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http://dx.doi.org/10.48022/mbl.2209.09004

Host Cellular Response during Enterohaemorrhagic Escherichia coli Shiga Toxin Exposure  

Kyung-Soo, Lee (Environmental Diseases Research Center, Korea Research Institute of Bioscience and Biotechnology)
Seo Young, Park (Environmental Diseases Research Center, Korea Research Institute of Bioscience and Biotechnology)
Moo-Seung, Lee (Environmental Diseases Research Center, Korea Research Institute of Bioscience and Biotechnology)
Publication Information
Microbiology and Biotechnology Letters / v.50, no.4, 2022 , pp. 441-456 More about this Journal
Abstract
Shiga toxins (Stxs) are major virulence factors from the enterohemorrhagic Escherichia coli (EHEC), a subset of Stx-producing Escherichia coli. Stxs are multi-functional, ribosome-inactivating proteins that underpin the development of hemolytic uremic syndrome (HUS) and central nervous system (CNS) damage. Currently, therapeutic options for the treatment of diseases caused by Stxs are limited and unsatisfactory. Furthermore, the pathophysiological mechanisms underpinning toxin-induced inflammation remain unclear. Numerous works have demonstrated that the various host ribotoxic stress-induced targets including p38 mitogen-activated protein kinase, its downstream substrate Mitogen-activated protein kinase-activated protein kinase 2, and apoptotic signaling via ER-stress sensors are activated in many different susceptible cell types following the regular retrograde transportation of the Stxs, eventually leading to disturbing intercellular communication. Therapeutic options targeting host cellular pathways induced by Stxs may represent a promising strategy for intervention in Stx-mediated acute renal dysfunction, retinal damage, and CNS damage. This review aims at fostering an in-depth understanding of EHEC Stxs-mediated pathogenesis through the toxin-host interactions.
Keywords
STEC; shiga toxins; hemolytic uremic syndrome; host responses; inflammation;
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1 Janowska-Wieczorek A, Majka M, Kijowski J, Baj-Krzyworzeka M, Reca R, Turner AR, et al. 2001. Platelet-derived microparticles bind to hematopoietic stem/progenitor cells and enhance their engraftment. Blood 98: 3143-3149.    DOI
2 Tkach M, Kowal J, Zucchetti AE, Enserink L, Jouve M, Lankar D, et al. 2017. Qualitative differences in T-cell activation by dendritic cell-derived extracellular vesicle subtypes. EMBO J. 36: 3012-3028.    DOI
3 Cho BS, Kim JO, Ha DH, Yi YW. 2018. Exosomes derived from human adipose tissue-derived mesenchymal stem cells alleviate atopic dermatitis. Stem Cell Res. Ther. 9: 187. 
4 van Niel G, D'Angelo G, Raposo G. 2018. Shedding light on the cell biology of extracellular vesicles. Nat. Rev. Mol. Cell Biol. 19: 213-228.    DOI
5 He C, Hu X, Weston TA, Jung RS, Sandhu J, Huang S, et al. 2018. Macrophages release plasma membrane-derived particles rich in accessible cholesterol. Proc. Natl. Acad. Sci. USA 115: E8499-E8508. 
6 Kim KM, Abdelmohsen K, Mustapic M, Kapogiannis D, Gorospe M. 2017. RNA in extracellular vesicles. Wiley Interdiscip Rev. RNA. 8: 10.1002/wrna.1413. doi: 10.1002/wrna.1413.    DOI
7 Latifkar A, Hur YH, Sanchez JC, Cerione RA, Antonyak MA. 2019. New insights into extracellular vesicle biogenesis and function. J. Cell Sci. 132: jcs222406. 
8 Stahl AL, Sartz L, Nelsson A, Bekassy ZD, Karpman D. 2009. Shiga toxin and lipopolysaccharide induce platelet-leukocyte aggregates and tissue factor release, a thrombotic mechanism in hemolytic uremic syndrome. PLoS One 4: e6990. 
9 Arvidsson I, Stahl AL, Hedstrom MM, Kristoffersson AC, Rylander C, Westman JS, et al. 2015. Shiga toxin-induced complement-mediated hemolysis and release of complement-coated red blood cell-derived microvesicles in hemolytic uremic syndrome. J. Immunol. 194: 2309-2318.    DOI
10 Ge S, Hertel B, Emden SH, Beneke J, Menne J, Haller H, von Vietinghoff S. 2012. Microparticle generation and leucocyte death in Shiga toxin-mediated HUS. Nephrol. Dial. Transplant. 27: 2768-2775.    DOI
11 Iordanov MS, Pribnow D, Magun JL, Dinh TH, Pearson JA, Chen SL, et al. 1997. Ribotoxic stress response: activation of the stress-activated protein kinase JNK1 by inhibitors of the peptidyl transferase reaction and by sequence-specific RNA damage to the alpha-sarcin/ricin loop in the 28S rRNA. Mol. Cell Biol. 17: 3373-3381.    DOI
12 Lee MS, Cherla RP, Leyva-Illades D, Tesh VL. 2009. Bcl-2 regulates the onset of shiga toxin 1-induced apoptosis in THP-1 cells. Infect. Immun. 77: 5233-5244.    DOI
13 Lim HS, Kim YJ, Kim BY, Park G, Jeong SJ. 2018. The anti-neuroinflammatory activity of tectorigenin pretreatment via downregulated NF-kappaB and ERK/JNK pathways in BV-2 microglial and microglia inactivation in mice with lipopolysaccharide. Front. Pharmacol. 9: 462. 
