Deciphering Gram-negative phage-inducible chromosomal island strategies for spreading in nature

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The concept that bacterial genomes within a single species can vary widely in gene content is not new. However, it was only with the arrival of the genomic era that the phenomenon has been properly understood. 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 consists of MGEs, which have moved freely within and between species, and have occasionally crossed intergeneric boundaries. In 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 to host adaptation. Not surprisingly, these elements are not just confined to the Staphylococci, but are widespread within Gram-positive bacteria. Recently, we have also demonstrated that similar elements occur widely in Gram-negative bacteria, conforming a unique class of MGEs, 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.Although our previous studies have deciphered how the PICI elements present in the Gram-positive bacteria are induced and horizontally transferred, two main questions remain to be determined in the biology of the Gram-negative PICIs: i) how these elements sense the presence of their helper phages, and ii) how they hijack the phage machinery for their own specific packaging, blocking phage reproduction. To decipher these two processes is of vital importance to understand how these elements spread in nature. In this project we will answer these questions. By achieving these objectives we will establish new paradigms involving pathogenicity islands in bacterial evolution and virulence, and will provide strategies to block pathogenicity island dissemination and the emergence of novel bacterial virulent clones.