Animal models of enteroaggregative Escherichia coli infection

Gut Microbes

Volumn 4, Issue 4, 2013, Pages 281-291

  Philipson, Casandra W ^a   Bassaganya Riera, Josep ^a,b   Hontecillas, Raquel ^a  

^a VIRGINIA BIOINFORMATICS INSTITUTE   (United States)

^b VIRGINIA MARYLAND REGIONAL COLLEGE OF VETERINARY MEDICINE   (United States)

Author keywords

Animal model; Computational modeling; EAEC pathogenesis; Enteroaggregative E. coli; Th17

Indexed keywords

CHEMOKINE RECEPTOR CCR6; CXCL1 CHEMOKINE; CYTOTOXIN; ENTEROTOXIN; FLAGELLIN; FODRIN; INTERLEUKIN 8; LACTOFERRIN; MACROPHAGE INFLAMMATORY PROTEIN 3ALPHA; PATTERN RECOGNITION RECEPTOR; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; SERINE PROTEASE AUTOTRANSPORTER TOXIN; SHIGA TOXIN; SODIUM CHLORIDE COTRANSPORTER; TIGHT JUNCTION PROTEIN; TOLL LIKE RECEPTOR; UNCLASSIFIED DRUG; VIRULENCE FACTOR;

ANIMAL MODEL; ANIMAL TISSUE; ANTIBIOTIC THERAPY; BACTERIAL COLONIZATION; BACTERIAL VIRULENCE; BACTERIOPHAGE; BIOFILM; CELL DIFFERENTIATION; ENTEROAGGREGATIVE ESCHERICHIA COLI; ESCHERICHIA COLI INFECTION; FIMBRIA; GASTROINTESTINAL BIOPSY; GENE EXPRESSION; GENETIC PREDISPOSITION; GNOTOBIOTICS; HEMOLYTIC UREMIC SYNDROME; HOST PATHOGEN INTERACTION; HUMAN; HUMAN TISSUE; IMMUNE RESPONSE; INFANTILE DIARRHEA; INTESTINE EPITHELIUM; INTESTINE FLORA; MALNUTRITION; MATHEMATICAL MODEL; MICROBIOME; MOUSE; MUCUS SECRETION; NONHUMAN; PATHOGENESIS; PATHOGENICITY ISLAND; PIGLET; PLASMID; RAT; REVIEW; SCID MOUSE; SHIGA TOXIN PRODUCING ESCHERICHIA COLI; SHIGELLA FLEXNERI; SINGLE NUCLEOTIDE POLYMORPHISM; SYSTEMS BIOLOGY; TH17 CELL; TRANSCRIPTION REGULATION; XENOGRAFT; ANIMAL; DIARRHEA; DISEASE MODEL; ESCHERICHIA COLI; GASTROENTERITIS; MICROBIOLOGY; PATHOGENICITY; PATHOLOGY;

ANIMALS; DIARRHEA; DISEASE MODELS, ANIMAL; ESCHERICHIA COLI; ESCHERICHIA COLI INFECTIONS; GASTROENTERITIS; HUMANS;

EID: 84880477221     PISSN: 19490976     EISSN: 19490984     Source Type: Journal    
DOI: 10.4161/gmic.24826     Document Type: Review

References (105)

1. Donnenberg MS, Whittam TS. Pathogenesis and evolution of virulence in enteropathogenic and enterohem-orrhagic Escherichia coli. J Clin Invest 2001; 107:539-48; PMID:11238553; http://dx.doi.org/10.1172/ JCI12404
2. Barton Behravesh C, Jones T F, Vugia DJ, Long C, Marcus R, Smith K, et al.; FoodNet Working Group. Deaths associated with bacterial pathogens transmitted commonly through food: foodborne diseases active surveillance network (FoodNet), 1996-2005. J Infect Dis 2011; 204:263-7; PMID:21673037; http://dx.doi. org/10.1093/infdis/jir263
3. Kaper JB, Nataro JP, Mobley HL. Pathogenic Escherichia coli. Nat Rev Microbiol 2004; 2:123-40; PMID:15040260; http://dx.doi.org/10.1038/nrmi-cro818
4. Gomes TA, Blake PA, Trabulsi LR. Prevalence of Escherichia coli strains with localized, diffuse, and aggregative adherence to HeLa cells in infants with diarrhea and matched controls. J Clin Microbiol 1989; 27:266-9; PMID:2563383
5. Huang DB, Nataro JP, DuPont HL, Kamat P P, Mhatre AD, Okhuysen PC, et al. Enteroaggregative Escherichia coli is a cause of acute diarrheal illness: a meta-analysis. Clin Infect Dis 2006; 43:556-63; PMID:16886146; http://dx.doi.org/10.1086/505869
6. Glandt M, Adachi JA, Mathewson JJ, Jiang ZD, DiCesare D, Ashley D, et al. Enteroaggregative Escherichia coli as a cause of traveler's diarrhea: clinical response to ciprofloxacin. Clin Infect Dis 1999; 29:335-8; PMID:10476738; http://dx.doi. org/10.1086/520211