14 Gray JS, Bae HK, Li JC, Lau AS, Pestka JJ. 2008. Double-stranded RNA-activated protein kinase mediates induction of interleukin-8 expression by deoxynivalenol, Shiga toxin 1, and ricin in monocytes. Toxicol. Sci. 105: 322-330.    DOI
15 Elliott TS, Shelton A, Greenwood D. 1987. The response of Escherichia coli to ciprofloxacin and norfloxacin. J. Med. Microbiol. 23: 83-88.    DOI
16 Angel Villegas N, Baronetti J, Albesa I, Etcheverria A, Becerra MC, Padola NL, et al. 2015. Effect of antibiotics on cellular stress generated in Shiga toxin-producing Escherichia coli O157:H7 and non-O157 biofilms. Toxicol. In Vitro 29: 1692-1700.    DOI
17 Ichinohe N, Ohara-Nemoto Y, Nemoto TK, Kimura S, Ichinohe S. 2009. Effects of fosfomycin on Shiga toxin-producing Escherichia coli: quantification of copy numbers of Shiga toxin-encoding genes and their expression levels using real-time PCR. J. Med. Microbiol. 58: 971-973.    DOI
18 Melton-Celsa A, Mohawk K, Teel L, O'Brien A. 2012. Pathogenesis of Shiga-toxin producing escherichia coli. Curr. Top. Microbiol. Immunol. 357: 67-103.    DOI
19 Griffin DE, Gentry MK, Brown JE. 1983. Isolation and characterization of monoclonal antibodies to Shiga toxin. Infect. Immun. 41: 430-433.    DOI
20 Strockbine NA, Marques LR, Holmes RK, O'Brien AD. 1985. Characterization of monoclonal antibodies against Shiga-like toxin from Escherichia coli. Infect. Immun. 50: 695-700.    DOI
21 Cheng LW, Henderson TD, Patfield S, Stanker LH, He X. 2013. Mouse in vivo neutralization of Escherichia coli Shiga toxin 2 with monoclonal antibodies. Toxins (Basel) 5: 1845-1858.    DOI
22 Smith MJ, Melton-Celsa AR, Sinclair JF, Carvalho HM, Robinson CM, O'Brien AD. 2009. Monoclonal antibody 11E10, which neutralizes shiga toxin type 2 (Stx2), recognizes three regions on the Stx2 A subunit, blocks the enzymatic action of the toxin in vitro, and alters the overall cellular distribution of the toxin. Infect. Immun. 77: 2730-2740.    DOI
23 Nakanishi K, Morikane S, Ichikawa S, Kurohane K, Niwa Y, Akimoto Y, et al. 2017. Protection of human colon cells from Shiga toxin by plant-based recombinant secretory IgA. Sci. Rep. 7: 45843. 
24 Ruano-Gallego D, Yara DA, Di Ianni L, Frankel G, Schϋller S, Fernandez LA. 2019. A nanobody targeting the translocated intimin receptor inhibits the attachment of enterohemorrhagic E. coli to human colonic mucosa. PLoS Pathog. 15: e1008031. 
25 Trachtman H, Cnaan A, Christen E, Gibbs K, Zhao S, Acheson DW, et al. 2003. Effect of an oral Shiga toxin-binding agent on diarrhea-associated hemolytic uremic syndrome in children: a randomized controlled trial. JAMA 290: 1337-1344.    DOI
26 LaCasse EC, Bray MR, Patterson B, Lim WM, Perampalam S, Radvanyi LG, et al. 1999. Shiga-like toxin-1 receptor on human breast cancer, lymphoma, and myeloma and absence from CD34(+) hematopoietic stem cells: implications for ex vivo tumor purging and autologous stem cell transplantation. Blood 94: 2901-2910. 
27 Nishikawa K, Matsuoka K, Kita E, Okabe N, Mizuguchi M, Hino K, et al. 2002. A therapeutic agent with oriented carbohydrates for treatment of infections by Shiga toxin-producing Escherichia coli O157:H7. Proc. Natl. Acad. Sci. USA 99: 7669-7674.    DOI
28 Nishikawa K, Matsuoka K, Watanabe M, Igai K, Hino K, Hatano K, et al. 2005. Identification of the optimal structure required for a Shiga toxin neutralizer with oriented carbohydrates to function in the circulation. J. Infect. Dis. 191: 2097-2105.    DOI
29 Watanabe M, Matsuoka K, Kita E, Igai K, Higashi N, Miyagawa A, et al. 2004. Oral therapeutic agents with highly clustered globotriose for treatment of Shiga toxigenic Escherichia coli infections. J. Infect. Dis. 189: 360-368.    DOI
30 Arab S, Russel E, Chapman WB, Rosen B, Lingwood CA. 1997. Expression of the verotoxin receptor glycolipid, globotriaosylceramide, in ovarian hyperplasias. Oncol. Res. 9: 553-563. 
