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

一个物种内的细菌基因组可以在基因含量上有很大差异的想法并不新鲜。然而，只有随着基因组时代的到来，这种现象才被正确地认识到。不仅基因组大小不同，而且在来自特定物种的不同菌株中存在的大量基因甚至没有关联，即在其他菌株中没有同源基因。这些基因大多携带在可移动的遗传元件上，包括质粒、噬菌体、致病岛、转座子或整合子，这些基因可能在细菌之间转移。因此，现在认为水平基因转移(HGT)在细菌进化中起着极其重要的作用。事实上，据估计，任何给定细菌物种现有遗传含量的20%左右是从其他生物获得的。这20%中可能有一半是MGES，它们在种内和种间自由移动，偶尔会跨越属间的边界。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对生活的各种适应，我们认为这是一种致病机制。在大多数致病细菌中，所有已知的细菌MGE都可能与致病机制有关，尤其令人震惊的是，基本上所有导致特定毒素介导性疾病的细菌毒素-毒素病-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MGE编码的。这一应用代表了一项从2003年开始并一直延伸到现在的漫长而高效的研究计划的高潮。在此期间，我们描述了一个新的可移动葡萄球菌致病岛家族，SAPI，它是几个重要超抗原的唯一来源，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，我们假设类似的元件广泛存在于细菌中，符合一类独特的可移动遗传元件，即噬菌体诱导的染色体岛(Picis)。我们认为，PICI已经在细菌世界中广泛传播，并且比它们的宿主生物扩散得慢得多。如果是真的，这些发现代表着一类新的MGE的发现，它对细菌世界的横向基因转移和毒力具有广泛的影响。该项目的总体目标是双重的：一方面，我们将试图证实这个新的、广泛存在的可移动遗传元件家族Picis的存在。另一方面，我们将试图通过编码新的和未表征的毒力基因来证明这些元件在毒力中具有重要作用。我们认为，我们的研究的成功完成将引入一种新的范式来理解致病岛的生物学，从而理解细菌的进化。我们的研究将通过获得MGES，特别是跨属的MGES，极大地提高对病原菌的进化和新的毒力克隆的显现的理解。

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.