7. Steiner TS, Lima AA, Nataro JP, Guerrant RL. Enteroaggregative Escherichia coli produce intestinal inflammation and growth impairment and cause inter-leukin-8 release from intestinal epithelial cells. J Infect Dis 1998; 177:88-96; PMID:9419174; http://dx.doi. org/10.1086/513809
8. Wanke CA, Mayer H, Weber R, Zbinden R, Watson DA, Acheson D. Enteroaggregative Escherichia coli as a potential cause of diarrheal disease in adults infected with human immunodeficiency virus. J Infect Dis 1998; 178:185-90; PMID:9652439; http://dx.doi. org/10.1086/515595
9. Kaur P, Chakraborti A, Asea A. Enteroaggregative Escherichia coli: An Emerging Enteric Food Borne Pathogen. Interdiscip Perspect Infect Dis 2010; 2010:254159; PMID:20300577; http://dx.doi. org/10.1155/2010/254159
10. Huang DB, Okhuysen PC, Jiang ZD, DuPont HL. Enteroaggregative Escherichia coli: an emerging enteric pathogen. Am J Gastroenterol 2004; 99:383-9; PMID:15046233; http://dx.doi.org/10.1111/j.1572-0241.2004.04041.x
11. Rasko DA, Webster DR, Sahl J W, Bashir A, Boisen N, Scheutz F, et al. Origins of the E. coli strain causing an outbreak of hemolytic-uremic syndrome in Germany. N Engl J Med 2011; 365:709-17; PMID:21793740; http://dx.doi.org/10.1056/NEJMoa1106920
12. Al Safadi R, Abu-Ali GS, Sloup RE, Rudrik JT, Waters CM, Eaton KA, et al. Correlation between in vivo biofilm formation and virulence gene expression in Escherichia coli O104:H4. PLoS One 2012; 7:e41628; PMID:22848550; http://dx.doi.org/10.1371/journal. pone.0041628
13. Koo HL, Jiang ZD, Brown E, Garcia C, Qi H, Dupont HL. Coliform contamination of vegetables obtained from popular restaurants in Guadalajara, Mexico, and Houston, Texas. Clin Infect Dis 2008; 47:218-21; PMID:18540820; http://dx.doi.org/10.1086/589249
14. Pawlowski S W, Warren CA, Guerrant R. Diagnosis and treatment of acute or persistent diarrhea. Gastroenterology 2009; 136:1874-86; PMID:19457416; http://dx.doi.org/10.1053/j.gas-tro.2009.02.072
15. Oundo JO, Kariuki SM, Boga HI, Muli FW, Iijima Y. High incidence of enteroaggregative Escherichia coli among food handlers in three areas of Kenya: a possible transmission route of travelers' diarrhea. J Travel Med 2008; 15:31-8; PMID:18217867; http://dx.doi. org/10.1111/j.1708-8305.2007.00174.x
16. Paredes-Paredes M, Okhuysen PC, Flores J, Mohamed JA, Padda RS, Gonzalez-Estrada A, et al. Seasonality of diarrheagenic Escherichia coli pathotypes in the US students acquiring diarrhea in Mexico. J Travel Med 2011; 18:121-5; PMID:21366796; http://dx.doi. org/10.1111/j.1708-8305.2010.00488.x
17. Jiang ZD, Okhuysen PC, Guo DC, He R, King TM, DuPont HL, et al. Genetic susceptibility to entero-aggregative Escherichia coli diarrhea: polymorphism in the interleukin-8 promotor region. J Infect Dis 2003; 188:506-11; PMID:12898436; http://dx.doi. org/10.1086/377102
18. Mohamed JA, DuPont HL, Jiang ZD, Belkind-Gerson J, Figueroa J F, Armitige LY, et al. A novel single-nucle-otide polymorphism in the lactoferrin gene is associated with susceptibility to diarrhea in North American travelers to Mexico. Clin Infect Dis 2007; 44:945-52; PMID:17342646; http://dx.doi.org/10.1086/512199
19. Nataro JP, Mai V, Johnson J, Blackwelder WC, Heimer R, Tirrell S, et al. Diarrheagenic Escherichia coli infection in Baltimore, Maryland, and New Haven, Connecticut. Clin Infect Dis 2006; 43:402-7; PMID:16838226; http://dx.doi.org/10.1086/505867
20. Al-Gallas N, Bahri O, Bouratbeen A, Ben Haasen A, Ben Aissa R. Etiology of acute diarrhea in children and adults in Tunis, Tunisia, with emphasis on diarrhea-genic Escherichia coli: prevalence, phenotyping, and molecular epidemiology. Am J Trop Med Hyg 2007; 77:571-82; PMID:17827382