31 Maak M, Nitsche U, Keller L, Wolf P, Sarr M, Thiebaud M, et al. 2011. Tumor-specific targeting of pancreatic cancer with Shiga toxin B-subunit. Mol. Cancer Ther. 10: 1918-1928.    DOI
32 Ohyama C, Fukushi Y, Satoh M, Saitoh S, Orikasa S, Nudelman E, et al. 1990. Changes in glycolipid expression in human testicular tumor. Int. J. Cancer 45: 1040-1044.    DOI
33 El Alaoui A, Schmidt F, Amessou M, Sarr M, Decaudin D, Florent JC, et al. 2007. Shiga toxin-mediated retrograde delivery of a topoisomerase I inhibitor prodrug. Angew. Chem. Int. Ed. Engl. 46: 6469-6472.    DOI
34 Heath-Engel HM, Lingwood CA. 2003. Verotoxin sensitivity of ECV304 cells in vitro and in vivo in a xenograft tumour model: VT1 as a tumour neovascular marker. Angiogenesis 6: 129-141.    DOI
35 El Alaoui A, Schmidt F, Sarr M, Decaudin D, Florent JC, Johannes L. 2008. Synthesis and properties of a mitochondrial peripheral benzodiazepine receptor conjugate. ChemMedChem. 3: 1687-1695.    DOI
36 Farkas-Himsley H, Hill R, Rosen B, Arab S, Lingwood CA. 1995. The bacterial colicin active against tumor cells in vitro and in vivo is verotoxin 1. Proc. Natl. Acad. Sci. USA 92: 6996-7000.    DOI
37 Salhia B, Rutka JT, Lingwood C, Nutikka A, Van Furth WR. 2002. The treatment of malignant meningioma with verotoxin. Neoplasia 4: 304-311.    DOI
38 Ishitoya S, Kurazono H, Nishiyama H, Nakamura E, Kamoto T, Habuchi T, et al. 2004. Verotoxin induces rapid elimination of human renal tumor xenografts in SCID mice. J. Urol. 171: 1309-1313.    DOI
39 Arab S, Rutka J, Lingwood C. 1999. Verotoxin induces apoptosis and the complete, rapid, long-term elimination of human astrocytoma xenografts in nude mice. Oncol. Res. 11: 33-39. 
40 Palermo MS, Exeni RA, Fernandez GC. 2009. Hemolytic uremic syndrome: pathogenesis and update of interventions. Expert Rev. Anti. Infect. Ther. 7: 697-707.    DOI
41 Lee MS, Kwon H, Lee EY, Kim DJ, Park JH, Tesh VL, et al. 2016. Shiga toxins activate the NLRP3 inflammasome pathway to promote both production of the proinflammatory cytokine interleukin-1beta and apoptotic cell death. Infect. Immun. 84: 172-186.    DOI
42 Shu Q, Gill HS. 2002. Immune protection mediated by the probiotic Lactobacillus rhamnosus HN001 (DR20) against Escherichia coli O157:H7 infection in mice. FEMS Immunol. Med. Microbiol. 34: 59-64.    DOI
43 Lee KS, Lee J, Lee P, Kim CU, Kim DJ, Jeong YJ, et al. 2020. Exosomes released from Shiga toxin 2a-treated human macrophages modulate inflammatory responses and induce cell death in toxin receptor expressing human cells. Cell. Microbiol. 22: e13249. 
44 Shu Q, Gill HS. 2001. A dietary probiotic (Bifidobacterium lactis HN019) reduces the severity of Escherichia coli O157:H7 infection in mice. Med. Microbiol. Immunol. 189: 147-152.   DOI
45 Lee MS, Tesh VL. 2019. Roles of shiga toxins in immunopathology. Toxins (Basel) 11: 212. 
46 Park JY, Jeong YJ, Park SK, Yoon SJ, Choi S, Jeong DG, et al. 2017. Shiga toxins induce apoptosis and ER stress in human retinal pigment epithelial cells. Toxins (Basel) 9: 319. 
47 Heredia N, Garcia S. 2018. Animals as sources of food-borne pathogens: A review. Anim. Nutr. 4: 250-255.    DOI
48 Griffin PM, Tauxe RV. 1991. The epidemiology of infections caused by Escherichia coli O157:H7, other enterohemorrhagic E. coli, and the associated hemolytic uremic syndrome. Epidemiol. Rev. 13: 60-98.    DOI
49 Majowicz SE, Scallan E, Jones-Bitton A, Sargeant JM, Stapleton J, Angulo FJ, et al. 2014. Global incidence of human Shiga toxin-producing Escherichia coli infections and deaths: a systematic review and knowledge synthesis. Foodborne Pathog. Dis. 11: 447-455.    DOI
50 Tarr PI, Gordon CA, Chandler WL. 2005. Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet 365: 1073-1086.    DOI
51 Kaper JB, Nataro JP, Mobley HL. 2004. Pathogenic Escherichia coli. Nat. Rev. Microbiol. 2: 123-140.    DOI
52 Havelaar AH, Kirk MD, Torgerson PR, Gibb HJ, Hald T, Lake RJ, et al. 2015. World health organization global estimates and regional comparisons of the burden of foodborne disease in 2010. PLoS Med. 12: e1001923. 
