Chapter 46 : Biomarkers of Gastrointestinal Host Responses to Microbial Infections

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:
Zoom in

Biomarkers of Gastrointestinal Host Responses to Microbial Infections, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555819071/9781555819088.ch46-1.gif /docserver/preview/fulltext/10.1128/9781555819071/9781555819088.ch46-2.gif


The gastrointestinal (GI) environment is a complex ecosystem, where the host lives in complete homeostasis with its microbiota, with the two generally maintaining a delicate balance (1, 2). An immune tolerance exists between the host and its microflora and is acquired soon after birth, preventing harmful inflammation in the setting of a normal microbiota (3–5). When an infection disturbs this stability, the host response is targeted towards rebuilding the equilibrium as quickly as possible. The initial barrier between this internal environment and the outside is the intestinal epithelial cell, which not only plays a role as a physical barrier and nutrient provider, but also protects its local milieu by initiating the immune response sequence (6, 7). The microbiota is also thought to play an important role in the immune response and regulation; this has been referred to as “host-commensal mutualism” (2, 3, 8, 9). The innate response, depending on the infection, may lead to activation of pro- or anti-inflammatory signaling pathways, producing cytokines and chemokines that protect the host from this invasion. However, in some instances, this response may become deleterious to the host and exacerbate the damage.

Citation: El Feghaly R, Bangar H, Haslam D. 2016. Biomarkers of Gastrointestinal Host Responses to Microbial Infections, p 663-682. In Persing D, Tenover F, Hayden R, Ieven M, Miller M, Nolte F, Tang Y, van Belkum A (ed), Molecular Microbiology. ASM Press, Washington, DC. doi: 10.1128/9781555819071.ch46
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of FIGURE 1

Antibacterial inflammatory responses against Typhimurium infection. Inflammatory cytokine production was triggered upon detection of Typhimurium by mononuclear cells, epithelial cells, and complements which leads to production of antibacterial responses by macrophage activation, neutrophil recruitment, and epithelial release of antimicrobials. (Adapted from reference .)

Citation: El Feghaly R, Bangar H, Haslam D. 2016. Biomarkers of Gastrointestinal Host Responses to Microbial Infections, p 663-682. In Persing D, Tenover F, Hayden R, Ieven M, Miller M, Nolte F, Tang Y, van Belkum A (ed), Molecular Microbiology. ASM Press, Washington, DC. doi: 10.1128/9781555819071.ch46
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 2

Innate immune responses during infection. Parasite infection to intestinal epithelial cells (IEC) leads to production of various antiparasite molecules which help to maintain epithelial integrity. Infected IECs increased production of inflammatory cytokines such as IL-15, IL-18, and INF-α/β which help in establishing immune effector mechanisms, such as IFN-γ production by NK cells and macrophages and cytotoxic NK cell activity. Dendritic cells produce cytokines (e.g., type I IFN and IL-12) that activate NK cells and IL-4 from an unknown cell may promote dendritic cell maturation. (Adapted from reference .)

Citation: El Feghaly R, Bangar H, Haslam D. 2016. Biomarkers of Gastrointestinal Host Responses to Microbial Infections, p 663-682. In Persing D, Tenover F, Hayden R, Ieven M, Miller M, Nolte F, Tang Y, van Belkum A (ed), Molecular Microbiology. ASM Press, Washington, DC. doi: 10.1128/9781555819071.ch46
Permissions and Reprints Request Permissions
Download as Powerpoint


1. Pang T, Leach ST, Katz T, Day AS, Ooi CY . 2014. Fecal biomarkers of intestinal health and disease in children. Front Pediatr 2 : 6[CrossRef].[PubMed]
2. Tchaptchet S, Hansen J . 2011. The Yin and Yang of host-commensal mutualism. Gut Microbes 2 : 347 352[CrossRef].[PubMed]
3. Abraham C, Medzhitov R . 2011. Interactions between the host innate immune system and microbes in inflammatory bowel disease. Gastroenterology 140 : 1729 1737[CrossRef].[PubMed]
4. Lotz M, Gütle D, Walther S, Ménard S, Bogdan C, Hornef MW . 2006. Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells. J Exp Med 203 : 973 984[CrossRef].[PubMed]
5. Jarry A, Bossard C, Bou-Hanna C, Masson D, Espaze E, Denis MG, Laboisse CL . 2008. Mucosal IL-10 and TGF-beta play crucial roles in preventing LPS-driven, IFN-gamma-mediated epithelial damage in human colon explants. J Clin Invest 118 : 1132 1142.[PubMed]
6. Dommett R, Zilbauer M, George JT, Bajaj-Elliott M . 2005. Innate immune defence in the human gastrointestinal tract. Mol Immunol 42 : 903 912[CrossRef].[PubMed]
7. Panja A, Siden E, Mayer L . 1995. Synthesis and regulation of accessory/proinflammatory cytokines by intestinal epithelial cells. Clin Exp Immunol 100 : 298 305[CrossRef].[PubMed]
8. Beaugerie L, Petit JC . 2004. Microbial-gut interactions in health and disease. Antibiotic-associated diarrhoea. Best Pract Res Clin Gastroenterol 18 : 337 352[CrossRef].[PubMed]
9. Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R . 2004. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118 : 229 241[CrossRef].[PubMed]
10. Ramasundara M, Leach ST, Lemberg DA, Day AS . 2009. Defensins and inflammation: the role of defensins in inflammatory bowel disease. J Gastroenterol Hepatol 24 : 202 208[CrossRef].[PubMed]
11. Wehkamp J, Schauber J, Stange EF . 2007. Defensins and cathelicidins in gastrointestinal infections. Curr Opin Gastroenterol 23 : 32 38[CrossRef].[PubMed]
12. Yang D, Chertov O, Bykovskaia SN, Chen Q, Buffo MJ, Shogan J, Anderson M, Schröder JM, Wang JM, Howard OM, Oppenheim JJ . 1999. Beta-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6. Science 286 : 525 528[CrossRef].[PubMed]
13. Yuan Q, Walker WA . 2004. Innate immunity of the gut: mucosal defense in health and disease. J Pediatr Gastroenterol Nutr 38 : 463 473[CrossRef].[PubMed]
14. Chaly YV, Paleolog EM, Kolesnikova TS, Tikhonov II, Petratchenko EV, Voitenok NN . 2000. Neutrophil alpha-defensin human neutrophil peptide modulates cytokine production in human monocytes and adhesion molecule expression in endothelial cells. Eur Cytokine Netw 11 : 257 266.[PubMed]
15. Wehkamp J, Stange EF, Fellermann K . 2009. Defensin-immunology in inflammatory bowel disease. Gastroenterol Clin Biol 33( Suppl 3) : S137 S144[CrossRef].[PubMed]
16. Ward PP, Uribe-Luna S, Conneely OM . 2002. Lactoferrin and host defense. Biochem Cell Biol 80 : 95 102[CrossRef].[PubMed]
17. Chen CC, Chang CJ, Lin TY, Lai MW, Chao HC, Kong MS . 2011. Usefulness of fecal lactoferrin in predicting and monitoring the clinical severity of infectious diarrhea. World J Gastroenterol 17 : 4218 4224[CrossRef].[PubMed]
18. Hase K, Eckmann L, Leopard JD, Varki N, Kagnoff MF . 2002. Cell differentiation is a key determinant of cathelicidin LL-37/human cationic antimicrobial protein 18 expression by human colon epithelium. Infect Immun 70 : 953 963[CrossRef].[PubMed]
19. Foell D, Wittkowski H, Vogl T, Roth J . 2007. S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules. J Leukoc Biol 81 : 28 37[CrossRef].[PubMed]
20. Kapel N, Benahmed N, Morali A, Svahn J, Canioni D, Goulet O, Ruemmele FM . 2009. Fecal beta-defensin-2 in children with inflammatory bowel diseases. J Pediatr Gastroenterol Nutr 48 : 117 120[CrossRef].[PubMed]
21. Abraham BP, Kane S . 2012. Fecal markers: calprotectin and lactoferrin. Gastroenterol Clin North Am 41 : 483 495[CrossRef].[PubMed]
22. Kane SV, Sandborn WJ, Rufo PA, Zholudev A, Boone J, Lyerly D, Camilleri M, Hanauer SB . 2003. Fecal lactoferrin is a sensitive and specific marker in identifying intestinal inflammation. Am J Gastroenterol 98 : 1309 1314[CrossRef].[PubMed]
23. Langhorst J, Elsenbruch S, Koelzer J, Rueffer A, Michalsen A, Dobos GJ . 2008. Noninvasive markers in the assessment of intestinal inflammation in inflammatory bowel diseases: performance of fecal lactoferrin, calprotectin, and PMN-elastase, CRP, and clinical indices. Am J Gastroenterol 103 : 162 169[CrossRef].[PubMed]
24. Walker TR, Land ML, Kartashov A, Saslowsky TM, Lyerly DM, Boone JH, Rufo PA . 2007. Fecal lactoferrin is a sensitive and specific marker of disease activity in children and young adults with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 44 : 414 422[CrossRef].[PubMed]
25. Leach ST, Yang Z, Messina I, Song C, Geczy CL, Cunningham AM, Day AS . 2007. Serum and mucosal S100 proteins, calprotectin (S100A8/S100A9) and S100A12, are elevated at diagnosis in children with inflammatory bowel disease. Scand J Gastroenterol 42 : 1321 1331[CrossRef].[PubMed]
26. Sidler MA, Leach ST, Day AS . 2008. Fecal S100A12 and fecal calprotectin as noninvasive markers for inflammatory bowel disease in children. Inflamm Bowel Dis 14 : 359 366[CrossRef].[PubMed]
27. D'Incà R, Dal Pont E, Di Leo V, Ferronato A, Fries W, Vettorato MG, Martines D, Sturniolo GC . 2007. Calprotectin and lactoferrin in the assessment of intestinal inflammation and organic disease. Int J Colorectal Dis 22 : 429 437[CrossRef].[PubMed]
28. Abraham C, Cho J . 2009. Interleukin-23/Th17 pathways and inflammatory bowel disease. Inflamm Bowel Dis 15 : 1090 1100[CrossRef].[PubMed]
29. Judd TA, Day AS, Lemberg DA, Turner D, Leach ST . 2011. Update of fecal markers of inflammation in inflammatory bowel disease. J Gastroenterol Hepatol 26 : 1493 1499[CrossRef].[PubMed]
30. Nielsen OH, Rüdiger N, Gaustadnes M, Horn T . 1997. Intestinal interleukin-8 concentration and gene expression in inflammatory bowel disease. Scand J Gastroenterol 32 : 1028 1034[CrossRef].[PubMed]
31. Chung-Faye G, Hayee B, Maestranzi S, Donaldson N, Forgacs I, Sherwood R . 2007. Fecal M2-pyruvate kinase (M2-PK): a novel marker of intestinal inflammation. Inflamm Bowel Dis 13 : 1374 1378[CrossRef].[PubMed]
32. Czub E, Herzig KH, Szaflarska-Popawska A, Kiehne K, Socha P, Woś H, Kamińska B, Blaszczyński M, Cichy W, Bala G, Brodzicki J, Grzybowska-Chlebowczyk U, Walkowiak J . 2007. Fecal pyruvate kinase: a potential new marker for intestinal inflammation in children with inflammatory bowel disease. Scand J Gastroenterol 42 : 1147 1150[CrossRef].[PubMed]
