistance in Escherichia coli. J Bacteriol. 1999;181(11):3525-3535. https://doi.org/10.1128/jb.181.11.3525-3535.1999
  60. Mata GM, Ferreira GM, Spira B. RpoS role in virulence and fitness in enteropathogenic Escherichia coli. PLoS One. 2017;12(6):e0180381. https://doi.org/10.1371/journal.pone.0180381
  61. Lim JY, Yoon J, Hovde CJ. A brief overview of Escherichia coli O157:H7 and its plasmid O157. J Microbiol Biotechnol. 2010;20(1):5-14. https://doi.org/10.4014/jmb.0908.08007
  62. Hersh BM, Farooq FT, Barstad DN, Blankenhorn DL, Slonczewski JL. A glutamate-dependent acid resistance gene in Escherichia coli. J Bacteriol. 1996;178(13):3978-3981. https://doi.org/10.1128/jb.178.13.3978-3981.1996
  63. Lu P, Ma D, Chen Y, Guo Y, Chen GQ, Deng H, et al. L-glutamine provides acid resistance for Escherichia coli through enzymatic release of ammonia. Cell Res. 2013;23(5):635-644. https://doi.org/10.1038/cr.2013.13
  64. Gong S, Richard H, Foster JW. YjdE (AdiC) is the arginine:agmatine antiporter essential for arginine-dependent acid resistance in Escherichia coli. J Bacteriol. 2003;185(15):4402-4409. https://doi.org/10.1128/JB.185.15.4402-4409.2003
  65. Kuper C, Jung K. CadC-mediated activation of the cadBA promoter in Escherichia coli. J Mol Microbiol Biotechnol. 2005;10(1):26-39. https://doi.org/10.1159/000090346
  66. Cantey JR, Inman LR. Diarrhea due to Escherichia coli strain RDEC-1 in the rabbit: the peyer's patch as the initial site of attachment and colonization. J Infect Dis. 1981;143(3):440-446. https://doi.org/10.1093/infdis/143.3.440
  67. Fitzhenry RJ, Reece S, Trabulsi LR, Heuschkel R, Murch S, Thomson M, et al. Tissue tropism of enteropathogenic Escherichia coli strains belonging to the O55 serogroup. Infect Immun. 2002;70(8):4362-4368. https://doi.org/10.1128/IAI.70.8.4362-4368.2002
  68. Inman LR, Cantey JR. Peyer's patch lymphoid follicle epithelial adherence of a rabbit enteropathogenic Escherichia coli (strain RDEC-1). Role of plasmid-mediated pili in initial adherence. J Clin Invest. 1984;74(1):90-95. https://doi.org/10.1172/JCI111423
  69. Martinez-Argudo I, Sands C, Jepson MA. Translocation of enteropathogenic Escherichia coli across an in vitro M cell model is regulated by its type III secretion system. Cell Microbiol. 2007;9(6):1538-1546. https://doi.org/10.1111/j.1462-5822.2007.00891.x
  70. Franken L, Schiwon M, Kurts C. Macrophages: sentinels and regulators of the immune system. Cell Microbiol. 2016;18(4):475-487. https://doi.org/10.1111/cmi.12580
  71. Freeman SA, Grinstein S. Phagocytosis: receptors, signal integration, and the cytoskeleton. Immunol Rev. 2014;262(1):193-215. https://doi.org/10.1111/imr.12212
  72. Quitard S, Dean P, Maresca M, Kenny B. The enteropathogenic Escherichia coli EspF effector molecule inhibits PI-3 kinase-mediated uptake independently of mitochondrial targeting. Cell Microbiol. 2006;8(6):972-981. https://doi.org/10.1111/j.1462-5822.2005.00680.x
  73. Marches O, Covarelli V, Dahan S, Cougoule C, Bhatta P, Frankel G, et al. EspJ of enteropathogenic and enterohaemorrhagic Escherichia coli inhibits opsono-phagocytosis. Cell Microbiol. 2008;10(5):1104-1115. https://doi.org/10.1111/j.1462-5822.2007.01112.x
  74. Dong N, Liu L, Shao F. A bacterial effector targets host DH-PH domain RhoGEFs and antagonizes macrophage phagocytosis. EMBO J. 2010;29(8):1363-1376. https://doi.org/10.1038/emboj.2010.33