53 Nagy B, Fekete PZ. 2005. Enterotoxigenic Escherichia coli in veterinary medicine. Int. J. Med. Microbiol. 295: 443-454.    DOI
54 DeVinney R, Stein M, Reinscheid D, Abe A, Ruschkowski S, Finlay BB. 1999. Enterohemorrhagic Escherichia coli O157:H7 produces Tir, which is translocated to the host cell membrane but is not tyrosine phosphorylated. Infect. Immun. 67: 2389-2398.    DOI
55 Jerse AE, Yu J, Tall BD, Kaper JB. 1990. A genetic locus of enteropathogenic Escherichia coli necessary for the production of attaching and effacing lesions on tissue culture cells. Proc. Natl. Acad. Sci. USA 87: 7839-7843.    DOI
56 Kenny B, DeVinney R, Stein M, Reinscheid DJ, Frey EA, Finlay BB. 1997. Enteropathogenic E. coli (EPEC) transfers its receptor for intimate adherence into mammalian cells. Cell 91: 511-520.    DOI
57 Melton-Celsa AR. 2014. Shiga Toxin (Stx) csification, structure, and function. Microbiol. Spectr. 2: EHEC-0024-2013. 
58 Pires SM, Majowicz S, Gill A, Devleesschauwer B. 2019. Global and regional source attribution of Shiga toxin-producing Escherichia coli infections using analysis of outbreak surveillance data. Epidemiol. Infect. 147: e236. 
59 Fukushima H, Hashizume T, Morita Y, Tanaka J, Azuma K, Mizumoto Y, et al. 1999. Clinical experiences in Sakai City Hospital during the massive outbreak of enterohemorrhagic Escherichia coli O157 infections in Sakai City, 1996. Pediatr. Int. 41: 213-217.    DOI
60 Bielaszewska M, Middendorf B, Kock R, Friedrich AW, Fruth A, Karch H, et al. 2008. Shiga toxin-negative attaching and effacing Escherichia coli: distinct clinical associations with bacterial phylogeny and virulence traits and inferred in-host pathogen evolution. Clin. Infect. Dis. 47: 208-217.    DOI
61 Erickson MC, Doyle MP. 2007. Food as a vehicle for transmission of Shiga toxin-producing Escherichia coli. J. Food Prot. 70: 2426-2449.    DOI
62 Persad AK, LeJeune JT. 2014. Animal reservoirs of Shiga toxin-producing Escherichia coli. Microbiol. Spectr. 2: EHEC-0027-2014. 
63 Espinosa L, Gray A, Duffy G, Fanning S, McMahon BJ. 2018. A scoping review on the prevalence of Shiga-toxigenic Escherichia coli in wild animal species. Zoonoses Public Health 65: 911-920.    DOI
64 Kim JS, Lee MS, Kim JH. 2020. Recent updates on outbreaks of Shiga toxin-producing Escherichia coli and its potential reservoirs. Front. Cell Infect. Microbiol. 10: 273. 
65 LeJeune JT, Besser TE, Merrill NL, Rice DH, Hancock DD. 2001. Livestock drinking water microbiology and the factors influencing the quality of drinking water offered to cattle. J. Dairy Sci. 84: 1856-1862.    DOI
66 Caprioli A, Morabito S, Brugere H, Oswald E. 2005. Enterohaemorrhagic Escherichia coli: emerging issues on virulence and modes of transmission. Vet. Res. 36: 289-311.    DOI
67 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.    DOI
68 Plunkett G, 3rd, Rose DJ, Durfee TJ, Blattner FR. 1999. Sequence of Shiga toxin 2 phage 933W from Escherichia coli O157:H7: Shiga toxin as a phage late-gene product. J. Bacteriol. 181: 1767-1778.    DOI
69 Krϋger A, Lucchesi PM. 2015. Shiga toxins and stx phages: highly diverse entities. Microbiology (Reading) 161: 451-462.    DOI
70 Coburn B, Sekirov I, Finlay BB. 2007. Type III secretion systems and disease. Clin. Microbiol. Rev. 20: 535-549.    DOI
71 Dean P, Kenny B. 2009. The effector repertoire of enteropathogenic E. coli: ganging up on the host cell. Curr. Opin. Microbiol. 12: 101-109.    DOI
72 Brunder W, Schmidt H, Karch H. 1996. KatP, a novel catalaseperoxidase encoded by the large plasmid of enterohaemorrhagic Escherichia coli O157:H7. Microbiology (Reading) 142 (Pt 11): 3305-3315.    DOI
73 Scheutz F, Teel LD, Beutin L, Pierard D, Buvens G, Karch H, et al. 2012. Multicenter evaluation of a sequence-based protocol for subtyping Shiga toxins and standardizing Stx nomenclature. J. Clin. Microbiol. 50: 2951-2963.    DOI
74 Bai X, Fu S, Zhang J, Fan R, Xu Y, Sun H, et al. 2018. Identification and pathogenomic analysis of an Escherichia coli strain producing a novel Shiga toxin 2 subtype. Sci. Rep. 8: 6756. 