33. Sýkora J, Siala K, Huml M, Varvařovská J, Schwarz J, Pomahačová R . 2010. Evaluation of faecal calprotectin as a valuable non-invasive marker in distinguishing gut pathogens in young children with acute gastroenteritis. Acta Paediatr 99 : 1389 1395[CrossRef].[PubMed]
34. Chen CC, Huang JL, Chang CJ, Kong MS . 2012. Fecal calprotectin as a correlative marker in clinical severity of infectious diarrhea and usefulness in evaluating bacterial or viral pathogens in children. J Pediatr Gastroenterol Nutr 55 : 541 547[CrossRef].[PubMed]
35. Geddes K, Rubino SJ, Magalhaes JG, Streutker C, Le Bourhis L, Cho JH, Robertson SJ, Kim CJ, Kaul R, Philpott DJ, Girardin SE . 2011. Identification of an innate T helper type 17 response to intestinal bacterial pathogens. Nat Med 17 : 837 844[CrossRef].[PubMed]
36. Rubino SJ, Geddes K, Girardin SE . 2012. Innate IL-17 and IL-22 responses to enteric bacterial pathogens. Trends Immunol 33 : 112 118[CrossRef].[PubMed]
37. Song X, Zhu S, Shi P, Liu Y, Shi Y, Levin SD, Qian Y . 2011. IL-17RE is the functional receptor for IL-17C and mediates mucosal immunity to infection with intestinal pathogens. Nat Immunol 12 : 1151 1158[CrossRef].[PubMed]
38. Long KZ, Rosado JL, Santos JI, Haas M, Al Mamun A, DuPont HL, Nanthakumar NN, Estrada-Garcia T . 2010. Associations between mucosal innate and adaptive immune responses and resolution of diarrheal pathogen infections. Infect Immun 78 : 1221 1228[CrossRef].[PubMed]
39. Mejias A, Suarez NM, Ramilo O . 2014. Detecting specific infections in children through host responses: a paradigm shift. Curr Opin Infect Dis 27 : 228 235[CrossRef].[PubMed]
40. Mejias A, Dimo B, Suarez NM, Garcia C, Suarez-Arrabal MC, Jartti T, Blankenship D, Jordan-Villegas A, Ardura MI, Xu Z, Banchereau J, Chaussabel D, Ramilo O . 2013. Whole blood gene expression profiles to assess pathogenesis and disease severity in infants with respiratory syncytial virus infection. PLoS Med 10 : e1001549[CrossRef].[PubMed]
41. Ramilo O, Mejías A . 2009. Shifting the paradigm: host gene signatures for diagnosis of infectious diseases. Cell Host Microbe 6 : 199 200[CrossRef].[PubMed]
42. Zaas AK, Chen M, Varkey J, Veldman T, Hero AO III, Lucas J, Huang Y, Turner R, Gilbert A, Lambkin-Williams R, Øien NC, Nicholson B, Kingsmore S, Carin L, Woods CW, Ginsburg GS . 2009. Gene expression signatures diagnose influenza and other symptomatic respiratory viral infections in humans. Cell Host Microbe 6 : 207 217[CrossRef].[PubMed]
43. Benson L, Song X, Campos J, Singh N . 2007. Changing epidemiology of Clostridium difficile-associated disease in children. Infect Control Hosp Epidemiol 28 : 1233 1235[CrossRef].[PubMed]
44. Cohen MB . 2009. Clostridium difficile infections: emerging epidemiology and new treatments. J Pediatr Gastroenterol Nutr 48( Suppl 2) : S63 S65[CrossRef].[PubMed]
45. McFarland LV . 2008. Update on the changing epidemiology of Clostridium difficile-associated disease. Nat Clin Pract Gastroenterol Hepatol 5 : 40 48[CrossRef].[PubMed]
46. Kelly CP, LaMont JT . 2008. Clostridium difficile—more difficult than ever. N Engl J Med 359 : 1932 1940[CrossRef].[PubMed]
47. Ozaki E, Kato H, Kita H, Karasawa T, Maegawa T, Koino Y, Matsumoto K, Takada T, Nomoto K, Tanaka R, Nakamura S . 2004. Clostridium difficile colonization in healthy adults: transient colonization and correlation with enterococcal colonization. J Med Microbiol 53 : 167 172[CrossRef].[PubMed]
48. Kato H, Kita H, Karasawa T, Maegawa T, Koino Y, Takakuwa H, Saikai T, Kobayashi K, Yamagishi T, Nakamura S . 2001. Colonisation and transmission of Clostridium difficile in healthy individuals examined by PCR ribotyping and pulsed-field gel electrophoresis. J Med Microbiol 50 : 720 727[CrossRef].[PubMed]
49. Alasmari F, Seiler SM, Hink T, Burnham CA, Dubberke ER . 2014. Prevalence and risk factors for asymptomatic Clostridium difficile carriage. Clin Infect Dis 59 : 216 222[CrossRef].[PubMed]
50. Rineh A, Kelso MJ, Vatansever F, Tegos GP, Hamblin MR . 2014. Clostridium difficile infection: molecular pathogenesis and novel therapeutics. Expert Rev Anti Infect Ther 12 : 131 150[CrossRef].[PubMed]
51. Gough E, Shaikh H, Manges AR . 2011. Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection. Clin Infect Dis 53 : 994 1002[CrossRef].[PubMed]
52. Buffie CG, Jarchum I, Equinda M, Lipuma L, Gobourne A, Viale A, Ubeda C, Xavier J, Pamer EG . 2012. Profound alterations of intestinal microbiota following a single dose of clindamycin results in sustained susceptibility to Clostridium difficile-induced colitis. Infect Immun 80 : 62 73[CrossRef].[PubMed]
53. Fuentes S, van Nood E, Tims S, Heikamp-de Jong I, ter Braak CJ, Keller JJ, Zoetendal EG, de Vos WM . 2014. Reset of a critically disturbed microbial ecosystem: faecal transplant in recurrent Clostridium difficile infection. ISME J 8 : 1621 1633[CrossRef].[PubMed]
54. Koenigsknecht MJ, Young VB . 2013. Faecal microbiota transplantation for the treatment of recurrent Clostridium difficile infection: current promise and future needs. Curr Opin Gastroenterol 29 : 628 632[CrossRef].[PubMed]
