Effect of the leptin receptor Q223R polymorphism on the host transcriptome following infection with Entamoeba histolytica

Nicole M. Mackey-Lawrence, Xiaoti Guo, Daniel E. Sturdevant, Kimmo Virtaneva, Matthew M. Hernandez, Eric Houpt, Alan Sher, Stephen F. Porcella, William A. Petri

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20 Scopus citations

Abstract

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 testthis, mice containing the humanized LEPRQor R allele at codon 223 were intracecally infected with E. histolytica. Susceptibility to amebiasis was assessed, and cecal tissues wereanalyzed for changes in gene expression. By 72 h postchallenge, all Q223 mice had cleared E. 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, and MMP9) 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 by E. histolytica.As such, they are important for the insight that they provide into this previously uncharacterized mechanism of mucosal immunity.

Original languageEnglish
Pages (from-to)1460-1470
Number of pages11
JournalInfection and Immunity
Volume81
Issue number5
DOIs
StatePublished - May 2013
Externally publishedYes

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