75 Lacher DW, Gangiredla J, Patel I, Elkins CA, Feng PC. 2016. Use of the Escherichia coli identification microarray for characterizing the health risks of Shiga toxin-producing Escherichia coli Isolated from foods. J. Food Prot. 79: 1656-1662.    DOI
76 Galiero G, Conedera G, Alfano D, Caprioli A. 2005. Isolation of verocytotoxin-producing Escherichia coli O157 from water buffaloes (Bubalus bubalis) in southern Italy. Vet. Rec. 156: 382-383.    DOI
77 Gyles CL. 2007. Shiga toxin-producing Escherichia coli: an overview. J. Anim. Sci. 85: E45-62.    DOI
78 Ferens WA, Hovde CJ. 2011. Escherichia coli O157:H7: animal reservoir and sources of human infection. Foodborne Pathog. Dis. 8: 465-487.    DOI
79 Pruimboom-Brees IM, Morgan TW, Ackermann MR, Nystrom ED, Samuel JE, Cornick NA, et al. 2000. Cattle lack vascular receptors for Escherichia coli O157:H7 Shiga toxins. Proc. Natl. Acad. Sci. USA 97: 10325-10329.    DOI
80 French E, Rodriguez-Palacios A, LeJeune JT. 2010. Enteric bacterial pathogens with zoonotic potential isolated from farm-raised deer. Foodborne Pathog. Dis. 7: 1031-1037.    DOI
81 Chandran A, Mazumder A. 2013. Prevalence of diarrhea-associated virulence genes and genetic diversity in Escherichia coli isolates from fecal material of various animal hosts. Appl. Environ. Microbiol. 79: 7371-7380.    DOI
82 Mohammed Hamzah A, Mohammed Hussein A, Mahmoud Khalef J. 2013. Isolation of Escherichia coli 0157:H7 strain from fecal samples of zoo animal. ScientificWorldJ. 2013: 843968. 
83 Nyholm O, Heinikainen S, Pelkonen S, Hallanvuo S, Haukka K, Siitonen A. 2015. Hybrids of shigatoxigenic and enterotoxigenic Escherichia coli (STEC/ETEC) among human and animal isolates in Finland. Zoonoses Public Health 62: 518-524.    DOI
84 Beutin L, Geier D, Steinrϋck H, Zimmermann S, Scheutz F. 1993. Prevalence and some properties of verotoxin (Shiga-like toxin)-producing Escherichia coli in seven different species of healthy domestic animals. J. Clin. Microbiol. 31: 2483-2488.    DOI
85 Ling H, Boodhoo A, Hazes B, Cummings MD, Armstrong GD, Brunton JL, et al. 1998. Structure of the shiga-like toxin I Bpentamer complexed with an analogue of its receptor Gb3. Biochemistry 37: 1777-1788.    DOI
86 Fao/Who Stec Expert G. 2019. Hazard identification and characterization: Criteria for categorizing Shiga toxin-producing Escherichia coli on a risk basis(dagger). J. Food Prot. 82: 7-21.    DOI
87 Ng TB, Wong JH, Wang H. 2010. Recent progress in research on ribosome inactivating proteins. Curr. Protein Pept. Sci. 11: 37-53.    DOI
88 Endo Y, Tsurugi K, Yutsudo T, Takeda Y, Ogasawara T, Igarashi K. 1988. Site of action of a Vero toxin (VT2) from Escherichia coli O157:H7 and of Shiga toxin on eukaryotic ribosomes. RNA N-glycosidase activity of the toxins. Eur. J. Biochem. 171: 45-50.    DOI
89 Stahl AL, Arvidsson I, Johansson KE, Chromek M, Rebetz J, Loos S, et al. 2015. A novel mechanism of bacterial toxin transfer within host blood cell-derived microvesicles. PLoS Pathog. 11: e1004619. 
90 Watanabe-Takahashi M, Yamasaki S, Murata M, Kano F, Motoyama J, Yamate J, et al. 2018. Exosome-associated Shiga toxin 2 is released from cells and causes severe toxicity in mice. Sci. Rep. 8: 10776. 