55. Madan R, Jr WA . 2012. Immune responses to Clostridium difficile infection. Trends Mol Med 18 : 658 666[CrossRef].[PubMed]
56. Peniche AG, Savidge TC, Dann SM . 2013. Recent insights into Clostridium difficile pathogenesis. Curr Opin Infect Dis 26 : 447 453.[PubMed]
57. Kelly CP, Kyne L . 2011. The host immune response to Clostridium difficile. J Med Microbiol 60 : 1070 1079[CrossRef].[PubMed]
58. Ishida Y, Maegawa T, Kondo T, Kimura A, Iwakura Y, Nakamura S, Mukaida N . 2004. Essential involvement of IFN-gamma in Clostridium difficile toxin A-induced enteritis. J Immunol 172 : 3018 3025[CrossRef].[PubMed]
59. He D, Sougioultzis S, Hagen S, Liu J, Keates S, Keates AC, Pothoulakis C, Lamont JT . 2002. Clostridium difficile toxin A triggers human colonocyte IL-8 release via mitochondrial oxygen radical generation. Gastroenterology 122 : 1048 1057[CrossRef].[PubMed]
60. Jafari NV, Kuehne SA, Bryant CE, Elawad M, Wren BW, Minton NP, Allan E, Bajaj-Elliott M . 2013. Clostridium difficile modulates host innate immunity via toxin-independent and dependent mechanism(s). PLoS One 8 : e69846[CrossRef].[PubMed]
61. Kim JM, Kim JS, Jun HC, Oh YK, Song IS, Kim CY . 2002. Differential expression and polarized secretion of CXC and CC chemokines by human intestinal epithelial cancer cell lines in response to Clostridium difficile toxin A. Microbiol Immunol 46 : 333 342[CrossRef].[PubMed]
62. Yoshino Y, Kitazawa T, Ikeda M, Tatsuno K, Yanagimoto S, Okugawa S, Yotsuyanagi H, Ota Y . 2013. Clostridium difficile flagellin stimulates toll-like receptor 5, and toxin B promotes flagellin-induced chemokine production via TLR5. Life Sci 92 : 211 217[CrossRef].[PubMed]
63. Sadighi Akha AA, Theriot CM, Erb-Downward JR, McDermott AJ, Falkowski NR, Tyra HM, Rutkowski DT, Young VB, Huffnagle GB . 2013. Acute infection of mice with Clostridium difficile leads to eIF2α phosphorylation and pro-survival signalling as part of the mucosal inflammatory response. Immunology 140 : 111 122[CrossRef].[PubMed]
64. Morteau O, Castagliuolo I, Mykoniatis A, Zacks J, Wlk M, Lu B, Pothoulakis C, Gerard NP, Gerard C . 2002. Genetic deficiency in the chemokine receptor CCR1 protects against acute Clostridium difficile toxin A enteritis in mice. Gastroenterology 122 : 725 733[CrossRef].[PubMed]
65. Bobo LD, El Feghaly RE, Chen YS, Dubberke ER, Han Z, Baker AH, Li J, Burnham CA, Haslam DB . 2013. MAPK-activated protein kinase 2 contributes to Clostridium difficile-associated inflammation. Infect Immun 81 : 713 722[CrossRef].[PubMed]
66. Warny M, Keates AC, Keates S, Castagliuolo I, Zacks JK, Aboudola S, Qamar A, Pothoulakis C, LaMont JT, Kelly CP . 2000. p38 MAP kinase activation by Clostridium difficile toxin A mediates monocyte necrosis, IL-8 production, and enteritis. J Clin Invest 105 : 1147 1156[CrossRef].[PubMed]
67. Kim H, Kokkotou E, Na X, Rhee SH, Moyer MP, Pothoulakis C, Lamont JT . 2005. Clostridium difficile toxin A-induced colonocyte apoptosis involves p53-dependent p21(WAF1/CIP1) induction via p38 mitogen-activated protein kinase. Gastroenterology 129 : 1875 1888[CrossRef].[PubMed]
68. El Feghaly RE, Stauber JL, Deych E, Gonzalez C, Tarr PI, Haslam DB . 2013. Markers of intestinal inflammation, not bacterial burden, correlate with clinical outcomes in Clostridium difficile infection. Clin Infect Dis 56 : 1713 1721[CrossRef].[PubMed]
69. El Feghaly RE, Stauber JL, Tarr PI, Haslam DB . 2013. Intestinal inflammatory biomarkers and outcome in pediatric Clostridium difficile infections. J. Pediatr. 163 : 1697– 1704 e1692.
70. Rao K, Erb-Downward JR, Walk ST, Micic D, Falkowski N, Santhosh K, Mogle JA, Ring C, Young VB, Huffnagle GB, Aronoff DM . 2014. The systemic inflammatory response to Clostridium difficile infection. PLoS One 9 : e92578[CrossRef].[PubMed]
71. Boone JH, Archbald-Pannone LR, Wickham KN, Carman RJ, Guerrant RL, Franck CT, Lyerly DM . 2014. Ribotype 027 Clostridium difficile infections with measurable stool toxin have increased lactoferrin and are associated with a higher mortality. Eur J Clin Microbiol Infect Dis 33 : 1045 1051[CrossRef].[PubMed]
72. Rao K, Walk ST, Micic D, Chenoweth E, Deng L, Galecki AT, Jain R, Trivedi I, Yu M, Santhosh K, Ring C, Young VB, Huffnagle GB, Aronoff DM . 2013. Procalcitonin levels associate with severity of Clostridium difficile infection. PLoS One 8 : e58265[CrossRef].[PubMed]
73. Khanafer N, Touré A, Chambrier C, Cour M, Reverdy ME, Argaud L, Vanhems P . 2013. Predictors of Clostridium difficile infection severity in patients hospitalised in medical intensive care. World J Gastroenterol 19 : 8034 8041[CrossRef].[PubMed]
74. Wren MW, Kinson R, Sivapalan M, Shemko M, Shetty NR . 2009. Detection of Clostridium difficile infection: a suggested laboratory diagnostic algorithm. Br J Biomed Sci 66 : 175 179.[PubMed]
75. Vaishnavi C, Bhasin D, Kochhar R, Singh K. 2000. Clostridium difficile toxin and faecal lactoferrin assays in adult patients. Microbes Infect 2 : 1827– 1830.