21. Sarantuya J, Nishi J, Wakimoto N, Erdene S, Nataro JP, Sheikh J, et al. Typical enteroaggregative Escherichia coli is the most prevalent pathotype among E. coli strains causing diarrhea in Mongolian children. J Clin Microbiol 2004; 42:133-9; PMID:14715743; http://dx.doi.org/10.1128/JCM.42.1.133-139.2004
22. Pabst WL, Altwegg M, Kind C, Mirjanic S, Hardegger D, Nadal D. Prevalence of enteroaggregative Escherichia coli among children with and without diarrhea in Switzerland. J Clin Microbiol 2003; 41:2289-93; PMID:12791838; http://dx.doi.org/10.1128/JCM.41.6.2289-2293.2003
23. Moyo SJ, Maselle SY, Matee MI, Langeland N, Mylvaganam H. Identification of diarrheagenic Escherichia coli isolated from infants and children in Dar es Salaam, Tanzania. BMC Infect Dis 2007; 7:92; PMID:17688682; http://dx.doi.org/10.1186/1471-2334-7-92
24. Alikhani MY, Sedighi I, Zamani A, Aslani MM, Sadrosadat T. Incidence of diarrhoeagenic Escherichia coli isolated from young children with diarrhoea in the west of Iran. Acta Microbiol Immunol Hung 2012; 59:367-74; PMID:22982640; http://dx.doi. org/10.1556/AMicr.59.2012.3.7
25. Vossenkämper A, Macdonald TT, Marchès O. Always one step ahead: How pathogenic bacteria use the type III secretion system to manipulate the intestinal muco-sal immune system. J Inflamm (Lond) 2011; 8:11; PMID:21539730; http://dx.doi.org/10.1186/1476-9255-8-11
26. Gouyer V, Gottrand F, Desseyn JL. The extraordinarily complex but highly structured organization of intestinal mucus-gel unveiled in multicolor images. PLoS One 2011; 6:e18761; PMID:21533274; http://dx.doi. org/10.1371/journal.pone.0018761
27. Eddy S F, Storey KB. p38 MAPK regulation of transcription factor targets in muscle and heart of the hibernating bat, Myotis lucifugus. Cell Biochem Funct 2007; 25:759-65; PMID:17487931; http://dx.doi. org/10.1002/cbf.1416
28. Eckmann L, Kagnoff M F. Intestinal mucosal responses to microbial infection. Springer Semin Immunopathol 2005; 27:181-96; PMID:15928914; http://dx.doi. org/10.1007/s00281-005-0207-5
29. Wells JM, Rossi O, Meijerink M, van Baarlen P. Epithelial crosstalk at the microbiota-mucosal interface. Proc Natl Acad Sci U S A 2011; 108(Suppl 1):4607-14; PMID:20826446; http://dx.doi.org/10.1073/ pnas.1000092107
30. Littman DR, Pamer EG. Role of the commensal microbiota in normal and pathogenic host immune responses. Cell Host Microbe 2011; 10:311-23; PMID:22018232; http://dx.doi.org/10.1016/j. chom.2011.10.004
31. Chaudhuri RR, Sebaihia M, Hobman JL, Webber MA, Leyton DL, Goldberg MD, et al. Complete genome sequence and comparative metabolic profiling of the prototypical enteroaggregative Escherichia coli strain 042. PLoS One 2010; 5:e8801; PMID:20098708; http://dx.doi.org/10.1371/journal.pone.0008801
32. Bernier C, Gounon P, Le Bouguénec C. Identification of an aggregative adhesion fimbria (AAF) type III-encoding operon in enteroaggregative Escherichia coli as a sensitive probe for detecting the AAF-encoding operon family. Infect Immun 2002; 70:4302-11; PMID:12117939; http://dx.doi.org/10.1128/ IAI.70.8.4302-4311.2002
33. Snelling AM, Macfarlane-Smith LR, Fletcher JN, Okeke IN. The commonly-used DNA probe for diffusely-adherent Escherichia coli cross-reacts with a subset of enteroaggregative E. coli. BMC Microbiol 2009; 9:269; PMID:20025771; http://dx.doi. org/10.1186/1471-2180-9-269
34. Cordeiro F, da Silva Gomes Pereira D, Rocha M, Asensi MD, Elias W P, Campos LC. Evaluation of a multiplex PCR for identification of enteroaggregative Escherichia coli. J Clin Microbiol 2008; 46:828-9; PMID:18077638; http://dx.doi.org/10.1128/ JCM.01865-07
