Chu Wilson H W, Tan Yi Han, Tan Si Yin, Chen Yahua, Yong Melvin, Lye David C, Kalimuddin Shirin, Archuleta Sophia, Gan Yunn-Hwen
Infectious Diseases Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, Singapore.
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, Singapore.
mBio. 2023 Aug 31;14(4):e0129723. doi: 10.1128/mbio.01297-23. Epub 2023 Aug 2.
Hypervirulent causes liver abscess and potentially devastating metastatic complications. The majority of -induced liver abscess are caused by the CG23-I sublineage of hypervirulent . This and some other lineages possess a >200-kb virulence plasmid. We discovered a novel protein IroP nestled in the virulence plasmid-encoded salmochelin operon that cross-regulates and suppresses the promoter activity of chromosomal type 3 fimbriae (T3F) gene transcription. IroP is itself repressed by iron through the ferric uptake regulator. Iron-rich conditions increase T3F and suppress capsule mucoviscosity, leading to biofilm formation and cell adhesion. Conversely, iron-poor conditions cause a transcriptional switch to hypermucoid capsule production and T3F repression. The likely acquisition of on mobile genetic elements and successful adaptive integration into the genetic circuitry of a major lineage of hypervirulent reveal a powerful example of plasmid chromosomal cross talk that confers an evolutionary advantage. Our discovery also addresses the conundrum of how the hypermucoid capsule that impedes adhesion could be regulated to facilitate biofilm formation and colonization. The acquired ability of the bacteria to alternate between a state favoring dissemination and one that favors colonization in response to iron availability through transcriptional regulation offers novel insights into the evolutionary success of this pathogen. IMPORTANCE Hypervirulent contributes to the majority of monomicrobial-induced liver abscess infections that can lead to several other metastatic complications. The large virulence plasmid is highly stable in major lineages, suggesting that it provides survival benefits. We discovered a protein IroP encoded on the virulence plasmid that suppresses expression of the type 3 fimbriae. IroP itself is regulated by iron, and we showed that iron regulates hypermucoid capsule production while inversely regulating type 3 fimbriae expression through IroP. The acquisition and integration of this inverse transcriptional switch between fimbriae and capsule mucoviscosity shows an evolved sophisticated plasmid-chromosomal cross talk that changes the behavior of hypervirulent in response to a key nutrient that could contribute to the evolutionary success of this pathogen.
高毒力菌株可导致肝脓肿，并可能引发具有潜在毁灭性的转移性并发症。大多数由该菌株引起的肝脓肿是由高毒力菌株的CG23-I亚系所致。该亚系及其他一些菌株拥有一个大于200 kb的毒力质粒。我们发现了一种新的蛋白质IroP，它位于毒力质粒编码的沙门菌素操纵子中，可交叉调节并抑制染色体3型菌毛（T3F）基因转录的启动子活性。IroP本身受铁通过铁摄取调节蛋白的抑制。富含铁的条件会增加T3F并抑制荚膜黏液性，从而导致生物膜形成和细胞黏附。相反，缺铁条件会导致转录转换至高黏液性荚膜产生并抑制T3F。该菌株可能在移动遗传元件上获得并成功适应性整合到高毒力菌株主要谱系的遗传回路中，这揭示了质粒-染色体相互作用的一个有力例子，赋予了进化优势。我们的发现还解决了一个难题，即如何调节阻碍黏附的高黏液性荚膜以促进生物膜形成和定植。细菌通过转录调节，根据铁的可用性在有利于传播的状态和有利于定植的状态之间交替的获得能力，为这种病原体的进化成功提供了新的见解。重要性 高毒力菌株导致了大多数单一微生物引起的肝脓肿感染，并可能引发其他几种转移性并发症。大型毒力质粒在主要谱系中高度稳定，表明它提供了生存优势。我们发现了一种编码在毒力质粒上的蛋白质IroP，它可抑制3型菌毛的表达。IroP本身受铁调节，并且我们表明铁调节高黏液性荚膜的产生，同时通过IroP反向调节3型菌毛的表达。这种菌毛和荚膜黏液性之间反向转录开关的获得和整合显示了一种进化而来的复杂质粒-染色体相互作用，它根据一种关键营养素改变高毒力菌株的行为，这可能有助于这种病原体的进化成功。