91 Brigotti M, Carnicelli D, Arfilli V, Tamassia N, Borsetti F, Fabbri E, et al. 2013. Identification of TLR4 as the receptor that recognizes Shiga toxins in human neutrophils. J. Immunol. 191: 4748-4758.    DOI
92 Brunder W, Schmidt H, Karch H. 1997. EspP, a novel extracellular serine protease of enterohaemorrhagic Escherichia coli O157:H7 cleaves human coagulation factor V. Mol. Microbiol. 24: 767-778.    DOI
93 Schϋller S, Heuschkel R, Torrente F, Kaper JB, Phillips AD. 2007. Shiga toxin binding in normal and inflamed human intestinal mucosa. Microbes Infect. 9: 35-39.    DOI
94 Bosse M, Sibold J, Scheidt HA, Patalag LJ, Kettelhoit K, Ries A, et al. 2019. Shiga toxin binding alters lipid packing and the domain structure of Gb3-containing membranes: a solid-state NMR study. Phys. Chem. Chem. Phys. 21: 15630-15638.    DOI
95 Zoja C, Morigi M, Remuzzi G. 2001. The role of the endothelium in hemolytic uremic syndrome. J. Nephrol. 14 Suppl 4: S58-62. 
96 Goldstein J, Loidl CF, Creydt VP, Boccoli J, Ibarra C. 2007. Intracerebroventricular administration of Shiga toxin type 2 induces striatal neuronal death and glial alterations: an ultrastructural study. Brain Res. 1161: 106-115.    DOI
97 Obrig TG. 2010. Escherichia coli Shiga toxin mechanisms of action in renal disease. Toxins (Basel) 2: 2769-2794.    DOI
98 Okuda T, Tokuda N, Numata S, Ito M, Ohta M, Kawamura K, et al. 2006. Targeted disruption of Gb3/CD77 synthase gene resulted in the complete deletion of globo-series glycosphingolipids and loss of sensitivity to verotoxins. J. Biol. Chem. 281: 10230-10235.    DOI
99 van de Kar NC, Monnens LA, Karmali MA, van Hinsbergh VW. 1992. Tumor necrosis factor and interleukin-1 induce expression of the verocytotoxin receptor globotriaosylceramide on human endothelial cells: implications for the pathogenesis of the hemolytic uremic syndrome. Blood 80: 2755-2764.    DOI
100 Zumbrun SD, Melton-Celsa AR, Smith MA, Gilbreath JJ, Merrell DS, O'Brien AD. 2013. Dietary choice affects Shiga toxin-producing Escherichia coli (STEC) O157:H7 colonization and disease. Proc. Natl. Acad. Sci. USA 110: E2126-2133. 
101 Sandvig K, Olsnes S, Brown JE, Petersen OW, van Deurs B. 1989. Endocytosis from coated pits of Shiga toxin: a glycolipid-binding protein from Shigella dysenteriae 1. J. Cell Biol. 108: 1331-1343.    DOI
102 Saint-Pol A, Yelamos B, Amessou M, Mills IG, Dugast M, Tenza D, et al. 2004. Clathrin adaptor epsinR is required for retrograde sorting on early endosomal membranes. Dev. Cell 6: 525-538.    DOI
103 Lauvrak SU, Walchli S, Iversen TG, Slagsvold HH, Torgersen ML, Spilsberg B, et al. 2006. Shiga toxin regulates its entry in a Syk-dependent manner. Mol. Biol. Cell 17: 1096-1109.    DOI
104 Torgersen ML, Lauvrak SU, Sandvig K. 2005. The A-subunit of surface-bound Shiga toxin stimulates clathrin-dependent uptake of the toxin. FEBS J. 272: 4103-4113.    DOI
105 Lauvrak SU, Torgersen ML, Sandvig K. 2004. Efficient endosome-to-Golgi transport of Shiga toxin is dependent on dynamin and clathrin. J. Cell Sci. 117: 2321-2331.    DOI
106 Renard HF, Garcia-Castillo MD, Chambon V, Lamaze C, Johannes L. 2015. Shiga toxin stimulates clathrin-independent endocytosis of the VAMP2, VAMP3 and VAMP8 SNARE proteins. J. Cell Sci. 128: 2891-2902.    DOI
107 Malyukova I, Murray KF, Zhu C, Boedeker E, Kane A, Patterson K, et al. 2009. Macropinocytosis in Shiga toxin 1 uptake by human intestinal epithelial cells and transcellular transcytosis. Am. J. Physiol. Gastrointest. Liver Physiol. 296: G78-92.    DOI
108 Lombardi D, Soldati T, Riederer MA, Goda Y, Zerial M, Pfeffer SR. 1993. Rab9 functions in transport between late endosomes and the trans Golgi network. EMBO J. 12: 677-682.    DOI
109 Itin C, Rancano C, Nakajima Y, Pfeffer SR. 1997. A novel assay reveals a role for soluble N-ethylmaleimide-sensitive fusion attachment protein in mannose 6-phosphate receptor transport from endosomes to the trans Golgi network. J. Biol. Chem. 272: 27737-27744.    DOI
