Mechanism underlying inhibition of intestinal apical Cl-/OH- exchange following infection with enteropathogenic E. coli

Ravinder K. Gill, Alip Borthakur, Kim Hodges, Jerrold R. Turner, Daniel R. Clayburgh, Seema Saksena, Ayesha Zaheer, Krishnamurthy Ramaswamy, Gail Hecht, Pradeep K. Dudeja

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105 Scopus citations

Abstract

Enteropathogenic E. coli (EPEC) is a major cause of infantile diarrhea, but the pathophysiology underlying associated diarrhea is poorly understood. We examined the role of the luminal membrane Cl-/OH- exchange process in EPEC pathogenesis using in vitro and in vivo models. Cl -/OH- exchange activity was measured as OH- gradient-driven 36Cl- uptake. EPEC infection (60 minutes-3 hours) inhibited apical Cl-/OH- exchange activity in human intestinal Caco-2 and T84 cells. This effect was dependent upon the bacterial type III secretory system (TTSS) and involved secreted effector molecules EspG and EspG2, known to disrupt the host microtubular network. The microtubule-disrupting agent colchicine (100 μM, 3 hours) also inhibited 36Cl- uptake. The plasma membrane expression of major apical anion exchanger DRA (SLC26A3) was considerably reduced in EPEC-infected cells, corresponding with decreased Cl-/OH- exchange activity. Confocal microscopic studies showed that EPEC infection caused a marked redistribution of DRA from the apical membrane to intracellular compartments. Interestingly, infection of cells with an EPEC mutant deficient in espG significantly attenuated the decrease in surface expression of DRA protein as compared with treatment with wild-type EPEC. EPEC infection in vivo (1 day) also caused marked redistribution of surface DRA protein in the mouse colon. Our data demonstrate that EspG and EspG2 play an important role in contributing to EPEC infection-associated inhibition of luminal membrane chloride transport via modulation of surface DRA expression.

Original languageEnglish (US)
Pages (from-to)428-437
Number of pages10
JournalJournal of Clinical Investigation
Volume117
Issue number2
DOIs
StatePublished - Feb 1 2007

ASJC Scopus subject areas

  • Medicine(all)

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    Gill, R. K., Borthakur, A., Hodges, K., Turner, J. R., Clayburgh, D. R., Saksena, S., Zaheer, A., Ramaswamy, K., Hecht, G., & Dudeja, P. K. (2007). Mechanism underlying inhibition of intestinal apical Cl-/OH- exchange following infection with enteropathogenic E. coli. Journal of Clinical Investigation, 117(2), 428-437. https://doi.org/10.1172/JCI29625