76. Vaishnavi C, Thapa BR, Thennarasu K, Singh K . 2002. Faecal lactoferrin assay as an adjunct to Clostridium difficile diarrhoea. Indian J Pathol Microbiol 45 : 69 73.[PubMed]
77. Steiner TS, Flores CA, Pizarro TT, Guerrant RL . 1997. Fecal lactoferrin, interleukin-1beta, and interleukin-8 are elevated in patients with severe Clostridium difficile colitis. Clin Diagn Lab Immunol 4 : 719 722.[PubMed]
78. Garey KW, Jiang ZD, Ghantoji S, Tam VH, Arora V, Dupont HL . 2010. A common polymorphism in the interleukin-8 gene promoter is associated with an increased risk for recurrent Clostridium difficile infection. Clin Infect Dis 51 : 1406 1410[CrossRef].[PubMed]
79. Darkoh C, Turnwald BP, Koo HL, Garey KW, Jiang ZD, Aitken SL, Dupont HL . 2014. Colonic Immunopathogenesis of Clostridium difficile Infections. Clin Vaccine Immunol 21 : 509 517.
80. Buonomo EL, Madan R, Pramoonjago P, Li L, Okusa MD, Petri WA Jr . 2013. Role of interleukin 23 signaling in Clostridium difficile colitis. J Infect Dis 208 : 917 920[CrossRef].[PubMed]
81. Koo HL, Ajami NJ, Jiang ZD, Dupont HL, Atmar RL, Lewis D, Byers P, Abraham P, Quijano RA, Musher DM, Young EJ . 2009. A nosocomial outbreak of norovirus infection masquerading as clostridium difficile infection. Clin Infect Dis 48 : e75 e77[CrossRef].[PubMed]
82. El Feghaly RE, Stauber JL, Tarr PI, Haslam DB . 2013. Viral co-infections are common and are associated with higher bacterial burden in children with clostridium difficile infection. J Pediatr Gastroenterol Nutr 57 : 813 816[CrossRef].[PubMed]
83. Bianco M, Fedele G, Quattrini A, Spigaglia P, Barbanti F, Mastrantonio P, Ausiello CM . 2011. Immunomodulatory activities of surface-layer proteins obtained from epidemic and hypervirulent Clostridium difficile strains. J Med Microbiol 60 : 1162 1167[CrossRef].[PubMed]
84. Gyles CL . 2007. Shiga toxin-producing Escherichia coli: an overview. J Anim Sci 85( Suppl) : E45 E62[CrossRef].[PubMed]
85. Lee MS, Kim MH, Tesh VL . 2013. Shiga toxins expressed by human pathogenic bacteria induce immune responses in host cells. J Microbiol 51 : 724 730[CrossRef].[PubMed]
86. Dean-Nystrom EA, Bosworth BT, Moon HW . 1997. Pathogenesis of O157:H7 Escherichia coli infection in neonatal calves. Adv Exp Med Biol 412 : 47 51[CrossRef].[PubMed]
87. Karmali MA . 2009. Host and pathogen determinants of verocytotoxin-producing Escherichia coli-associated hemolytic uremic syndrome. Kidney Int Suppl 75( Suppl.) : S4 S7[CrossRef].[PubMed]
88. McDaniel TK, Jarvis KG, Donnenberg MS, Kaper JB . 1995. A genetic locus of enterocyte effacement conserved among diverse enterobacterial pathogens. Proc Natl Acad Sci USA 92 : 1664 1668[CrossRef].[PubMed]
89. Xue Y, Zhang H, Wang H, Hu J, Du M, Zhu MJ . 2014. Host inflammatory response inhibits Escherichia coli O157:H7 adhesion to gut epithelium through augmentation of mucin expression. Infect Immun 82 : 1921 1930[CrossRef].[PubMed]
90. Hauf N, Chakraborty T . 2003. Suppression of NF-kappa B activation and proinflammatory cytokine expression by Shiga toxin-producing Escherichia coli. J Immunol 170 : 2074 2082[CrossRef].[PubMed]
91. Harrison LM, van Haaften WC, Tesh VL . 2004. Regulation of proinflammatory cytokine expression by Shiga toxin 1 and/or lipopolysaccharides in the human monocytic cell line THP-1. Infect Immun 72 : 2618 2627[CrossRef].[PubMed]
92. Lentz EK, Cherla RP, Jaspers V, Weeks BR, Tesh VL . 2010. Role of tumor necrosis factor alpha in disease using a mouse model of Shiga toxin-mediated renal damage. Infect Immun 78 : 3689 3699[CrossRef].[PubMed]
93. Tesh VL . 1998. Virulence of enterohemorrhagic Escherichia coli: role of molecular crosstalk. Trends Microbiol 6 : 228 233[CrossRef].[PubMed]
94. Yamasaki C, Nishikawa K, Zeng XT, Katayama Y, Natori Y, Komatsu N, Oda T, Natori Y . 2004. Induction of cytokines by toxins that have an identical RNA N-glycosidase activity: shiga toxin, ricin, and modeccin. Biochim Biophys Acta 1671 : 44 50[CrossRef].[PubMed]
95. Raqib R, Lindberg AA, Björk L, Bardhan PK, Wretlind B, Andersson U, Andersson J . 1995. Down-regulation of gamma interferon, tumor necrosis factor type I, interleukin 1 (IL-1) type I, IL-3, IL-4, and transforming growth factor beta type I receptors at the local site during the acute phase of Shigella infection. Infect Immun 63 : 3079 3087.[PubMed]
96. Stearns-Kurosawa DJ, Oh SY, Cherla RP, Lee MS, Tesh VL, Papin J, Henderson J, Kurosawa S . 2013. Distinct renal pathology and a chemotactic phenotype after enterohemorrhagic Escherichia coli shiga toxins in non-human primate models of hemolytic uremic syndrome. Am J Pathol 182 : 1227 1238[CrossRef].[PubMed]