110 Itin C, Ulitzur N, Mϋhlbauer B, Pfeffer SR. 1999. Mapmodulin, cytoplasmic dynein, and microtubules enhance the transport of mannose 6-phosphate receptors from endosomes to the trans-golgi network. Mol. Biol. Cell 10: 2191-2197.    DOI
111 Miwako I, Yamamoto A, Kitamura T, Nagayama K, Ohashi M. 2001. Cholesterol requirement for cation-independent mannose 6-phosphate receptor exit from multivesicular late endosomes to the Golgi. J. Cell Sci. 114: 1765-1776.    DOI
112 Iversen TG, Skretting G, Llorente A, Nicoziani P, van Deurs B, Sandvig K. 2001. Endosome to Golgi transport of ricin is independent of clathrin and of the Rab9- and Rab11-GTPases. Mol. Biol. Cell 12: 2099-2107.    DOI
113 Sandvig K, Grimmer S, Lauvrak SU, Torgersen ML, Skretting G, van Deurs B, et al. 2002. Pathways followed by ricin and Shiga toxin into cells. Histochem. Cell Biol. 117: 131-141.    DOI
114 Lauvrak SU, Llorente A, Iversen TG, Sandvig K. 2002. Selective regulation of the Rab9-independent transport of ricin to the Golgi apparatus by calcium. J. Cell Sci. 115: 3449-3456.    DOI
115 Mallard F, Antony C, Tenza D, Salamero J, Goud B, Johannes L. 1998. Direct pathway from early/recycling endosomes to the Golgi apparatus revealed through the study of shiga toxin B-fragment transport. J. Cell Biol. 143: 973-990.    DOI
116 Wilcke M, Johannes L, Galli T, Mayau V, Goud B, Salamero J. 2000. Rab11 regulates the compartmentalization of early endosomes required for efficient transport from early endosomes to the trans-golgi network. J. Cell Biol. 151: 1207-1220.    DOI
117 Utskarpen A, Slagsvold HH, Dyve AB, Skanland SS, Sandvig K. 2007. SNX1 and SNX2 mediate retrograde transport of Shiga toxin. Biochem. Biophys. Res. Commun. 358: 566-570.    DOI
118 Johannes L, Popoff V. 2008. Tracing the retrograde route in protein trafficking. Cell 135: 1175-1187.    DOI
119 White J, Johannes L, Mallard F, Girod A, Grill S, Reinsch S, et al. 1999. Rab6 coordinates a novel Golgi to ER retrograde transport pathway in live cells. J.Cell Biol. 147: 743-760.    DOI
120 Jackson ME, Simpson JC, Girod A, Pepperkok R, Roberts LM, Lord JM. 1999. The KDEL retrieval system is exploited by Pseudomonas exotoxin A, but not by Shiga-like toxin-1, during retrograde transport from the Golgi complex to the endoplasmic reticulum. J. Cell Sci. 112 (Pt 4): 467-475.    DOI
121 Girod A, Storrie B, Simpson JC, Johannes L, Goud B, Roberts LM, et al. 1999. Evidence for a COP-I-independent transport route from the Golgi complex to the endoplasmic reticulum. Nat. Cell Biol. 1: 423-430.    DOI
122 Chan YS, Ng TB. 2016. Shiga toxins: from structure and mechanism to applications. Appl. Microbiol. Biotechnol. 100: 1597-1610.    DOI
123 Amessou M, Carrez D, Patin D, Sarr M, Grierson DS, Croisy A, et al. 2008. Retrograde delivery of photosensitizer (TPPp-O-beta-GluOH)3 selectively potentiates its photodynamic activity. Bioconjug. Chem. 19: 532-538.    DOI
124 Garred O, Dubinina E, Polesskaya A, Olsnes S, Kozlov J, Sandvig K. 1997. Role of the disulfide bond in Shiga toxin A-chain for toxin entry into cells. J. Biol. Chem. 272: 11414-11419.    DOI
125 Nowakowska-Golacka J, Sominka H, Sowa-Rogozinska N, Slominska-Wojewodzka M. 2019. Toxins utilize the endoplasmic reticulum-associated protein degradation pathway in their intoxication process. Int. J. Mol. Sci. 20: 1307. 
126 Yu M, Haslam DB. 2005. Shiga toxin is transported from the endoplasmic reticulum following interaction with the luminal chaperone HEDJ/ERdj3. Infect. Immun. 73: 2524-2532.    DOI
127 Elmore S. 2007. Apoptosis: a review of programmed cell death. Toxicol. Pathol. 35: 495-516.    DOI
128 Braicu C, Buse M, Busuioc C, Drula R, Gulei D, Raduly L, et al. 2019. A comprehensive review on MAPK: A promising therapeutic target in cancer. Cancers (Basel) 11: 1618. 
