Molecular biology of the PICIs, a novel and widespread family of mobile genetic elements involved in bacterial virulence

单一物种内的细菌基因组在基因含量上差异很大，这一想法并不新鲜。然而，直到基因组时代的到来，这种现象才被正确地认识到。不仅基因组大小不同；在来自特定物种的不同菌株中存在的大量基因甚至不相关，即在其他菌株中没有同源基因。这些基因大多携带在移动遗传元件（MGEs）上，包括质粒、噬菌体、致病性岛、转座子或整合子，它们可以在细菌之间潜在地转移。因此，现在假设水平基因转移（HGT）在细菌进化中起着极其重要的作用。事实上，据估计，任何一种细菌的现存遗传成分中，约有20%是从其他生物体中获得的。在这20%中，可能有一半是由MGEs组成的，它们在物种内部和物种之间自由移动，偶尔也会跨越属间边界。对于兼性病原体，MGEs主要负责抗生素耐药性，环境适应和宿主组织中各种各样的生命适应，我们认为这是发病机制。在大多数致病菌中，所有已知种类的细菌MGEs都可能参与致病机制，特别引人注目的是，基本上所有引起特定毒素介导疾病的细菌毒素-毒素-如PVL肺炎，白喉，痢疾，中毒性休克综合征，食物中毒，坏死性肺炎，烫伤皮肤综合征，肉毒杆菌中毒，溶血性尿毒症综合征或坏死性筋膜炎，都是由MGEs编码的。这个应用程序代表了一个长期和高生产力的研究计划的高潮，从2003年开始，一直延伸到现在。在此期间，我们描述了一个新的移动葡萄球菌致病性岛家族，SaPIs，它是几种重要超级抗原的唯一来源，包括中毒性休克综合征毒素-1和肠毒素B和C，以及与宿主适应相关的其他毒力因子的来源。现在，我们假设类似的元素在细菌中广泛存在，符合一类独特的可移动遗传元素，噬菌体诱导染色体岛（PICIs）。我们认为pici在细菌世界中广泛传播，并且比宿主生物分化得慢得多。如果这是真的，这些发现代表了一类新的MGE的发现，它对细菌世界的横向基因转移和毒力有广泛的影响。这个项目的总体目标是双重的：一方面，我们将试图确认这种新颖而广泛的移动遗传元件家族的存在，pici。另一方面，我们将尝试通过编码新的和未表征的毒力基因来证明这些元素在毒力中起重要作用。我们认为，我们的研究的成功完成将为理解致病性岛屿的生物学和细菌进化引入一个新的范式。我们的研究将通过获得MGEs，特别是跨属的MGEs，极大地提高对致病菌进化和新毒力克隆的认识。

The idea that bacterial genomes within one single species can vary widely in gene content is not new. However, it was only with the advent of the genomic era that the phenomenon has been properly perceived. Not only was the genome size different; a significant number of the genes present in different strains from a specific species were not even related i.e. had no homologous genes in the others. Most of these genes were carried on mobile genetics elements (MGEs), including plasmids, bacteriophages, pathogenicity islands, transposons or integrons, which can be potentially transferred among bacteria. Thus, it is now assumed that horizontal gene transfer (HGT) has had an extremely important role in bacterial evolution. Indeed it has been estimated that some 20% of the extant genetic content of any given bacterial species has been acquired from other organisms. Perhaps half of this 20% consists of MGEs, which have moved freely within and between species and have occasionally crossed intergeneric boundaries. With facultative pathogens, MGEs are largely responsible for antibiotic resistance, environmental adaptations and the wide variety of adaptations to life in host tissues that we perceive as pathogenesis. In most pathogenic bacteria, all known classes of bacterial MGEs may contribute to pathogenesis, and it is particularly striking that essentially all of the bacterial toxins that cause specific toxin-mediated diseases - toxinoses - such as PVL pneumonia, diphtheria, dysentery, toxic shock syndrome, food poisoning, necrotizing pneumonia, scalded skin syndrome, botulism, hemolytic-uremic syndrome or necrotizing fasciitis, are encoded by MGEs.This application represents the culmination of a long and highly productive research program starting in 2003 and extending to the present. During this time we have characterised a novel family of mobile staphylococcal pathogenicity islands, the SaPIs, which are the only source of several important superantigens, including toxic shock syndrome toxin-1 and enterotoxins B and C, as well as the source for other virulence factors related with host adaptation. Now, we hypothesise that similar elements occur widely in bacteria, conforming a unique class of mobile genetic elements, the phage-inducible chromosomal islands (PICIs). We suggest that the PICIs have spread widely throughout the bacterial world, and have diverged much more slowly than their host organisms. If true, these findings represent the discovery of a new class of MGE, which have a broad impact on lateral gene transfer and virulence in the bacterial world.The overall goal of this project is double: on one hand, we will try to confirm the existence of this novel and widespread family of mobile genetic elements, the PICIs. On the other hand, we will try to demonstrate that these elements have an important role in virulence by encoding novel and uncharacterised virulent genes. We propose that the successful completion of our research will introduce a new paradigm in the understanding of the biology of pathogenicity islands and therefore of bacterial evolution. Our studies will greatly enhance understanding of the evolution of pathogenic bacteria and apparition of novel virulence clones through the acquisition of MGEs, especially across genera.