97. Thorpe CM, Smith WE, Hurley BP, Acheson DW . 2001. Shiga toxins induce, superinduce, and stabilize a variety of C-X-C chemokine mRNAs in intestinal epithelial cells, resulting in increased chemokine expression. Infect Immun 69 : 6140 6147[CrossRef].[PubMed]
98. Santos RL . 2014. Pathobiology of salmonella, intestinal microbiota, and the host innate immune response. Front Immunol 5 : 252[CrossRef].[PubMed]
99. Thorpe CM, Hurley BP, Lincicome LL, Jacewicz MS, Keusch GT, Acheson DW . 1999. Shiga toxins stimulate secretion of interleukin-8 from intestinal epithelial cells. Infect Immun 67 : 5985 5993.[PubMed]
100. Jeong KI, Zhang Q, Nunnari J, Tzipori S . 2010. A piglet model of acute gastroenteritis induced by Shigella dysenteriae Type 1. J Infect Dis 201 : 903 911[CrossRef].[PubMed]
101. Foster GH, Tesh VL . 2002. Shiga toxin 1-induced activation of c-Jun NH(2)-terminal kinase and p38 in the human monocytic cell line THP-1: possible involvement in the production of TNF-alpha. J Leukoc Biol 71 : 107 114.[PubMed]
102. Stricklett PK, Hughes AK, Kohan DE . 2005. Inhibition of p38 mitogen-activated protein kinase ameliorates cytokine up-regulated shigatoxin-1 toxicity in human brain microvascular endothelial cells. J Infect Dis 191 : 461 471[CrossRef].[PubMed]
103. Leyva-Illades D, Cherla RP, Lee MS, Tesh VL . 2012. Regulation of cytokine and chemokine expression by the ribotoxic stress response elicited by Shiga toxin type 1 in human macrophage-like THP-1 cells. Infect Immun 80 : 2109 2120[CrossRef].[PubMed]
104. Murata K, Higuchi T, Takada K, Oida K, Horie S, Ishii H . 2006. Verotoxin-1 stimulation of macrophage-like THP-1 cells up-regulates tissue factor expression through activation of c-Yes tyrosine kinase: possible signal transduction in tissue factor up-regulation. Biochim Biophys Acta 1762 : 835 843[CrossRef].[PubMed]
105. Cherla RP, Lee SY, Mulder RA, Lee MS, Tesh VL . 2009. Shiga toxin 1-induced proinflammatory cytokine production is regulated by the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling pathway. Infect Immun 77 : 3919 3931[CrossRef].[PubMed]
106. DuPont HL, Levine MM, Hornick RB, Formal SB . 1989. Inoculum size in shigellosis and implications for expected mode of transmission. J Infect Dis 159 : 1126 1128[CrossRef].[PubMed]
107. Phalipon A, Sansonetti PJ . 2007. Shigella's ways of manipulating the host intestinal innate and adaptive immune system: a tool box for survival? Immunol Cell Biol 85 : 119 129[CrossRef].[PubMed]
108. Marteyn B, Gazi A, Sansonetti P . 2012. Shigella: a model of virulence regulation in vivo. Gut Microbes 3 : 104 120[CrossRef].[PubMed]
109. Sasakawa C . 2010. A new paradigm of bacteria-gut interplay brought through the study of Shigella. Proc Jpn Acad, Ser B, Phys Biol Sci 86 : 229 243[CrossRef].[PubMed]
110. Suzuki T, Franchi L, Toma C, Ashida H, Ogawa M, Yoshikawa Y, Mimuro H, Inohara N, Sasakawa C, Nuñez G . 2007. Differential regulation of caspase-1 activation, pyroptosis, and autophagy via Ipaf and ASC in Shigella-infected macrophages. PLoS Pathog 3 : e111[CrossRef].[PubMed]
111. Suzuki T, Nakanishi K, Tsutsui H, Iwai H, Akira S, Inohara N, Chamaillard M, Nuñez G, Sasakawa C . 2005. A novel caspase-1/toll-like receptor 4-independent pathway of cell death induced by cytosolic Shigella in infected macrophages. J Biol Chem 280 : 14042 14050[CrossRef].[PubMed]
112. Raqib R, Ekberg C, Sharkar P, Bardhan PK, Zychlinsky A, Sansonetti PJ, Andersson J . 2002. Apoptosis in acute shigellosis is associated with increased production of Fas/Fas ligand, perforin, caspase-1, and caspase-3 but reduced production of Bcl-2 and interleukin-2. Infect Immun 70 : 3199 3207[CrossRef].[PubMed]
113. Ashida H, Ogawa M, Mimuro H, Sasakawa C . 2009. Shigella infection of intestinal epithelium and circumvention of the host innate defense system. Curr Top Microbiol Immunol 337 : 231 255[CrossRef].[PubMed]
114. Ogawa M, Handa Y, Ashida H, Suzuki M, Sasakawa C . 2008. The versatility of Shigella effectors. Nat Rev Microbiol 6 : 11 16[CrossRef].[PubMed]
115. Pore D, Mahata N, Pal A, Chakrabarti MK . 2010. 34 kDa MOMP of Shigella flexneri promotes TLR2 mediated macrophage activation with the engagement of NF-kappaB and p38 MAP kinase signaling. Mol Immunol 47 : 1739 1746[CrossRef].[PubMed]
116. Arondel J, Singer M, Matsukawa A, Zychlinsky A, Sansonetti PJ . 1999. Increased interleukin-1 (IL-1) and imbalance between IL-1 and IL-1 receptor antagonist during acute inflammation in experimental Shigellosis. Infect Immun 67 : 6056 6066.[PubMed]
