E-GEOD-43372 - The Effect of the Leptin Receptor Q223R Polymorphism on the Host Transcriptome Following Infection with E. histolytica

Status
Released on 5 June 2013, last updated on 17 June 2013
Organism
Mus musculus
Samples (54)
Array (1)
Protocols (7)
Description
Resistance to amebiasis is associated with a polymorphism in the leptin receptor. Previous studies demonstrated that humans with the ancestral Q223 leptin receptor allele were nearly four times less likely to be infected with Entamoeba histolytica than those carrying the mutant R223 allele. We hypothesized that the Q223 allele protected against E. histolytica via STAT3-mediated transcription of genes required for mucosal immunity. To test this, mice containing the humanized LEPR Q or R allele at codon 223 were intracecally infected with E. histolytica. Susceptibility to amebiasis was assessed, and cecal tissues analyzed for changes in gene expression. By 72 h post-challenge all Q223 mice had cleared E. histolytica, whereas 39% of 223R mice were infected. 37 genes were differentially expressed in response to infection at 72 h, including pro-inflammatory genes (CXCL2, calprotectin (S100A8/9), Pla2g7, Itbg2, and MMP9) and functions pertaining to the movement and activity of immune cells. A comparison at 12 h post-challenge of infected Q223 vs. R223 mice identified a subset of differentially-expressed genes, many of which were closely linked to leptin signaling. Further analyses indicated that the Q223 gene expression pattern was consistent with a suppressed apoptotic response to infection, while 223R showed increased cellular proliferation and recruitment. These studies are the first to illuminate the downstream effects of leptin receptor polymorphisms on intestinal infection by E. histolytica. As such, they are important for the insight that they provide to this previously uncharacterized mechanism of mucosal immunity. Resistance to amebiasis is associated with a polymorphism in the leptin receptor. Previous studies demonstrated that humans with the ancestral Q223 leptin receptor allele were nearly four times less likely to be infected with Entamoeba histolytica than those carrying the mutant R223 allele. We hypothesized that the Q223 allele protected against E. histolytica via STAT3-mediated transcription of genes required for mucosal immunity. To test this, mice containing the humanized LEPR Q or R allele at codon 223 were intracecally infected with E. histolytica. Susceptibility to amebiasis was assessed, and cecal tissues analyzed for changes in gene expression. By 72 h post-challenge all Q223 mice had cleared E. histolytica, whereas 39% of 223R mice were infected. 37 genes were differentially expressed in response to infection at 72 h, including pro-inflammatory genes (CXCL2, calprotectin (S100A8/9), Pla2g7, Itbg2, and MMP9) and functions pertaining to the movement and activity of immune cells. A comparison at 12 h post-challenge of infected Q223 vs. R223 mice identified a subset of differentially-expressed genes, many of which were closely linked to leptin signaling. Further analyses indicated that the Q223 gene expression pattern was consistent with a suppressed apoptotic response to infection, while 223R showed increased cellular proliferation and recruitment. These studies are the first to illuminate the downstream effects of leptin receptor polymorphisms on intestinal infection by E. histolytica. As such, they are important for the insight that they provide to this previously uncharacterized mechanism of mucosal immunity. Control (non-infected QQ or RR) vs. infected with E. histolytica at two time points (12hour and 72 hour)
Experiment type
transcription profiling by array 
Contacts
Dan Sturdevant <dsturdevant@niaid.nih.gov>, Alan Sher, Daniel E Sturdevant, Eric Houpt, Kimmo Virtaneva, Matthew M Hernandez, Nicole M Mackey-Lawrence, Stephen F Porcella, William A Petri Jr, Xiaoti Guo
Citation
Effect of the leptin receptor Q223R polymorphism on the host transcriptome following infection with Entamoeba histolytica. Mackey-Lawrence NM, Guo X, Sturdevant DE, Virtaneva K, Hernandez MM, Houpt E, Sher A, Porcella SF, Petri WA Jr. , Europe PMC 23429533
MIAME
PlatformsProtocolsVariablesProcessedRaw
Files
Investigation descriptionE-GEOD-43372.idf.txt
Sample and data relationshipE-GEOD-43372.sdrf.txt
Raw data (2)E-GEOD-43372.raw.1.zip, E-GEOD-43372.raw.2.zip
Processed data (1)E-GEOD-43372.processed.1.zip
Array designA-AFFY-130.adf.txt
Links