Diarrhea as a cause of mortality in a mouse model of infectious colitis.
BACKGROUND
Comparative characterization of genome-wide transcriptional changes during infection can help elucidate the mechanisms underlying host susceptibility. In this study, transcriptional profiling of the mouse colon was carried out in two cognate lines of mice that differ in their response to Citrobacter rodentium infection; susceptible inbred FVB/N and resistant outbred Swiss Webster mice. Gene expression in the distal colon was determined prior to infection, and at four and nine days post-inoculation using a whole mouse genome Affymetrix array.


RESULTS
Computational analysis identified 462 probe sets more than 2-fold differentially expressed between uninoculated resistant and susceptible mice. In response to C. rodentium infection, 5,123 probe sets were differentially expressed in one or both lines of mice. Microarray data were validated by quantitative real-time RT-PCR for 35 selected genes and were found to have a 94% concordance rate. Transcripts represented by 1,547 probe sets were differentially expressed between susceptible and resistant mice regardless of infection status, a host effect. Genes associated with transport were over-represented to a greater extent than even immune response-related genes. Electrolyte analysis revealed reduction in serum levels of chloride and sodium in susceptible animals.


CONCLUSIONS
The results support the hypothesis that mortality in C. rodentium-infected susceptible mice is associated with impaired intestinal ion transport and development of fatal fluid loss and dehydration. These studies contribute to our understanding of the pathogenesis of C. rodentium and suggest novel strategies for the prevention and treatment of diarrhea associated with intestinal bacterial infections.
Borenshtein
Diana
D
Department of Biological Engineering, Massachusetts Institute of Technology, Massachusetts Avenue, Cambridge, MA 02139, USA.
Fry
Rebecca C
RC
Groff
Elizabeth B
EB
Nambiar
Prashant R
PR
Carey
Vincent J
VJ
Fox
James G
JG
Schauer
David B
DB
D000818:Animals; D017920:Antiporters / Q000235:genetics; D030741:Carbonic Anhydrase IV / Q000235:genetics; D044082:Citrobacter rodentium; D003092:Colitis / Q000235:genetics* / Q000382:microbiology / Q000401:mortality; D003967:Diarrhea / Q000235:genetics* / Q000382:microbiology / Q000401:mortality; D004195:Disease Models, Animal; D004403:Dysentery / Q000235:genetics* / Q000382:microbiology / Q000401:mortality; D004573:Electrolytes / Q000097:blood; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D023281:Genomics; D007422:Intestines / Q000503:physiopathology; D017136:Ion Transport / Q000235:genetics; D051379:Mice; D008815:Mice, Inbred Strains; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D000076988:Sulfate Transporters
D017920:Antiporters; D004573:Electrolytes; C489860:Slc26a3 protein, mouse; D000076988:Sulfate Transporters; D030741:Carbonic Anhydrase IV