Fatal Hemorrhage Induced by Subtilase Cytotoxin from Shiga-toxigenic Escherichia Coli

Overview

Journal Microb Pathog

Specialties Infectious Diseases
Microbiology

Date 2011 Jan 15

PMID 21232591

Citations 16

Authors

Takeshi Furukawa

Kinnosuke Yahiro

Atsushi B Tsuji

Yasuhiro Terasaki

Naoko Morinaga

Masaru Miyazaki

Yuh Fukuda

Tsuneo Saga

Joel Moss

Masatoshi Noda

Affiliations

Soon will be listed here.

Abstract

Subtilase cytotoxin (SubAB) is an AB(5) type toxin produced by a subset of Shiga-toxigenic Escherichia coli. The A subunit is a subtilase-like serine protease and cleaves an endoplasmic reticulum chaperone BiP. The B subunit binds to a receptor on the cell surface. Although SubAB is lethal for mice, the cause of death is not clear. In this study, we demonstrate in mice that SubAB induced small bowel hemorrhage and a coagulopathy characterized by thrombocytopenia, prolonged prothrombin time and activated partial thromboplastin time. SubAB also induced inflammatory changes in the small intestine as detected by ¹⁸F-fluoro-2-deoxy-d-glucose positron emission tomography imaging and histochemical analysis. Using RT-PCR and ELISA, SubAB was shown to increase interleukin-6 in a time-dependent manner. Thus, our results indicate that death in SubAB-treated mice may be associated with severe inflammatory response and hemorrhage of the small intestine, accompanied by coagulopathy and IL6 production.

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References

Wolfson J, May K, Thorpe C, Jandhyala D, Paton J, Paton A . Subtilase cytotoxin activates PERK, IRE1 and ATF6 endoplasmic reticulum stress-signalling pathways. Cell Microbiol. 2008; 10(9):1775-86. PMC: 2575110. DOI: 10.1111/j.1462-5822.2008.01164.x. View

Morinaga N, Yahiro K, Matsuura G, Moss J, Noda M . Subtilase cytotoxin, produced by Shiga-toxigenic Escherichia coli, transiently inhibits protein synthesis of Vero cells via degradation of BiP and induces cell cycle arrest at G1 by downregulation of cyclin D1. Cell Microbiol. 2007; 10(4):921-9. PMC: 3021990. DOI: 10.1111/j.1462-5822.2007.01094.x. View

Paik J, Lee K, Choe Y, Choi Y, Kim B . Augmented 18F-FDG uptake in activated monocytes occurs during the priming process and involves tyrosine kinases and protein kinase C. J Nucl Med. 2004; 45(1):124-8. View

Huang T, Wan Y, Zhu Y, Fang X, Hiramatsu N, Hayakawa K . Downregulation of gap junction expression and function by endoplasmic reticulum stress. J Cell Biochem. 2009; 107(5):973-83. DOI: 10.1002/jcb.22202. View

Paton A, Beddoe T, Thorpe C, Whisstock J, Wilce M, Rossjohn J . AB5 subtilase cytotoxin inactivates the endoplasmic reticulum chaperone BiP. Nature. 2006; 443(7111):548-52. DOI: 10.1038/nature05124. View

Love C, Tomas M, Tronco G, Palestro C . FDG PET of infection and inflammation. Radiographics. 2005; 25(5):1357-68. DOI: 10.1148/rg.255045122. View

Venge P, Moberg L, Bjornsson E, Bergstrom M, Langstrom B, Hakansson L . Mechanisms of basal and cytokine-induced uptake of glucose in normal human eosinophils: relation to apoptosis. Respir Med. 2003; 97(10):1109-19. DOI: 10.1016/s0954-6111(03)00143-4. View

Fueger B, Czernin J, Hildebrandt I, Tran C, Halpern B, Stout D . Impact of animal handling on the results of 18F-FDG PET studies in mice. J Nucl Med. 2006; 47(6):999-1006. View

Dran G, Fernandez G, Rubel C, Bermejo E, Gomez S, Meiss R . Protective role of nitric oxide in mice with Shiga toxin-induced hemolytic uremic syndrome. Kidney Int. 2002; 62(4):1338-48. DOI: 10.1111/j.1523-1755.2002.kid554.x. View

10.

Horii Y, Muraguchi A, Iwano M, Matsuda T, Hirayama T, Yamada H . Involvement of IL-6 in mesangial proliferative glomerulonephritis. J Immunol. 1989; 143(12):3949-55. View

11.

Watson S, Gibbins J . Collagen receptor signalling in platelets: extending the role of the ITAM. Immunol Today. 1998; 19(6):260-4. DOI: 10.1016/s0167-5699(98)01267-5. View

12.

Cook G, Fogelman I, Maisey M . Normal physiological and benign pathological variants of 18-fluoro-2-deoxyglucose positron-emission tomography scanning: potential for error in interpretation. Semin Nucl Med. 1996; 26(4):308-14. DOI: 10.1016/s0001-2998(96)80006-7. View

13.

Yamazaki H, Hiramatsu N, Hayakawa K, Tagawa Y, Okamura M, Ogata R . Activation of the Akt-NF-kappaB pathway by subtilase cytotoxin through the ATF6 branch of the unfolded protein response. J Immunol. 2009; 183(2):1480-7. PMC: 2762936. DOI: 10.4049/jimmunol.0900017. View

14.

Lu Y, Cai X, Gu L, Wang Q, Huang W, Bao D . Experimental study of controlled fluid resuscitation in the treatment of severe and uncontrolled hemorrhagic shock. J Trauma. 2007; 63(4):798-804. DOI: 10.1097/TA.0b013e31815202c9. View

15.

Paton J, Paton A . Pathogenesis and diagnosis of Shiga toxin-producing Escherichia coli infections. Clin Microbiol Rev. 1998; 11(3):450-79. PMC: 88891. DOI: 10.1128/CMR.11.3.450. View

16.

Yahiro K, Morinaga N, Satoh M, Matsuura G, Tomonaga T, Nomura F . Identification and characterization of receptors for vacuolating activity of subtilase cytotoxin. Mol Microbiol. 2006; 62(2):480-90. DOI: 10.1111/j.1365-2958.2006.05379.x. View

17.

van der Laan D, Haugan T, Barnes P . Effect of a compressive uniaxial strain on the critical current density of grain boundaries in superconducting YBa2Cu3O7-delta films. Phys Rev Lett. 2009; 103(2):027005. DOI: 10.1103/PhysRevLett.103.027005. View

18.

Kondo Y, Tokuda N, Fan X, Yamashita T, Honke K, Takematsu H . Glycosphingolipids are not pivotal receptors for Subtilase cytotoxin in vivo: sensitivity analysis with glycosylation-defective mutant mice. Biochem Biophys Res Commun. 2008; 378(2):179-81. DOI: 10.1016/j.bbrc.2008.10.163. View

19.

Morinaga N, Yahiro K, Matsuura G, Watanabe M, Nomura F, Moss J . Two distinct cytotoxic activities of subtilase cytotoxin produced by shiga-toxigenic Escherichia coli. Infect Immun. 2006; 75(1):488-96. PMC: 1828409. DOI: 10.1128/IAI.01336-06. View

20.

Ulich T, Del Castillo J, Guo K . In vivo hematologic effects of recombinant interleukin-6 on hematopoiesis and circulating numbers of RBCs and WBCs. Blood. 1989; 73(1):108-10. View