35. Aslani MM, Alikhani MY, Zavari A, Yousefi R, Zamani AR. Characterization of enteroaggregative Escherichia coli (EAEC) clinical isolates and their antibiotic resistance pattern. Int J Infect Dis 2011; 15:e136-9; PMID:21130676; http://dx.doi.org/10.1016/j. ijid.2010.10.002
36. Morin N, Santiago AE, Ernst RK, Guillot SJ, Nataro JP. Characterization of the AggR regulon in enteroag-gregative Escherichia coli. Infect Immun 2013; 81:122-32; PMID:23090962; http://dx.doi.org/10.1128/ IAI.00676-12
37. Dudley EG, Thomson NR, Parkhill J, Morin N P, Nataro JP. Proteomic and microarray characterization of the AggR regulon identifies a pheU patho-genicity island in enteroaggregative Escherichia coli. Mol Microbiol 2006; 61:1267-82; PMID:16925558; http://dx.doi.org/10.1111/j.1365-2958.2006.05281.x
38. Ren CP, Chaudhuri RR, Fivian A, Bailey CM, Antonio M, Barnes WM, et al. The ETT2 gene cluster, encoding a second type III secretion system from Escherichia coli, is present in the majority of strains but has undergone widespread mutational attrition. J Bacteriol 2004; 186:3547-60; PMID:15150243; http://dx.doi. org/10.1128/JB.186.11.3547-3560.2004
39. Aschtgen MS, Bernard CS, De Bentzmann S, Lloubès R, Cascales E. SciN is an outer membrane lipopro-tein required for type VI secretion in enteroaggrega-tive Escherichia coli. J Bacteriol 2008; 190:7523-31; PMID:18805985; http://dx.doi.org/10.1128/ JB.00945-08
40. Estrada-Garcia T, Navarro-Garcia F. Enteroaggregative Escherichia coli pathotype: a genetically heterogeneous emerging foodborne enteropathogen. FEMS Immunol Med Microbiol 2012; 66:281-98; PMID:22775224; http://dx.doi.org/10.1111/j.1574-695X.2012.01008.x
41. Hicks S, Candy DC, Phillips AD. Adhesion of entero-aggregative Escherichia coli to pediatric intestinal mucosa in vitro. Infect Immun 1996; 64:4751-60; PMID:8890236
42. Nataro JP, Deng Y, Maneval DR, German AL, Martin WC, Levine MM. Aggregative adherence fimbriae I of enteroaggregative Escherichia coli mediate adherence to HEp-2 cells and hemagglutination of human erythrocytes. Infect Immun 1992; 60:2297-304; PMID:1350273
43. Boisen N, Struve C, Scheutz F, Krogfelt KA, Nataro JP. New adhesin of enteroaggregative Escherichia coli related to the Afa/Dr/AAF family. Infect Immun 2008; 76:3281-92; PMID:18443096; http://dx.doi. org/10.1128/IAI.01646-07
44. Harrington SM, Dudley EG, Nataro JP. Pathogenesis of enteroaggregative Escherichia coli infection. FEMS Microbiol Lett 2006; 254:12-8; PMID:16451173; http://dx.doi.org/10.1111/j.1574-6968.2005.00005.x
45. Strauman MC, Harper JM, Harrington SM, Boll EJ, Nataro JP. Enteroaggregative Escherichia coli disrupts epithelial cell tight junctions. Infect Immun 2010; 78:4958-64; PMID:20823198; http://dx.doi. org/10.1128/IAI.00580-10
46. Boll EJ, Struve C, Sander A, Demma Z, Nataro JP, McCormick BA, et al. The fimbriae of enteroaggrega-tive Escherichia coli induce epithelial inflammation in vitro and in a human intestinal xenograft model. J Infect Dis 2012; 206:714-22; PMID:22723643; http://dx.doi.org/10.1093/infdis/jis417
47. Sheikh J, Czeczulin JR, Harrington S, Hicks S, Henderson IR, Le Bouguénec C, et al. A novel disper-sin protein in enteroaggregative Escherichia coli. J Clin Invest 2002; 110:1329-37; PMID:12417572
