Decreased expression of colonic Slc26a3 and carbonic anhydrase iv as a cause of fatal infectious diarrhea in mice.
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.
Borenshtein
Diana
D
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. Diana.Borenshtein@miltenyibiotec.com
Schlieper
Katherine A
KA
Rickman
Barry H
BH
Chapman
Jeannie M
JM
Schweinfest
Clifford W
CW
Fox
James G
JG
Schauer
David B
DB
D000818:Animals; D017920:Antiporters / Q000235:genetics / Q000502:physiology*; D018988:Bacterial Translocation; D030741:Carbonic Anhydrase IV / Q000235:genetics / Q000502:physiology*; D002712:Chlorides / Q000378:metabolism; D044082:Citrobacter rodentium / Q000472:pathogenicity*; D003106:Colon / Q000378:metabolism*; D003967:Diarrhea / Q000209:etiology*; D004198:Disease Susceptibility; D004756:Enterobacteriaceae Infections / Q000150:complications* / Q000401:mortality / Q000473:pathology; D005260:Female; D005440:Fluid Therapy; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D013045:Species Specificity; D000076988:Sulfate Transporters
D017920:Antiporters; D002712:Chlorides; C489860:Slc26a3 protein, mouse; D000076988:Sulfate Transporters; D030741:Carbonic Anhydrase IV