Effect of the Leptin Receptor Q223R Polymorphism on the Host Transcriptome following Infection with Entamoeba histolytica
ABSTRACTResistance 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 withEntamoeba histolyticathan those carrying the mutant R223 allele. We hypothesized that the Q223 allele protected againstE. histolyticavia STAT3-mediated transcription of genes required for mucosal immunity. To test this, mice containing the humanizedLEPRQ or R allele at codon 223 were intracecally infected withE. histolytica. Susceptibility to amebiasis was assessed, and cecal tissues were analyzed for changes in gene expression. By 72 h postchallenge, all Q223 mice had clearedE. histolytica, whereas 39% of 223R mice were infected. Thirty-seven genes were differentially expressed in response to infection at 72 h, including proinflammatory genes (CXCL2,S100A8/9,PLA2G7,ITBG2, andMMP9) and functions pertaining to the movement and activity of immune cells. A comparison at 12 h postchallenge of infected Q223 versus 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 byE. histolytica. As such, they are important for the insight that they provide into this previously uncharacterized mechanism of mucosal immunity.