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Caenorhabditis elegans as a model to elucidate host-pathogen interactions for human bacterial pathogens

机译:秀丽隐杆线虫作为阐明人类细菌病原体宿主与病原体相互作用的模型

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The soil nematode Caenorhabditis elegans is a popular host utilized to model bacterial virulence and microbial pathogenesis in vivo. This thesis explores the use of C. elegans for the study of host-pathogen interactions for two Gram-negative bacteria, Burkholderia thailandensis and Salmonella enterica.We conducted a RNA interference screen to identify host genes capable of modulating the infection outcomes of C. elegans infected with B. thailandensis. We discovered that during infection, the cell junction protein LIN-7 appeared to modulate the evolutionarily conserved DAF-2 insulin/IGF-1 signalling pathway, culminating on both the FOXO transcription factor DAF-16 and the heat-shock factor 1. Moreover, LIN-7 regulated nematode survival during infection with other Gram-negative bacteria. Tissue-specific experiments also revealed that this interaction between LIN-7 and the DAF-2 signalling pathway operated mainly in nematode tissues outside the intestine (Paper I).Through a forward genetics screen using ultraviolet light, we identified pt1 as a novel allele of the unc-7 innexin gene. We found that the pt1 mutant exhibited enhanced survival only when infected with Burkholderia spp. We further defined a specific subclass of unc-7 interacting genes, unc-9 and goa-1, in a unique pathway which probably involves calcium ion fluxes (Paper II).Next we characterized a new aspect of S. enterica virulence. We observed that S. enterica provoked oxidative stress in the hypodermal tissues of infected C. elegans even though there was no apparent invasion beyond the intestinal epithelium. Via chemical and mutational interference, we found this phenomenon to be deleterious to the host. Genetic inactivation of the bacterial thioredoxin 1 strongly abrogated pathogenicity of S. enterica as well as the emergence of oxidative stress, thereby suggesting a novel role for this virulence factor (Paper III).Finally, we investigated the combinatorial effects of the proton pump inhibitor omeprazole and the salicylidene acylhydrazide INP0010 during S. enterica infection. We observed disparate effects when they were used in combination and applied to different infection models including the epithelial and macrophage-like cell lines and C. elegans. The nematode can thus provide a platform for testing virulence inhibitors, allowing the elucidation of their mechanisms in the context of a whole organism (Paper IV).
机译:土壤线虫秀丽隐杆线虫(Caenorhabditis elegans)是一种流行的宿主,可用于在体内模拟细菌毒力和微生物发病机理。本文探讨了秀丽隐杆线虫在研究两种革兰氏阴性菌Burkholderia thailandensis和沙门氏菌的宿主-病原体相互作用中的用途。我们进行了RNA干扰筛选,以鉴定能够调节秀丽隐杆线虫感染结果的宿主基因。感染了B. thailandensis。我们发现,在感染过程中,细胞连接蛋白LIN-7似乎可以调节进化上保守的DAF-2胰岛素/ IGF-1信号通路,最终达到FOXO转录因子DAF-16和热休克因子1的高度。 LIN-7调节了其他革兰氏阴性细菌感染期间线虫的存活。组织特异性实验还揭示了LIN-7和DAF-2信号通路之间的相互作用主要在肠道外的线虫组织中起作用(论文I)。通过使用紫外光进行正向遗传学筛选,我们鉴定出pt1是一种新的等位基因unc-7内毒素基因。我们发现pt1突变体仅在被Burkholderia spp感染时才表现出增强的存活率。我们在可能涉及钙离子通量的独特途径中进一步定义了unc-7相互作用基因的特定亚类unc-9和goa-1(论文II)。接下来,我们对肠炎链球菌毒力的一个新方面进行了描述。我们观察到,即使在肠上皮细胞外没有明显的侵袭,肠炎链球菌也会在被感染的秀丽隐杆线虫的皮下组织中引起氧化应激。通过化学和突变干扰,我们发现该现象对宿主有害。细菌硫氧还蛋白1的基因失活极大地消除了肠炎链球菌的致病性以及氧化应激的出现,从而暗示了这种毒力因子的新作用(论文III)。最后,我们研究了质子泵抑制剂奥美拉唑的组合作用。以及沙门氏菌感染期间的水杨基酰肼INP0010。当将它们组合使用并应用于不同的感染模型(包括上皮细胞和巨噬细胞样细胞系以及秀丽隐杆线虫)时,我们观察到了不同的效果。因此,线虫可以提供一个测试毒力抑制剂的平台,从而在整个生物体的背景下阐明其机理(第四篇论文)。

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