Department of Biology, University of Louisville, Louisville, Kentucky, United States of America.
PLoS One. 2012;7(6):e38097. doi: 10.1371/journal.pone.0038097. Epub 2012 Jun 11.
Salmonella enterica is a bacterial pathogen of humans that can proliferate within epithelial cells as well as professional phagocytes of the immune system. While much has been learned about the microbial genes that influence the infectious process through decades of intensive research, relatively little is known about the host factors that affect infection. We performed a genome-wide siRNA screen to identify host genes that Salmonella enterica serovar Typhimurium (S. typhimurium) utilizes to facilitate growth within human epithelial cells. In this screen, with siRNAs targeting every predicted gene in the human genome, we identified 252 new human-host-susceptibility factors (HSFs) for S. typhimurium. We also identified 39 genes whose silencing results in increased intracellular growth of S. typhimurium. The HSFs identified are regulated most centrally by NFκB and associate with each other through an extremely dense network of interactions that center around a group of kinases. Most genes identified were not previously appreciated as playing roles in the intracellular lifecycle of S. enterica. Numerous HSFs identified with interesting characteristics that could play plausible roles in mediating intracellular microbial growth are discussed. Importantly, this study reveals significant overlap between the host network that supports S. typhimurium growth within human epithelial cells and the one that promotes the growth of Mycobacterium tuberculosis within human macrophages. In addition to providing much new information about the molecular mechanisms underlying S. enterica-host cell interplay, all 252 HSFs identified are candidates for new anti-microbial targets for controlling S. enterica infections, and some may provide broad-spectrum anti-microbial activity.
肠道沙门氏菌是一种人类致病菌，它可以在肠道上皮细胞和免疫系统的专业吞噬细胞内增殖。尽管经过几十年的密集研究，人们已经了解了许多影响感染过程的微生物基因，但对于影响感染的宿主因素却知之甚少。我们进行了全基因组 siRNA 筛选，以确定肠道沙门氏菌（S. typhimurium）利用的宿主基因，从而促进其在人肠道上皮细胞内的生长。在这项筛选中，我们使用靶向人类基因组中每个预测基因的 siRNA，鉴定出 252 个新的人类易感性宿主因子（HSFs）。我们还鉴定出 39 个基因，其沉默导致 S. typhimurium 的细胞内生长增加。鉴定出的 HSFs 主要受到 NFκB 的调控，并通过一个以一组激酶为中心的极其密集的相互作用网络相互关联。大多数被鉴定的基因以前并没有被认为在肠道沙门氏菌的细胞内生命周期中发挥作用。我们讨论了许多具有有趣特征的 HSFs，这些特征可能在介导细胞内微生物生长中发挥作用。重要的是，这项研究揭示了支持 S. typhimurium 在人肠道上皮细胞内生长的宿主网络与促进人巨噬细胞中结核分枝杆菌生长的宿主网络之间存在显著重叠。除了提供有关肠道沙门氏菌与宿主细胞相互作用的分子机制的大量新信息外，所有鉴定出的 252 个 HSFs 都是控制肠道沙门氏菌感染的新型抗菌靶点的候选者，其中一些可能具有广谱抗菌活性。
