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Potent diarrheagenic mechanism mediated by the cooperative action of three enteropathogenic Escherichia coli-injected effector proteins

Lookup NU author(s): Dr Paul Dean, Professor Brendan Kenny

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Abstract

Enteropathogenic Escherichia coli (EPEC) induces a severe watery diarrhea responsible for several hundred thousand infant deaths each year by a process correlated with the loss (effacement) of absorptive microvilli. Effacement is linked to the locus of enterocyte effacement pathogenicity island that encodes an "injection system," "effector" proteins, and the Intimin outer membrane protein. Here, we reveal that effacement (i) is a two-step process, (ii) requires the cooperative action of three injected effectors (Map, EspF, and Tir) as well as Intimin, and (iii) leads to the retention, not release (into the extracellular milieu), of the detached microvillar material. We also discover that EPEC rapidly inactivates the sodium-D-glucose cotransporter (SGLT-1) by multiple mechanisms. Indeed, the finding that one mechanism occurs more rapidly than microvilli effacement provides a plausible explanation for the rapid onset of severe watery diarrhea, given the crucial role of SGLT-1 in the daily uptake of ≈6 liters of fluids from the normal intestine. The importance of SGLT-1 in the disease process is supported by severe EPEC diarrheal cases being refractory to oral rehydration therapy (dependent on SGLT-1 function). Moreover, the identification of effector activities that alter microvilli structure and SGLT-1 function provides new tools for studying the underlying regulatory processes. © 2006 by The National Academy of Sciences of the USA.


Publication metadata

Author(s): Dean P, Maresca M, Schüller S, Phillips A, Kenny B

Publication type: Article

Publication status: Published

Journal: Proceedings of the National Academy of Sciences of the United States of America

Year: 2006

Volume: 103

Issue: 6

Pages: 1876-1881

ISSN (print): 0027-8424

ISSN (electronic): 1091-6490

Publisher: National Academy of Sciences

URL: http://dx.doi.org/10.1073/pnas.0509451103

DOI: 10.1073/pnas.0509451103

PubMed id: 16446436


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