  75. Mogensen TH. Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev. 2009;22(2):240-273. https://doi.org/10.1128/CMR.00046-08
  76. Edwards LA, Bajaj-Elliott M, Klein NJ, Murch SH, Phillips AD. Bacterial-epithelial contact is a key determinant of host innate immune responses to enteropathogenic and enteroaggregative Escherichia coli. PLoS One. 2011;6(10):e27030. https://doi.org/10.1371/journal.pone.0027030
  77. Zhou X, Giron JA, Torres AG, Crawford JA, Negrete E, Vogel SN, et al. Flagellin of enteropathogenic Escherichia coli stimulates interleukin-8 production in T84 cells. Infect Immun. 2003;71(4):2120-2129. https://doi.org/10.1128/IAI.71.4.2120-2129.2003
  78. Santos AS, Finlay BB. Bringing down the host: enteropathogenic and enterohaemorrhagic Escherichia coli effector-mediated subversion of host innate immune pathways. Cell Microbiol. 2015;17(3):318-332. https://doi.org/10.1111/cmi.12412
  79. Yen H, Karino M, Tobe T. Modulation of the inflammasome signaling pathway by enteropathogenic and enterohemorrhagic Escherichia coli. Front Cell Infect Microbiol. 2016;6:89. https://doi.org/10.3389/fcimb.2016.00089
  80. Yan D, Quan H, Wang L, Liu F, Liu H, Chen J, et al. Enteropathogenic Escherichia coli Tir recruits cellular SHP-2 through ITIM motifs to suppress host immune response. Cell Signal. 2013;25(9):1887-1894. https://doi.org/10.1016/j.cellsig.2013.05.020
  81. Newton HJ, Pearson JS, Badea L, Kelly M, Lucas M, Holloway G, et al. The type III effectors NleE and NleB from enteropathogenic E. coli and OspZ from Shigella block nuclear translocation of NF-kappaB p65. PLoS Pathog. 2010;6(5):e1000898. https://doi.org/10.1371/journal.ppat.1000898
  82. Nadler C, Baruch K, Kobi S, Mills E, Haviv G, Farago M, et al. The type III secretion effector NleE inhibits NF-kappaB activation. PLoS Pathog. 2010;6(1):e1000743. https://doi.org/10.1371/journal.ppat.1000743
  83. Gao X, Wan F, Mateo K, Callegari E, Wang D, Deng W, et al. Bacterial effector binding to ribosomal protein s3 subverts NF-kappaB function. PLoS Pathog. 2009;5(12):e1000708. https://doi.org/10.1371/journal.ppat.1000708
  84. Yen H, Ooka T, Iguchi A, Hayashi T, Sugimoto N, Tobe T. NleC, a type III secretion protease, compromises NF-κB activation by targeting p65/RelA. PLoS Pathog. 2010;6(12):e1001231. https://doi.org/10.1371/journal.ppat.1001231
  85. Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, et al. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol. 2009;183(2):787-791. https://doi.org/10.4049/jimmunol.0901363
  86. Yen H, Sugimoto N, Tobe T. Enteropathogenic Escherichia coli uses NleA to inhibit NLRP3 inflammasome activation. PLoS Pathog. 2015;11(9):e1005121. https://doi.org/10.1371/journal.ppat.1005121
  87. Blasche S, Mortl M, Steuber H, Siszler G, Nisa S, Schwarz F, et al. The E. coli effector protein NleF is a caspase inhibitor. PLoS One. 2013;8(3):e58937. https://doi.org/10.1371/journal.pone.0058937
  88. Savkovic SD, Koutsouris A, Hecht G. Attachment of a noninvasive enteric pathogen, enteropathogenic Escherichia coli, to cultured human intestinal epithelial monolayers induces transmigration of neutrophils. Infect Immun. 1996;64(11):4480-4487. https://doi.org/10.1128/iai.64.11.4480-4487.1996
  89. Goddard PJ, Sanchez-Garrido J, Slater SL, Kalyan M, Ruano-Gallego D, Marches O, et al. Enteropathogenic Escherichia coli stimulates effector-driven rapid caspase-4 activation in human macrophages. Cell Rep. 2019;27(4):1008-1017.e6. https://doi.org/10.1016/j.celrep.2019.03.100