129 Ching JC, Jones NL, Ceponis PJ, Karmali MA, Sherman PM. 2002. Escherichia coli shiga-like toxins induce apoptosis and cleavage of poly(ADP-ribose) polymerase via in vitro activation of caspases. Infect. Immun. 70: 4669-4677.    DOI
130 Tang B, Li Q, Zhao XH, Wang HG, Li N, Fang Y, et al. 2015. Shiga toxins induce autophagic cell death in intestinal epithelial cells via the endoplasmic reticulum stress pathway. Autophagy 11: 344-354.    DOI
131 Kyriakis JM, Avruch J. 2001. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol. Rev. 81: 807-869.    DOI
132 Wada T, Penninger JM. 2004. Mitogen-activated protein kinases in apoptosis regulation. Oncogene 23: 2838-2849.    DOI
133 Smith WE, Kane AV, Campbell ST, Acheson DW, Cochran BH, Thorpe CM. 2003. Shiga toxin 1 triggers a ribotoxic stress response leading to p38 and JNK activation and induction of apoptosis in intestinal epithelial cells. Infect. Immun. 71: 1497-1504.    DOI
134 Cherla RP, Lee SY, Mees PL, Tesh VL. 2006. Shiga toxin 1-induced cytokine production is mediated by MAP kinase pathways and translation initiation factor eIF4E in the macrophage-like THP-1 cell line. J. Leukoc. Biol. 79: 397-407.    DOI
135 Jandhyala DM, Ahluwalia A, Obrig T, Thorpe CM. 2008. ZAK: a MAP3Kinase that transduces Shiga toxin and ricin-induced proinflammatory cytokine expression. Cell Microbiol. 10: 1468-1477.    DOI
136 Ketelut-Carneiro N, Fitzgerald KA. 2022. Apoptosis, pyroptosis, and necroptosis-oh my! the many ways a cell can die. J. Mol. Biol. 434: 167378. 
137 Kim I, Xu W, Reed JC. 2008. Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat. Rev. Drug Discov. 7: 1013-1030.    DOI
138 Coll RC, Schroder K, Pelegrin P. 2022. NLRP3 and pyroptosis blockers for treating inflammatory diseases. Trends Pharmacol. Sci. 43: 653-668.    DOI
139 Platnich JM, Chung H, Lau A, Sandall CF, Bondzi-Simpson A, Chen HM, et al. 2018. Shiga toxin/lipopolysaccharide activates caspase-4 and gasdermin D to trigger mitochondrial reactive oxygen species upstream of the NLRP3 inflammasome. Cell Rep. 25: 1525-1536 e1527. 
140 Pinatih KJP, Suardana IW, Widiasih DA, Suharsono H. 2021. Shiga-like toxin produced by local isolates of Escherichia coli O157:H7 induces apoptosis of the T47 breast cancer cell line. Breast Cancer (Auckl) 15: 11782234211010120. 
141 Calfon M, Zeng H, Urano F, Till JH, Hubbard SR, Harding HP, et al. 2002. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 415: 92-96.    DOI
142 Lee AH, Iwakoshi NN, Glimcher LH. 2003. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol. Cell Biol. 23: 7448-7459.    DOI
143 Hetz C. 2012. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat. Rev. Mol. Cell Biol. 13: 89-102.    DOI
144 Lee SY, Lee MS, Cherla RP, Tesh VL. 2008. Shiga toxin 1 induces apoptosis through the endoplasmic reticulum stress response in human monocytic cells. Cell. Microbiol. 10: 770-780.    DOI
145 Lee KS, Lee J, Lee P, Jeon BC, Song MY, Kwak S, et al. 2022. Inhibition of O-GlcNAcylation protects from Shiga toxin-mediated cell injury and lethality in host. EMBO Mol. Med. 14: e14678. 
146 Sattler R, Tymianski M. 2000. Molecular mechanisms of calcium-dependent excitotoxicity. J. Mol. Med. (Berl). 78: 3-13.    DOI
147 Parello CS, Mayer CL, Lee BC, Motomochi A, Kurosawa S, Stearns-Kurosawa DJ. 2015. Shiga toxin 2-induced endoplasmic reticulum stress is minimized by activated protein C but does not correlate with lethal kidney injury. Toxins (Basel) 7: 170-186.    DOI
148 Coe H, Michalak M. 2009. Calcium binding chaperones of the endoplasmic reticulum. Gen. Physiol. Biophys. 28 Spec No Focus: F96-F103. 
149 Kuznetsov G, Brostrom MA, Brostrom CO. 1992. Demonstration of a calcium requirement for secretory protein processing and export. Differential effects of calcium and dithiothreitol. J. Biol. Chem. 267: 3932-3939.    DOI
150 Johansson KE, Stahl AL, Arvidsson I, Loos S, Tontanahal A, Rebetz J, et al. 2019. Shiga toxin signals via ATP and its effect is blocked by purinergic receptor antagonism. Sci. Rep. 9: 14362. 
151 Kostova EB, Beuger BM, Klei TR, Halonen P, Lieftink C, Beijersbergen R, et al. 2015. Identification of signalling cascades involved in red blood cell shrinkage and vesiculation. Biosci. Rep. 35: e00187. 
152 Liu R, Klich I, Ratajczak J, Ratajczak MZ, Zuba-Surma EK. 2009. Erythrocyte-derived microvesicles may transfer phosphatidylserine to the surface of nucleated cells and falsely 'mark' them as apoptotic. Eur. J. Haematol. 83: 220-229.    DOI
153 Majka M, Kijowski J, Lesko E, Gozdizk J, Zupanska B, Ratajczak MZ. 2007. Evidence that platelet-derived microvesicles may transfer platelet-specific immunoreactive antigens to the surface of endothelial cells and CD34+ hematopoietic stem/progenitor cells--implication for the pathogenesis of immune thrombocytopenias. Folia Histochem. Cytobiol. 45: 27-32.