48. Mortensen NP, Fowlkes JD, Maggart M, Doktycz MJ, Nataro JP, Drusano G, et al. Effects of sub-minimum inhibitory concentrations of ciprofloxacin on enteroaggregative Escherichia coli and the role of the surface protein dispersin. Int J Antimicrob Agents 2011; 38:27-34; PMID:21570813; http://dx.doi. org/10.1016/j.ijantimicag.2011.03.011
49. Harrington SM, Sheikh J, Henderson IR, Ruiz-Perez F, Cohen PS, Nataro J P. The Pic protease of enteroaggre-gative Escherichia coli promotes intestinal colonization and growth in the presence of mucin. Infect Immun 2009; 77:2465-73; PMID:19349428; http://dx.doi. org/10.1128/IAI.01494-08
50. Henderson IR, Czeczulin J, Eslava C, Noriega F, Nataro JP. Characterization of pic, a secreted protease of Shigella flexneri and enteroaggregative Escherichia coli. Infect Immun 1999; 67:5587-96; PMID:10531204
51. Navarro-Garcia F, Gutierrez-Jimenez J, Garcia-Tovar C, Castro LA, Salazar-Gonzalez H, Cordova V. Pic, an autotransporter protein secreted by different pathogens in the Enterobacteriaceae family, is a potent mucus secretagogue. Infect Immun 2010; 78:4101-9; PMID:20696826; http://dx.doi.org/10.1128/ IAI.00523-10
52. Ruiz-Perez F, Wahid R, Faherty CS, Kolappaswamy K, Rodriguez L, Santiago A, et al. Serine protease autotransporters from Shigella flexneri and pathogenic Escherichia coli target a broad range of leukocyte glyco-proteins. Proc Natl Acad Sci U S A 2011; 108:12881-6; PMID:21768350; http://dx.doi.org/10.1073/ pnas.1101006108
53. Sheikh J, Hicks S, Dall'Agnol M, Phillips AD, Nataro JP. Roles for Fis and YafK in biofilm formation by enteroaggregative Escherichia coli. Mol Microbiol 2001; 41:983-97; PMID:11555281; http://dx.doi. org/10.1046/j.1365-2958.2001.02512.x
54. Telli M, Guiral E, Martínez JA, Almela M, Bosch J, Vila J, et al. Prevalence of enterotoxins among Escherichia coli isolates causing bacteraemia. FEMS Microbiol Lett 2010; 306:117-21; PMID:20529132; http://dx.doi.org/10.1111/j.1574-6968.2010.01945.x
55. Mohamed JA, Huang DB, Jiang ZD, DuPont HL, Nataro JP, Belkind-Gerson J, et al. Association of putative enteroaggregative Escherichia coli virulence genes and biofilm production in isolates from travelers to developing countries. J Clin Microbiol 2007; 45:121-6; PMID:17093030; http://dx.doi.org/10.1128/ JCM.01128-06
56. Ménard L P, Dubreuil JD. Enteroaggregative Escherichia coli heat-stable enterotoxin 1 (EAST1): a new toxin with an old twist. Crit Rev Microbiol 2002; 28:43-60; PMID:12003040; http://dx.doi.org/10.1080/1040-840291046687
57. Savarino SJ, McVeigh A, Watson J, Cravioto A, Molina J, Echeverria P, et al. Enteroaggregative Escherichia coli heat-stable enterotoxin is not restricted to entero-aggregative E. coli. J Infect Dis 1996; 173:1019-22; PMID:8603943; http://dx.doi.org/10.1093/ infdis/173.4.1019
58. Huang DB, Mohanty A, DuPont HL, Okhuysen PC, Chiang T. A review of an emerging enteric pathogen: enteroaggregative Escherichia coli. J Med Microbiol 2006; 55:1303-11; PMID:17005776; http://dx.doi. org/10.1099/jmm.0.46674-0
59. Navarro-García F, Sears C, Eslava C, Cravioto A, Nataro J P. Cytoskeletal effects induced by pet, the serine protease enterotoxin of enteroaggregative Escherichia coli. Infect Immun 1999; 67:2184-92; PMID:10225873
60. Navarro-Garcia F, Sonnested M, Teter K. Host-Toxin Interactions Involving EspC and Pet, Two Serine Protease Autotransporters of the Enterobacteriaceae. Toxins (Basel) 2010; 2:1134-47; PMID:21243083; http://dx.doi.org/10.3390/toxins2051134
61. Navarro-Garcia F, Elias W P. Autotransporters and virulence of enteroaggregative E. coli. Gut Microbes 2011; 2:13-24; PMID:21637014; http://dx.doi.org/10.4161/ gmic.2.1.14933