117. Sansonetti PJ, Phalipon A, Arondel J, Thirumalai K, Banerjee S, Akira S, Takeda K, Zychlinsky A . 2000. Caspase-1 activation of IL-1beta and IL-18 are essential for Shigella flexneri-induced inflammation. Immunity 12 : 581 590[CrossRef].[PubMed]
118. Abreu MT, Vora P, Faure E, Thomas LS, Arnold ET, Arditi M . 2001. Decreased expression of Toll-like receptor-4 and MD-2 correlates with intestinal epithelial cell protection against dysregulated proinflammatory gene expression in response to bacterial lipopolysaccharide. J Immunol 167 : 1609 1616[CrossRef].[PubMed]
119. Sansonetti PJ, Arondel J, Huerre M, Harada A, Matsushima K . 1999. Interleukin-8 controls bacterial transepithelial translocation at the cost of epithelial destruction in experimental shigellosis. Infect Immun 67 : 1471 1480.[PubMed]
120. Raqib R, Wretlind B, Andersson J, Lindberg AA . 1995. Cytokine secretion in acute shigellosis is correlated to disease activity and directed more to stool than to plasma. J Infect Dis 171 : 376 384[CrossRef].[PubMed]
121. Greenberg DE, Jiang ZD, Steffen R, Verenker MP, DuPont HL . 2002. Markers of inflammation in bacterial diarrhea among travelers, with a focus on enteroaggregative Escherichia coli pathogenicity. J Infect Dis 185 : 944 949[CrossRef].[PubMed]
122. Ogawa M, Yoshimori T, Suzuki T, Sagara H, Mizushima N, Sasakawa C . 2005. Escape of intracellular Shigella from autophagy. Science 307 : 727 731[CrossRef].[PubMed]
123. West NP, Sansonetti P, Mounier J, Exley RM, Parsot C, Guadagnini S, Prévost MC, Prochnicka-Chalufour A, Delepierre M, Tanguy M, Tang CM . 2005. Optimization of virulence functions through glucosylation of Shigella LPS. Science 307 : 1313 1317[CrossRef].[PubMed]
124. Ingersoll MA, Moss JE, Weinrauch Y, Fisher PE, Groisman EA, Zychlinsky A . 2003. The ShiA protein encoded by the Shigella flexneri SHI-2 pathogenicity island attenuates inflammation. Cell Microbiol 5 : 797 807[CrossRef].[PubMed]
125. Kim DW, Lenzen G, Page AL, Legrain P, Sansonetti PJ, Parsot C . 2005. The Shigella flexneri effector OspG interferes with innate immune responses by targeting ubiquitin-conjugating enzymes. Proc Natl Acad Sci USA 102 : 14046 14051[CrossRef].[PubMed]
126. Islam D, Bandholtz L, Nilsson J, Wigzell H, Christensson B, Agerberth B, Gudmundsson G . 2001. Downregulation of bactericidal peptides in enteric infections: a novel immune escape mechanism with bacterial DNA as a potential regulator. Nat Med 7 : 180 185[CrossRef].[PubMed]
127. Taylor A, Verhagen J, Blaser K, Akdis M, Akdis CA . 2006. Mechanisms of immune suppression by interleukin-10 and transforming growth factor-beta: the role of T regulatory cells. Immunology 117 : 433 442[CrossRef].[PubMed]
128. Konradt C, Frigimelica E, Nothelfer K, Puhar A, Salgado-Pabon W, di Bartolo V, Scott-Algara D, Rodrigues CD, Sansonetti PJ, Phalipon A . 2011. The Shigella flexneri type three secretion system effector IpgD inhibits T cell migration by manipulating host phosphoinositide metabolism. Cell Host Microbe 9 : 263 272[CrossRef].[PubMed]
129. Le-Barillec K, Magalhaes JG, Corcuff E, Thuizat A, Sansonetti PJ, Phalipon A, Di Santo JP . 2005. Roles for T and NK cells in the innate immune response to Shigella flexneri. J Immunol 175 : 1735 1740[CrossRef].[PubMed]
130. Niesel DW, Hess CB, Cho YJ, Klimpel KD, Klimpel GR . 1986. Natural and recombinant interferons inhibit epithelial cell invasion by Shigella spp. Infect Immun 52 : 828 833.[PubMed]
131. Way SS, Borczuk AC, Dominitz R, Goldberg MB . 1998. An essential role for gamma interferon in innate resistance to Shigella flexneri infection. Infect Immun 66 : 1342 1348.[PubMed]
132. Islam MM, Azad AK, Bardhan PK, Raqib R, Islam D . 1994. Pathology of shigellosis and its complications. Histopathology 24 : 65 71[CrossRef].[PubMed]
133. Sellge G, Magalhaes JG, Konradt C, Fritz JH, Salgado-Pabon W, Eberl G, Bandeira A, Di Santo JP, Sansonetti PJ, Phalipon A . 2010. Th17 cells are the dominant T cell subtype primed by Shigella flexneri mediating protective immunity. J Immunol 184 : 2076 2085[CrossRef].[PubMed]
134. McSorley SJ . 2014. Immunity to intestinal pathogens: lessons learned from Salmonella. Immunol Rev 260 : 168 182[CrossRef].[PubMed]
135. Santos RL, Raffatellu M, Bevins CL, Adams LG, Tükel C, Tsolis RM, Bäumler AJ . 2009. Life in the inflamed intestine, Salmonella style. Trends Microbiol 17 : 498 506[CrossRef].[PubMed]
