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Infection and Immunity, September 2009, p. 3639-3650, Vol. 77, No. 9
0019-9567/09/$08.00+0     doi:10.1128/IAI.00225-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Decreased Expression of Colonic Slc26a3 and Carbonic Anhydrase IV as a Cause of Fatal Infectious Diarrhea in Mice ^,

Diana Borenshtein,^1* Katherine A. Schlieper,² Barry H. Rickman,^2, Jeannie M. Chapman,^3, Clifford W. Schweinfest,³ James G. Fox,² and David B. Schauer^1,2

Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139,¹ Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139,² Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina 29403³

Received 26 February 2009/ Returned for modification 7 April 2009/ Accepted 12 June 2009

Citrobacter rodentium causes epithelial hyperplasia and colitis and is used as a model for enteropathogenic and enterohemorrhagic Escherichia coli infections. Little or no mortality develops in most inbred strains of mice, but C3H and FVB/N mice exhibit fatal outcomes of infection. Here we test the hypothesis that decreased intestinal transport activity during C. rodentium infection results in fatality in C3H/HeOu and FVB/N mice. Susceptible strains were compared to resistant C57BL/6 mice and to inbred strains SWR and SJL of Swiss origin, which have not been previously characterized for outcomes of C. rodentium infection. Mortality in susceptible strains C3H/HeOu and FVB/N was associated with significant fluid loss in feces, a remarkable downregulation of Slc26a3 and carbonic anhydrase IV (CAIV) message and protein expression, retention of chloride in stool, and hypochloremia, suggesting defects in intestinal chloride absorption. SWR, SJL, and C57BL/6 mice were resistant and survived the infection. Fluid therapy fully prevented mortality in C3H/HeOu and FVB/N mice without affecting clinical disease. Common pathogenic mechanisms, such as decreased levels of expression of Slc26a3 and CAIV, affect intestinal ion transport in C. rodentium-infected FVB and C3H mice, resulting in profound electrolyte loss, dehydration, and mortality. Intestinal chloride absorption pathways are likely a potential target for the treatment of infectious diarrhea.

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* Corresponding author. Present address: Miltenyi Biotec, Inc., 12740 Earhart Ave., Auburn, CA 95602-9027. Phone: (978) 241-0489. Fax: (866) 886-1212. E-mail: Diana.Borenshtein{at}miltenyibiotec.com

Published ahead of print on 22 June 2009.

We dedicate this article to the memory of our valued teacher, colleague, and friend, David B. Schauer, who passed away from cardiac arrest during revision of the manuscript, leaving us all with a deep sense of sadness, loss, gratitude, and love.

Editor: B. A. McCormick

Present address: San Diego County Animal Disease Diagnostic Laboratory, Department of Agriculture, Weights and Measures, San Diego, CA 92123.

Present address: Division of Natural Sciences and Engineering, University of South Carolina Upstate, Spartanburg, SC 29303.

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Infection and Immunity, September 2009, p. 3639-3650, Vol. 77, No. 9
0019-9567/09/$08.00+0     doi:10.1128/IAI.00225-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.