62. Boisen N, Ruiz-Perez F, Scheutz F, Krogfelt KA, Nataro JP. Short report: high prevalence of serine protease autotransporter cytotoxins among strains of enteroag-gregative Escherichia coli. Am J Trop Med Hyg 2009; 80:294-301; PMID:19190229
63. Boisen N, Scheutz F, Rasko DA, Redman JC, Persson S, Simon J, et al. Genomic characterization of entero-aggregative Escherichia coli from children in Mali. J Infect Dis 2012; 205:431-44; PMID:22184729; http://dx.doi.org/10.1093/infdis/jir757
64. Guignot J, Chaplais C, Coconnier-Polter MH, Servin AL. The secreted autotransporter toxin, Sat, functions as a virulence factor in Afa/Dr diffusely adhering Escherichia coli by promoting lesions in tight junction of polarized epithelial cells. Cell Microbiol 2007; 9:204-21; PMID:16903846; http://dx.doi. org/10.1111/j.1462-5822.2006.00782.x
65. Al-Hasani K, Navarro-Garcia F, Huerta J, Sakellaris H, Adler B. The immunogenic SigA enterotoxin of Shigella flexneri 2a binds to HEp-2 cells and induces fodrin redistribution in intoxicated epithelial cells. PLoS One 2009; 4:e8223; PMID:20011051; http:// dx.doi.org/10.1371/journal.pone.0008223
66. Rohde H, Qin J, Cui Y, Li D, Loman NJ, Hentschke M, et al.; E. coli O104:H4 Genome Analysis Crowd-Sourcing Consortium. Open-source genomic analysis of Shiga-toxin-producing E. coli O104:H4. N Engl J Med 2011; 365:718-24; PMID:21793736; http:// dx.doi.org/10.1056/NEJMoa1107643
67. Pacheco AR, Sperandio V. Shiga toxin in entero-hemorrhagic E.coli: regulation and novel anti-virulence strategies. Front Cell Infect Microbiol 2012; 2:81; PMID:22919672; http://dx.doi.org/10.3389/ fcimb.2012.00081
68. Lingwood CA, Binnington B, Manis A, Branch DR. Globotriaosyl ceramide receptor function - where membrane structure and pathology intersect. FEBS Lett 2010; 584:1879-86; PMID:19948172; http:// dx.doi.org/10.1016/j.febslet.2009.11.089
69. Frank C, Werber D, Cramer J P, Askar M, Faber M, an der Heiden M, et al.; HUS Investigation Team. Epidemic profile of Shiga-toxin-producing Escherichia coli O104:H4 outbreak in Germany. N Engl J Med 2011; 365:1771-80; PMID:21696328; http://dx.doi. org/10.1056/NEJMoa1106483
70. Laing CR, Zhang Y, Gilmour MW, Allen V, Johnson R, Thomas JE, et al. A comparison of Shiga-toxin 2 bacteriophage from classical enterohemorrhagic Escherichia coli serotypes and the German E. coli O104:H4 outbreak strain. PLoS One 2012; 7:e37362; PMID:22649523; http://dx.doi.org/10.1371/journal. pone.0037362
71. Brzuszkiewicz E, Thürmer A, Schuldes J, Leimbach A, Liesegang H, Meyer FD, et al. Genome sequence analyses of two isolates from the recent Escherichia coli outbreak in Germany reveal the emergence of a new pathotype: Entero-Aggregative-Haemorrhagic Escherichia coli (EAHEC). Arch Microbiol 2011; 193:883-91; PMID:21713444; http://dx.doi. org/10.1007/s00203-011-0725-6
72. Grad YH, Lipsitch M, Feldgarden M, Arachchi HM, Cerqueira GC, Fitzgerald M, et al. Genomic epidemiology of the Escherichia coli O104:H4 outbreaks in Europe, 2011. Proc Natl Acad Sci U S A 2012; 109:3065-70; PMID:22315421; http://dx.doi. org/10.1073/pnas.1121491109
73. Edwards LA, Bajaj-Elliott M, Klein NJ, Murch SH, Phillips AD. Bacterial-epithelial contact is a key determinant of host innate immune responses to entero-pathogenic and enteroaggregative Escherichia coli. PLoS One 2011; 6:e27030; PMID:22046438; http:// dx.doi.org/10.1371/journal.pone.0027030
74. Steiner TS, Nataro J P, Poteet-Smith CE, Smith JA, Guerrant RL. Enteroaggregative Escherichia coli expresses a novel flagellin that causes IL-8 release from intestinal epithelial cells. J Clin Invest 2000; 105:1769-77; PMID:10862792; http://dx.doi.org/10.1172/ JCI8892