  90. Berndt V, Beckstette M, Volk M, Dersch P, Bronstrup M. Metabolome and transcriptome-wide effects of the carbon storage regulator A in enteropathogenic Escherichia coli. Sci Rep. 2019;9(1):138. https://doi.org/10.1038/s41598-018-36932-w
  91. Law D, Wilkie KM, Freeman R, Gould FK. The iron uptake mechanisms of enteropathogenic Escherichia coli: the use of haem and haemoglobin during growth in an iron-limited environment. J Med Microbiol. 1992;37(1):15-21. https://doi.org/10.1099/00222615-37-1-15
  92. Pal RR, Baidya AK, Mamou G, Bhattacharya S, Socol Y, Kobi S, et al. Pathogenic E. coli extracts nutrients from infected host cells utilizing injectisome components. Cell. 2019;177(3):683-696.e18. https://doi.org/10.1016/j.cell.2019.02.022
  93. Ashokkumar B, Kumar JS, Hecht GA, Said HM. Enteropathogenic Escherichia coli inhibits intestinal vitamin B1 (thiamin) uptake: studies with human-derived intestinal epithelial Caco-2 cells. Am J Physiol Gastrointest Liver Physiol. 2009;297(4):G825-G833. https://doi.org/10.1152/ajpgi.00250.2009
  94. Dalebroux ZD, Swanson MS. ppGpp: magic beyond RNA polymerase. Nat Rev Microbiol. 2012;10(3):203-212. https://doi.org/10.1038/nrmicro2720
  95. Cashel M. The control of ribonucleic acid synthesis in Escherichia coli. IV. Relevance of unusual phosphorylated compounds from amino acid-starved stringent strains. J Biol Chem. 1969;244(12):3133-3141. https://doi.org/10.1016/S0021-9258(18)93106-6
  96. Xiao H, Kalman M, Ikehara K, Zemel S, Glaser G, Cashel M. Residual guanosine 3',5'-bispyrophosphate synthetic activity of relA null mutants can be eliminated by spoT null mutations. J Biol Chem. 1991;266(9):5980-5990. https://doi.org/10.1016/S0021-9258(19)67694-5
  97. Mechold U, Potrykus K, Murphy H, Murakami KS, Cashel M. Differential regulation by ppGpp versus pppGpp in Escherichia coli. Nucleic Acids Res. 2013;41(12):6175-6189. https://doi.org/10.1093/nar/gkt302
  98. Zuo Y, Wang Y, Steitz TA. The mechanism of E. coli RNA polymerase regulation by ppGpp is suggested by the structure of their complex. Mol Cell. 2013;50(3):430-436. https://doi.org/10.1016/j.molcel.2013.03.020
  99. Jishage M, Kvint K, Shingler V, Nystrom T. Regulation of sigma factor competition by the alarmone ppGpp. Genes Dev. 2002;16(10):1260-1270. https://doi.org/10.1101/gad.227902
  100. Jin DJ, Cagliero C, Zhou YN. Growth rate regulation in Escherichia coli. FEMS Microbiol Rev. 2012;36(2):269-287. https://doi.org/10.1111/j.1574-6976.2011.00279.x
  101. Magnusson LU, Gummesson B, Joksimovic P, Farewell A, Nystrom T. Identical, independent, and opposing roles of ppGpp and DksA in Escherichia coli. J Bacteriol. 2007;189(14):5193-5202. https://doi.org/10.1128/JB.00330-07
  102. Hauryliuk V, Atkinson GC, Murakami KS, Tenson T, Gerdes K. Recent functional insights into the role of (p)ppGpp in bacterial physiology. Nat Rev Microbiol. 2015;13(5):298-309. https://doi.org/10.1038/nrmicro3448
  103. Wendrich TM, Blaha G, Wilson DN, Marahiel MA, Nierhaus KH. Dissection of the mechanism for the stringent factor RelA. Mol Cell. 2002;10(4):779-788. https://doi.org/10.1016/S1097-2765(02)00656-1
  104. Potrykus K, Cashel M. (p)ppGpp: still magical? Annu Rev Microbiol. 2008;62(1):35-51. https://doi.org/10.1146/annurev.micro.62.081307.162903
