Department of Medicine, Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
Infect Immun. 2013 May;81(5):1460-70. doi: 10.1128/IAI.01383-12. Epub 2013 Feb 19.
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 were analyzed 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.
抗阿米巴病与瘦素受体的多态性有关。先前的研究表明，与携带突变 R223 等位基因的人相比，具有祖先 Q223 瘦素受体等位基因的人感染溶组织内阿米巴的可能性要低近四倍。我们假设 Q223 等位基因通过 STAT3 介导的黏膜免疫所需基因的转录来保护免受 E. histolytica 的侵害。为了验证这一点，用编码 223 位密码子的 Q 或 R 等位基因对含有人类 LEPR 的小鼠进行了内细胞感染。评估了对阿米巴病的易感性，并分析了盲肠组织中基因表达的变化。在挑战后 72 小时，所有 Q223 小鼠均清除了 E. histolytica，而 223R 小鼠中有 39%感染。在 72 小时时，有 37 个基因对感染有差异表达，包括促炎基因（CXCL2、S100A8/9、PLA2G7、ITGB2 和 MMP9）和与免疫细胞运动和活性相关的功能。在感染后 12 小时对 Q223 与 R223 小鼠的比较中，鉴定了一组差异表达的基因，其中许多与瘦素信号密切相关。进一步的分析表明，Q223 基因表达模式与感染时凋亡反应的抑制一致，而 223R 则显示出细胞增殖和募集的增加。这些研究首次阐明了瘦素受体多态性对溶组织内阿米巴肠道感染的下游影响。因此，它们对于提供对这种以前未被表征的黏膜免疫机制的深入了解非常重要。