75. Khan MA, Kang J, Steiner TS. Enteroaggregative Escherichia coli flagellin-induced interleukin-8 secretion requires Toll-like receptor 5-dependent p38 MAP kinase activation. Immunology 2004; 112:651-60; PMID:15270737; http://dx.doi.org/10.1111/j.1365-2567.2004.01923.x
76. Harrington SM, Strauman MC, Abe CM, Nataro J P. Aggregative adherence fimbriae contribute to the inflammatory response of epithelial cells infected with enteroaggregative Escherichia coli. Cell Microbiol 2005; 7:1565-78; PMID:16207244; http://dx.doi. org/10.1111/j.1462-5822.2005.00588.x
77. Patton LM, Saggart BS, Ahmed NK, Leff JA, Repine JE. Interleukin-1 beta-induced neutrophil recruitment and acute lung injury in hamsters. Inflammation 1995; 19:23-9; PMID:7705884; http://dx.doi.org/10.1007/ BF01534377
78. Greenberg DE, Jiang ZD, Steffen R, Verenker M P, DuPont HL. Markers of inflammation in bacterial diarrhea among travelers, with a focus on enteroag-gregative Escherichia coli pathogenicity. J Infect Dis 2002; 185:944-9; PMID:11920319; http://dx.doi. org/10.1086/339617
79. Yen CC, Shen CJ, Hsu WH, Chang YH, Lin HT, Chen HL, et al. Lactoferrin: an iron-binding antimicrobial protein against Escherichia coli infection. Biometals 2011; 24:585-94; PMID:21327478; http:// dx.doi.org/10.1007/s10534-011-9423-8
80. Bouckenooghe AR, Dupont HL, Jiang ZD, Adachi J, Mathewson JJ, Verenkar M P, et al. Markers of enteric inflammation in enteroaggregative Escherichia coli diarrhea in travelers. Am J Trop Med Hyg 2000; 62:711-3; PMID:11304060
81. Philipson C W, Bassaganya-Riera J, Viladomiu M, Pedragosa M, Guerrant RL, Roche JK, et al. The role of peroxisome proliferator-activated receptor γ in immune responses to enteroaggregative Escherichia coli infection. PLoS One 2013; 8:e57812; PMID:23469071; http://dx.doi.org/10.1371/journal.pone.0057812
82. Chinetti G, Fruchart JC, Staels B. Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation. Inflamm Res 2000; 49:497-505; PMID:11089900; http://dx.doi.org/10.1007/ s000110050622
83. Adachi M, Kurotani R, Morimura K, Shah Y, Sanford M, Madison BB, et al. Peroxisome proliferator activated receptor gamma in colonic epithelial cells protects against experimental inflammatory bowel disease. Gut 2006; 55:1104-13; PMID:16547072; http://dx.doi. org/10.1136/gut.2005.081745
84. Peck A, Mellins ED. Precarious balance: Th17 cells in host defense. Infect Immun 2010; 78:32-8; PMID:19901061; http://dx.doi.org/10.1128/ IAI.00929-09
85. Liang SC, Tan XY, Luxenberg D P, Karim R, Dunussi-Joannopoulos K, Collins M, et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med 2006; 203:2271-9; PMID:16982811; http:// dx.doi.org/10.1084/jem.20061308
86. Adachi JA, Ericsson CD, Jiang ZD, DuPont MW, Pallegar SR, DuPont HL. Natural history of enteroag-gregative and enterotoxigenic Escherichia coli infection among US travelers to Guadalajara, Mexico. J Infect Dis 2002; 185:1681-3; PMID:12023779; http:// dx.doi.org/10.1086/340419
87. Okhuysen PC, Dupont HL. Enteroaggregative Escherichia coli (EAEC): a cause of acute and persistent diarrhea of worldwide importance. J Infect Dis 2010; 202:503-5; PMID:20594108; http://dx.doi. org/10.1086/654895
88. Vial PA, Robins-Browne R, Lior H, Prado V, Kaper JB, Nataro JP, et al. Characterization of enteroadherent-aggregative Escherichia coli, a putative agent of diarrheal disease. J Infect Dis 1988; 158:70-9; PMID:2899125; http://dx.doi.org/10.1093/infdis/158.1.70