  105. Battesti A, Bouveret E. Acyl carrier protein/SpoT interaction, the switch linking SpoT-dependent stress response to fatty acid metabolism. Mol Microbiol. 2006;62(4):1048-1063. https://doi.org/10.1111/j.1365-2958.2006.05442.x
  106. Okada Y, Makino S, Tobe T, Okada N, Yamazaki S. Cloning of rel from Listeria monocytogenes as an osmotolerance involvement gene. Appl Environ Microbiol. 2002;68(4):1541-1547. https://doi.org/10.1128/AEM.68.4.1541-1547.2002
  107. Khakimova M, Ahlgren HG, Harrison JJ, English AM, Nguyen D. The stringent response controls catalases in Pseudomonas aeruginosa and is required for hydrogen peroxide and antibiotic tolerance. J Bacteriol. 2013;195(9):2011-2020. https://doi.org/10.1128/JB.02061-12
  108. Kanjee U, Gutsche I, Alexopoulos E, Zhao B, El Bakkouri M, Thibault G, et al. Linkage between the bacterial acid stress and stringent responses: the structure of the inducible lysine decarboxylase. EMBO J. 2011;30(5):931-944. https://doi.org/10.1038/emboj.2011.5
  109. Wells DH, Gaynor EC. Helicobacter pylori initiates the stringent response upon nutrient and pH downshift. J Bacteriol. 2006;188(10):3726-3729. https://doi.org/10.1128/JB.188.10.3726-3729.2006
  110. Cairo G, Recalcati S, Mantovani A, Locati M. Iron trafficking and metabolism in macrophages: contribution to the polarized phenotype. Trends Immunol. 2011;32(6):241-247. https://doi.org/10.1016/j.it.2011.03.007
  111. Forman HJ, Torres M. Reactive oxygen species and cell signaling: respiratory burst in macrophage signaling. Am J Respir Crit Care Med. 2002;166(12 Pt 2):S4-S8. https://doi.org/10.1164/rccm.2206007
  112. Savina A, Jancic C, Hugues S, Guermonprez P, Vargas P, Moura IC, et al. NOX2 controls phagosomal pH to regulate antigen processing during crosspresentation by dendritic cells. Cell. 2006;126(1):205-218. https://doi.org/10.1016/j.cell.2006.05.035
  113. Vogt SL, Green C, Stevens KM, Day B, Erickson DL, Woods DE, et al. The stringent response is essential for Pseudomonas aeruginosa virulence in the rat lung agar bead and Drosophila melanogaster feeding models of infection. Infect Immun. 2011;79(10):4094-4104. https://doi.org/10.1128/IAI.00193-11
  114. Mansour SC, Pletzer D, de la Fuente-Nunez C, Kim P, Cheung GY, Joo HS, et al. Bacterial abscess formation is controlled by the stringent stress response and can be targeted therapeutically. EBioMedicine. 2016;12:219-226. https://doi.org/10.1016/j.ebiom.2016.09.015
  115. Strugeon E, Tilloy V, Ploy MC, Da Re S. The stringent response promotes antibiotic resistance dissemination by regulating integron integrase expression in biofilms. MBio. 2016;7(4):7.
  116. Dalebroux ZD, Svensson SL, Gaynor EC, Swanson MS. ppGpp conjures bacterial virulence. Microbiol Mol Biol Rev. 2010;74(2):171-199. https://doi.org/10.1128/MMBR.00046-09
  117. Spira B, Ferreira GM, de Almeida LG. relA enhances the adherence of enteropathogenic Escherichia coli. PLoS One. 2014;9(3):e91703. https://doi.org/10.1371/journal.pone.0091703
  118. Nakanishi N, Abe H, Ogura Y, Hayashi T, Tashiro K, Kuhara S, et al. ppGpp with DksA controls gene expression in the locus of enterocyte effacement (LEE) pathogenicity island of enterohaemorrhagic Escherichia coli through activation of two virulence regulatory genes. Mol Microbiol. 2006;61(1):194-205. https://doi.org/10.1111/j.1365-2958.2006.05217.x
  119. Furniss RC, Clements A. Regulation of the locus of enterocyte effacement in attaching and effacing pathogens. J Bacteriol 2017;200(2):200.