136. Broz P, Ohlson MB, Monack DM . 2012. Innate immune response to Salmonella typhimurium, a model enteric pathogen. Gut Microbes 3 : 62 70[CrossRef].[PubMed]
137. Winter SE, Thiennimitr P, Winter MG, Butler BP, Huseby DL, Crawford RW, Russell JM, Bevins CL, Adams LG, Tsolis RM, Roth JR, Bäumler AJ . 2010. Gut inflammation provides a respiratory electron acceptor for Salmonella. Nature 467 : 426 429[CrossRef].[PubMed]
138. Stecher B, Robbiani R, Walker AW, Westendorf AM, Barthel M, Kremer M, Chaffron S, Macpherson AJ, Buer J, Parkhill J, Dougan G, von Mering C, Hardt WD . 2007. Salmonella enterica serovar typhimurium exploits inflammation to compete with the intestinal microbiota. PLoS Biol 5 : 2177 2189[CrossRef].[PubMed]
139. Barman M, Unold D, Shifley K, Amir E, Hung K, Bos N, Salzman N . 2008. Enteric salmonellosis disrupts the microbial ecology of the murine gastrointestinal tract. Infect Immun 76 : 907 915[CrossRef].[PubMed]
140. Thiennimitr P, Winter SE, Bäumler AJ . 2012. Salmonella, the host and its microbiota. Curr Opin Microbiol 15 : 108 114[CrossRef].[PubMed]
141. Rydström A, Wick MJ . 2007. Monocyte recruitment, activation, and function in the gut-associated lymphoid tissue during oral Salmonella infection. J Immunol 178 : 5789 5801[CrossRef].[PubMed]
142. Eckmann L, Kagnoff MF . 2001. Cytokines in host defense against Salmonella. Microbes Infect 3 : 1191– 1200.
143. Godinez I, Haneda T, Raffatellu M, George MD, Paixão TA, Rolán HG, Santos RL, Dandekar S, Tsolis RM, Bäumler AJ . 2008. T cells help to amplify inflammatory responses induced by Salmonella enterica serotype Typhimurium in the intestinal mucosa. Infect Immun 76 : 2008 2017[CrossRef].[PubMed]
144. Srinivasan A, Salazar-Gonzalez RM, Jarcho M, Sandau MM, Lefrancois L, McSorley SJ . 2007. Innate immune activation of CD4 T cells in salmonella-infected mice is dependent on IL-18. J Immunol 178 : 6342 6349[CrossRef].[PubMed]
145. Müller AJ, Hoffmann C, Galle M, Van Den Broeke A, Heikenwalder M, Falter L, Misselwitz B, Kremer M, Beyaert R, Hardt WD . 2009. The S. Typhimurium effector SopE induces caspase-1 activation in stromal cells to initiate gut inflammation. Cell Host Microbe 6 : 125 136[CrossRef].[PubMed]
146. Mastroeni P, Clare S, Khan S, Harrison JA, Hormaeche CE, Okamura H, Kurimoto M, Dougan G . 1999. Interleukin 18 contributes to host resistance and gamma interferon production in mice infected with virulent Salmonella typhimurium. Infect Immun 67 : 478 483.[PubMed]
147. Miao EA, Leaf IA, Treuting PM, Mao DP, Dors M, Sarkar A, Warren SE, Wewers MD, Aderem A . 2010. Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria. Nat Immunol 11 : 1136 1142[CrossRef].[PubMed]
148. Lara-Tejero M, Sutterwala FS, Ogura Y, Grant EP, Bertin J, Coyle AJ, Flavell RA, Galán JE . 2006. Role of the caspase-1 inflammasome in Salmonella typhimurium pathogenesis. J Exp Med 203 : 1407 1412[CrossRef].[PubMed]
149. Raffatellu M, Santos RL, Chessa D, Wilson RP, Winter SE, Rossetti CA, Lawhon SD, Chu H, Lau T, Bevins CL, Adams LG, Bäumler AJ . 2007. The capsule encoding the viaB locus reduces interleukin-17 expression and mucosal innate responses in the bovine intestinal mucosa during infection with Salmonella enterica serotype Typhi. Infect Immun 75 : 4342 4350[CrossRef].[PubMed]
150. Raffatellu M, Santos RL, Verhoeven DE, George MD, Wilson RP, Winter SE, Godinez I, Sankaran S, Paixao TA, Gordon MA, Kolls JK, Dandekar S, Bäumler AJ . 2008. Simian immunodeficiency virus-induced mucosal interleukin-17 deficiency promotes Salmonella dissemination from the gut. Nat Med 14 : 421 428[CrossRef].[PubMed]
151. Godinez I, Raffatellu M, Chu H, Paixão TA, Haneda T, Santos RL, Bevins CL, Tsolis RM, Bäumler AJ . 2009. Interleukin-23 orchestrates mucosal responses to Salmonella enterica serotype Typhimurium in the intestine. Infect Immun 77 : 387 398[CrossRef].[PubMed]
152. Ye P, Rodriguez FH, Kanaly S, Stocking KL, Schurr J, Schwarzenberger P, Oliver P, Huang W, Zhang P, Zhang J, Shellito JE, Bagby GJ, Nelson S, Charrier K, Peschon JJ, Kolls JK . 2001. Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense. J Exp Med 194 : 519 527[CrossRef].[PubMed]
153. Raffatellu M, George MD, Akiyama Y, Hornsby MJ, Nuccio SP, Paixao TA, Butler BP, Chu H, Santos RL, Berger T, Mak TW, Tsolis RM, Bevins CL, Solnick JV, Dandekar S, Bäumler AJ . 2009. Lipocalin-2 resistance confers an advantage to Salmonella enterica serotype Typhimurium for growth and survival in the inflamed intestine. Cell Host Microbe 5 : 476 486[CrossRef].[PubMed]