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

Lead Research Organisation: University of Glasgow
Department Name: College of Medical, Veterinary &Life Sci

Abstract

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.

Technical Summary

Bacteria are successful as commensal organisms or pathogens partly because they rapidly adapt to selective pressures imparted by the human host. Mobile genetic elements (MGEs) play a central role in this adaptation process and are a means to transfer genetic information (DNA) among and within bacterial species. Importantly, MGEs encode putative virulence factors and molecules that confer resistance to antibiotics. Inasmuch as bacterial infections are a significant problem worldwide and continue to emerge in epidemic waves, there has been significant effort to understand the agents that effect DNA movement.

In recent years, we have extensively characterised a family of pathogenicity islands in Staphylococcus aureus, SaPIs, which contribute substantively to horizontal gene transfer, host adaptation and virulence. Here we hypothesise that similar elements occur widely in bacteria, that these are not defective prophages, despite their annotations in GenBank, but are rather a unique class of mobile genetic elements, the phage-inducible chromosomal islands (PICIs). Overall, 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 phage-inducible chromosomal islands of bacteria (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.

Planned Impact

Bacterial genomes are in constant evolution, with the appearance of new virulent clones. However, the mechanistic basis for this process is not well understood. In spite of their evident role in the bacterial pathogenesis, environmental and genetic factors that regulate transfer of mobile genetic elements in bacterial populations are largely unknown. In fact, and paradoxically, hospitals, where the pressure to eliminate pathogenic bacteria is higher, have evolved as one of the major forces promoting antibiotic resistance and increasing the arsenal of virulence genes in most clinically relevant pathogenic bacteria.

We propose that the novel PICI family of MGEs is a key factor in the pathogenesis of most clinically relevant bacterial and in the appearance of novel virulence clones. In support of this, the prototypical member of the family, the SaPIs, have a high impact in the virulence of S. aureus. In addition, these elements have been also involved in the adaptation of S. aureus to new hosts and in the development of new virulent clones, clearly confirming their role in pathogenesis. Understanding the biology of the members of this family, how they evolve and how they are transferred will provide new strategies to prevent the apparition of new virulent clones as well as new strategies to combat bacterial infections.

Because of the multi-faceted, cross-disciplinary and wide-ranging nature of the proposed project, a relatively large number of academic disciplines will benefit, both nationally and internationally, from the work; these include bacteriology, virology, immunology, cell biology, vaccinology or pharmacology. In addition, the development of novel approaches for studying bacterial evolution and virulence, together with the identification of potential vaccine antigens and drug targets, will make a significant contribution to combating an important human infectious diseases and will have a major impact on improving human health, a MRC priority area. These data may be of value to companies with an interest in treating bacterial infections. In this way, we feel the project could be of great value to industry.

Publications

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Description Alberto Marina 
Organisation Spanish National Research Council (CSIC)
Department State Agency Superior Council for Scientific Research
Country Spain 
Sector Public 
PI Contribution Alberto is helping us in deciphering the structure of some phage and SaPI proteins of interest.
Collaborator Contribution We provide the biological model analysed in this collaboration.
Impact Several papers published.
Start Year 2010
 
Description Gail Christie 
Organisation University of Virginia (UVa)
Department Cell and Molecular Biology
Country United States 
Sector Academic/University 
PI Contribution We have identified the genes involved in the induction and packaging of the Staphylococcal pathogenicity islands (SaPIs).
Collaborator Contribution Gail's lab has been working in the mechanism by which SaPIs hijack the phage machinery for their tramsfer.
Impact Several papers published.
Start Year 2008
 
Description Richard Novick 
Organisation New York University
Country United States 
Sector Academic/University 
PI Contribution We have discovered a novel family of mobile genetic elements, the PICIs.
Collaborator Contribution Both teams are deciphering the biology of this novel family of mobile genetic elements.
Impact Several papers published.