  120. Bustamante VH, Santana FJ, Calva E, Puente JL. Transcriptional regulation of type III secretion genes in enteropathogenic Escherichia coli: Ler antagonizes H-NS-dependent repression. Mol Microbiol. 2001;39(3):664-678. https://doi.org/10.1046/j.1365-2958.2001.02209.x
  121. Iyoda S, Watanabe H. Positive effects of multiple pch genes on expression of the locus of enterocyte effacement genes and adherence of enterohaemorrhagic Escherichia coli O157 : H7 to HEp-2 cells. Microbiology (Reading). 2004;150(Pt 7):2357-2571. https://doi.org/10.1099/mic.0.27100-0
  122. Steimle A, Autenrieth IB, Frick JS. Structure and function: lipid A modifications in commensals and pathogens. Int J Med Microbiol. 2016;306(5):290-301. https://doi.org/10.1016/j.ijmm.2016.03.001
  123. Schakermann M, Langklotz S, Narberhaus F. FtsH-mediated coordination of lipopolysaccharide biosynthesis in Escherichia coli correlates with the growth rate and the alarmone (p)ppGpp. J Bacteriol. 2013;195(9):1912-1919. https://doi.org/10.1128/JB.02134-12
  124. Raetz CR, Whitfield C. Lipopolysaccharide endotoxins. Annu Rev Biochem. 2002;71(1):635-700. https://doi.org/10.1146/annurev.biochem.71.110601.135414
  125. Zhao G, Weatherspoon N, Kong W, Curtiss R 3rd, Shi Y. A dual-signal regulatory circuit activates transcription of a set of divergent operons in Salmonella typhimurium. Proc Natl Acad Sci U S A. 2008;105(52):20924-20929. https://doi.org/10.1073/pnas.0807071106
  126. Charity JC, Blalock LT, Costante-Hamm MM, Kasper DL, Dove SL. Small molecule control of virulence gene expression in Francisella tularensis. PLoS Pathog. 2009;5(10):e1000641. https://doi.org/10.1371/journal.ppat.1000641
  127. Dalebroux ZD, Yagi BF, Sahr T, Buchrieser C, Swanson MS. Distinct roles of ppGpp and DksA in Legionella pneumophila differentiation. Mol Microbiol. 2010;76(1):200-219. https://doi.org/10.1111/j.1365-2958.2010.07094.x
  128. Klinkenberg LG, Lee JH, Bishai WR, Karakousis PC. The stringent response is required for full virulence of Mycobacterium tuberculosis in guinea pigs. J Infect Dis. 2010;202(9):1397-1404. https://doi.org/10.1086/656524
  129. Na HS, Kim HJ, Lee HC, Hong Y, Rhee JH, Choy HE. Immune response induced by Salmonella typhimurium defective in ppGpp synthesis. Vaccine. 2006;24(12):2027-2034. https://doi.org/10.1016/j.vaccine.2005.11.031
  130. Park SI, Jeong JH, Choy HE, Rhee JH, Na HS, Lee TH, et al. Immune response induced by ppGpp-defective Salmonella enterica serovar Gallinarum in chickens. J Microbiol. 2010;48(5):674-681. https://doi.org/10.1007/s12275-010-0179-6
  131. Gaca AO, Abranches J, Kajfasz JK, Lemos JA. Global transcriptional analysis of the stringent response in Enterococcus faecalis. Microbiology (Reading). 2012;158(Pt 8):1994-2004. https://doi.org/10.1099/mic.0.060236-0
  132. Muller CM, Conejero L, Spink N, Wand ME, Bancroft GJ, Titball RW. Role of RelA and SpoT in Burkholderia pseudomallei virulence and immunity. Infect Immun. 2012;80(9):3247-3255. https://doi.org/10.1128/IAI.00178-12
  133. Pizarro-Cerda J, Tedin K. The bacterial signal molecule, ppGpp, regulates Salmonella virulence gene expression. Mol Microbiol. 2004;52(6):1827-1844. https://doi.org/10.1111/j.1365-2958.2004.04122.x
  134. Wexselblatt E, Oppenheimer-Shaanan Y, Kaspy I, London N, Schueler-Furman O, Yavin E, et al. Relacin, a novel antibacterial agent targeting the Stringent Response. PLoS Pathog. 2012;8(9):e1002925. https://doi.org/10.1371/journal.ppat.1002925
  135. Wexselblatt E, Kaspy I, Glaser G, Katzhendler J, Yavin E. Design, synthesis and structure-activity relationship of novel Relacin analogs as inhibitors of Rel proteins. Eur J Med Chem. 2013;70:497-504. https://doi.org/10.1016/j.ejmech.2013.10.036
  136. Syal K, Flentie K, Bhardwaj N, Maiti K, Jayaraman N, Stallings CL, et al. Synthetic (p)ppGpp analogue is an inhibitor of stringent response in mycobacteria. Antimicrob Agents Chemother. 2017;61(6):61.
  137. de la Fuente-Nunez C, Reffuveille F, Haney EF, Straus SK, Hancock RE. Broad-spectrum anti-biofilm peptide that targets a cellular stress response. PLoS Pathog. 2014;10(5):e1004152. https://doi.org/10.1371/journal.ppat.1004152
  138. Pletzer D, Wolfmeier H, Bains M, Hancock RE. Synthetic peptides to target stringent response-controlled virulence in a Pseudomonas aeruginosa murine cutaneous infection model. Front Microbiol. 2017;8:1867. https://doi.org/10.3389/fmicb.2017.01867