89. Black RE, Cousens S, Johnson HL, Lawn JE, Rudan I, Bassani DG, et al.; Child Health Epidemiology Reference Group of WHO and UNICEF. Global, regional, and national causes of child mortality in 2008: a systematic analysis. Lancet 2010; 375:1969-87; PMID:20466419; http://dx.doi.org/10.1016/S0140-6736(10)60549-1
90. Tzipori S, Montanaro J, Robins-Browne RM, Vial P, Gibson R, Levine MM. Studies with enteroag-gregative Escherichia coli in the gnotobiotic piglet gastroenteritis model. Infect Immun 1992; 60:5302-6; PMID:1452364
91. Saif LJ, Ward LA, Yuan L, Rosen BI, To TL. The gnotobiotic piglet as a model for studies of disease pathogenesis and immunity to human rotaviruses. Arch Virol Suppl 1996; 12:153-61; PMID:9015112
92. Birchall MA, Bailey M, Barker EV, Rothkötter HJ, Otto K, Macchiarini P. Model for experimental revas-cularized laryngeal allotransplantation. Br J Surg 2002; 89:1470-5; PMID:12390394; http://dx.doi. org/10.1046/j.1365-2168.2002.02234.x
93. Rothkötter HJ, Sowa E, Pabst R. The pig as a model of developmental immunology. Hum Exp Toxicol 2002; 21:533-6; PMID:12458912; http://dx.doi. org/10.1191/0960327102ht293oa
94. Roche JK, Cabel A, Sevilleja J, Nataro J, Guerrant RL. Enteroaggregative Escherichia coli (EAEC) impairs growth while malnutrition worsens EAEC infection: a novel murine model of the infection malnutrition cycle. J Infect Dis 2010; 202:506-14; PMID:20594107; http://dx.doi.org/10.1086/654894
95. Morin N, Tirling C, Ivison SM, Kaur A P, Nataro JP, Steiner TS. Autoactivation of the AggR regulator of enteroaggregative Escherichia coli in vitro and in vivo. FEMS Immunol Med Microbiol 2010; 58:344-55; PMID:20132305
96. Ideker T, Galitski T, Hood L. A new approach to decoding life: systems biology. Annu Rev Genomics Hum Genet 2001; 2:343-72; PMID:11701654; http:// dx.doi.org/10.1146/annurev.genom.2.1.343
97. Kitano H. Computational systems biology. Nature 2002; 420:206-10; PMID:12432404; http://dx.doi. org/10.1038/nature01254
98. Aujla SJ, Dubin PJ, Kolls JK. Th17 cells and muco-sal host defense. Semin Immunol 2007; 19:377-82; PMID:18054248; http://dx.doi.org/10.1016/j. smim.2007.10.009
99. Liévin-Le Moal V, Servin AL. The front line of enteric host defense against unwelcome intrusion of harmful microorganisms: mucins, antimicrobial peptides, and microbiota. Clin Microbiol Rev 2006; 19:315-37; PMID:16614252; http://dx.doi.org/10.1128/ CMR.19.2.315-337.2006
100. Goss PJ, Peccoud J. Quantitative modeling of stochastic systems in molecular biology by using stochastic Petri nets. Proc Natl Acad Sci U S A 1998; 95:6750-5; PMID:9618484; http://dx.doi.org/10.1073/ pnas.95.12.6750
101. Alves R, Antunes F, Salvador A. Tools for kinetic modeling of biochemical networks. Nat Biotechnol 2006; 24:667-72; PMID:16763599; http://dx.doi. org/10.1038/nbt0606-667
102. Bonabeau E. Agent-based modeling: methods and techniques for simulating human systems. Proc Natl Acad Sci U S A 2002; 99(Suppl 3):7280-7; PMID:12011407; http://dx.doi.org/10.1073/pnas.082080899
103. Hoops S, Sahle S, Gauges R, Lee C, Pahle J, Simus N, et al. COPASI--a COmplex PAthway SImulator. Bioinformatics 2006; 22:3067-74; PMID:17032683; http://dx.doi.org/10.1093/bioinformatics/btl485
104. Trottier P P. Deterministic Modeling Of Infectious Diseases: Theory and Methods. The Internet Journal of Infectious Diseases 2001; 1.
105. Carbo A, Hontecillas R, Kronsteiner B, Viladomiu M, Pedragosa M, Lu P, et al. Systems modeling of molecular mechanisms controlling cytokine-driven CD4+ T cell differentiation and phenotype plasticity.