Urinary tract infections (UTIs) are predominantly caused by uropathogenic Escherichia coli (UPEC). UPEC pathogenesis requires passage through a severe population bottleneck involving intracellular bacterial communities (IBCs) that are clonal expansions of a single invading UPEC bacterium in a urothelial superficial facet cell. IBCs occur only during acute pathogenesis. The bacteria in IBCs form the founder population that develops into persistent extracellular infections. Only a small fraction of UPEC organisms proceed through the IBC cycle, regardless of the inoculum size. This dramatic reduction in population size precludes the utility of genomic mutagenesis technologies for identifying genes important for persistence. To circumvent this bottleneck, we previously identified 29 positively selected genes (PSGs) within UPEC and hypothesized that they contribute to virulence. Here, we show that 8 of these 29 PSGs are required for fitness during persistent bacteriuria. Conversely, 7/8 of these PSG mutants showed essentially no phenotype in acute UTI. Deletion of the PSG argI leads to arginine auxotrophy. Relative to the other arg genes, argI in the B2 clade (which comprises most UPEC strains) of E. coli has diverged from argI in other E. coli clades. Replacement of argI in a UPEC strain with a non-UPEC argI allele complemented the arginine auxotrophy but not the persistent bacteriuria defect, showing that the UPEC argI allele contributes to persistent infection. These results highlight the complex roles of metabolic pathways during infection and demonstrate that evolutionary approaches can identify infection-specific gene functions downstream of population bottlenecks, shedding light on virulence and the genetic evolution of pathogenesis.

中文翻译：

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精氨酸合成的细菌致病性分支的致病性分支之间揭示了对尿道生境的调整。

尿路感染（UTI）主要由尿路致病性大肠杆菌引起（UPEC）。UPEC的发病机理需要通过涉及细胞内细菌群落（IBC）的严重种群瓶颈，该菌群是单个侵入的UPEC细菌在尿路上皮浅表小平面细胞中的克隆扩增。IBC仅在急性发病过程中发生。中型散货箱中的细菌形成了原始种群，并发展成为持续的细胞外感染。不管接种体的大小如何，只有一小部分UPEC生物体会经历IBC循环。种群数量的急剧减少使基因组诱变技术无法用于鉴定对持久性重要的基因。为了规避这一瓶颈，我们先前在UPEC中确定了29个阳性选择的基因（PSG），并假设它们有助于毒力。这里，我们显示，这29个PSG中有8个是持续性细菌尿期间健身所必需的。相反，这些PSG突变体中的7/8在急性UTI中基本上没有表现型。删除PSGargI导致精氨酸营养缺陷。相对于其它ARG基因，ARGI在B2进化枝（其包含最UPEC菌株）的大肠杆菌已经从发散ARGI在其他大肠杆菌进化枝。的替换ARGI在UPEC菌株与非UPEC ARGI等位基因补充了精氨酸营养缺陷型的，但不是持续性菌缺陷，表明UPEC ARGI等位基因有助于持续感染。这些结果突出了代谢途径在感染过程中的复杂作用，并证明了进化方法可以识别种群瓶颈下游的感染特异性基因功能，从而减轻了毒力和发病机理的遗传进化。