Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
GERMS platform, Genome Institute of Singapore, Singapore.
mSphere. 2019 Apr 10;4(2):e00693-18. doi: 10.1128/mSphere.00693-18.
Most urinary tract infections (UTIs) are caused by uropathogenic (UPEC), which depends on an extracellular organelle (type 1 pili) for adherence to bladder cells during infection. Type 1 pilus expression is partially regulated by inversion of a piece of DNA referred to as , which contains the promoter for the operon encoding type 1 pili. inversion is regulated by up to five recombinases collectively known as Fim recombinases. These Fim recombinases are currently known to regulate two other switches: the and switches. A long-standing question has been whether the Fim recombinases regulate the inversion of other switches, perhaps to coordinate expression for adhesion or virulence. We answered this question using whole-genome sequencing with a newly developed algorithm (structural variation detection using relative entropy [SVRE]) for calling structural variations using paired-end short-read sequencing. SVRE identified all of the previously known switches, refining the specificity of which recombinases act at which switches. Strikingly, we found no new inversions that were mediated by the Fim recombinases. We conclude that the Fim recombinases are each highly specific for a small number of switches. We hypothesize that the unlinked Fim recombinases have been recruited to regulate , and only, as a secondary locus; this further implies that regulation of type 1 pilus expression (and its role in gastrointestinal and/or genitourinary colonization) is important enough, on its own, to influence the evolution and maintenance of multiple additional genes within the accessory genome of UTI is a common ailment that affects more than half of all women during their lifetime. The leading cause of UTIs is UPEC, which relies on type 1 pili to colonize and persist within the bladder during infection. The regulation of type 1 pili is remarkable for an epigenetic mechanism in which a section of DNA containing a promoter is inverted. The inversion mechanism relies on what are thought to be dedicated recombinase genes; however, the full repertoire for these recombinases is not known. We show here that there are no additional targets beyond those already identified for the recombinases in the entire genome of two UPEC strains, arguing that type 1 pilus expression itself is the driving evolutionary force for the presence of these recombinase genes. This further suggests that targeting the type 1 pilus is a rational alternative nonantibiotic strategy for the treatment of UTI.
大多数尿路感染（UTI）是由尿路致病性大肠杆菌（UPEC）引起的，它在感染过程中依靠一种细胞外细胞器（I 型菌毛）与膀胱细胞结合。I 型菌毛的表达部分受 DNA 片段的反转调控，该片段称为，其中包含编码 I 型菌毛的操纵子的启动子。 反转由多达五个称为 Fim 重组酶的重组酶共同调节。目前已知这些 Fim 重组酶调节另外两个开关： 和 开关。一个长期存在的问题是，Fim 重组酶是否调节其他开关的反转，也许是为了协调粘附或毒力的表达。我们使用全基因组测序并结合一种新开发的算法（使用相对熵的结构变异检测 [SVRE]）来回答这个问题，该算法用于使用配对末端短读测序调用结构变异。SVRE 鉴定了所有先前已知的开关，提高了哪些重组酶在哪些开关上起作用的特异性。引人注目的是，我们没有发现由 Fim 重组酶介导的新反转。我们得出的结论是，Fim 重组酶对于少数几个开关非常特异。我们假设未连接的 Fim 重组酶被招募来调节 和 ，作为次要基因座；这进一步意味着 I 型菌毛表达的调节（及其在胃肠道和/或泌尿生殖道定植中的作用）本身足够重要，足以影响 UPEC 辅助基因组中多个额外基因的进化和维持。尿路感染是一种常见疾病，超过一半的女性在其一生中都会受到影响。UTI 的主要原因是 UPEC，它依赖于 I 型菌毛在感染过程中定植和在膀胱中持续存在。I 型菌毛的调节以一种表观遗传机制为特征，其中包含启动子的 DNA 片段被反转。反转机制依赖于被认为是专门的重组酶基因；然而，这些重组酶的全部 repertoire 尚不清楚。我们在这里表明，在两个 UPEC 菌株的整个基因组中，除了已经确定的重组酶之外，没有其他靶点，这表明 I 型菌毛表达本身是这些重组酶基因存在的驱动进化力。这进一步表明，针对 I 型菌毛是治疗 UTI 的一种合理的非抗生素替代策略。
