Helper and satellite pathogenicity islands: the discovery of two novel subcellular elements with a huge impact on bacterial pathogenesis and evolution

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

Abstract

In recent decades, most pathogens have become progressively more contagious, more virulent and more resistant to antibiotics. This implies a rather dynamic evolutionary capability, representing a remarkable level of genomic plasticity, most probably maintained by horizontal gene transfer (HGT). HGT can, in a single step, transform a benign bacterium into a virulent pathogen. This is especially true for several notorious pathogens, including Staphylococcus aureus, used in this project as model, for which phage-mediated HGT enables relatively benign strains to cause lethal infections. Consequently, understanding bacterial horizontal gene transfer is vital to establishing how virulent clones emerge and disseminate, especially in the context of the global antibiotic crisis. Phages and pathogenicity islands make up a key component of the wider horizontal transfer map. Our results in support of this proposal have demonstrated that our current understanding of how the clinically relevant S. aureus pathogenicity islands (SaPIs) can be mobilised are extremely narrow in scope, and that we have underestimated the power of SaPIs as subcellular organisms. We describe here that a subset of SaPIs has evolved an intriguing strategy that promotes their high transfer by pirating other SaPIs. This elegant strategy allows intra- and inter-generic SaPI transfer. In this project, we will establish the molecular bases of this unprecedented strategy. Achieving this objective we will establish novel paradigms involving pathogenicity islands in bacterial evolution and virulence.

Technical Summary

Staphylococcal pathogenicity islands (SaPIs) reside passively in the host chromosome, under the control of the SaPI-encoded master repressor, Stl. It has been assumed that SaPI de-repression is effected by specific phage proteins that bind to Stl, initiating the SaPI cycle. Different SaPIs encode different Stl repressors, so each requires a specific phage protein for its de-repression. Broadening this narrow vision, we report here that a subset of SaPIs, the satellite SaPIs, ensures their promiscuous transfer by targeting other SaPIs, the helper SaPIs. This elegant strategy allows intra- and inter-generic SaPI transfer, highlighting these elements as one of nature's most fascinating subcellular parasites. The characterisation of this fascinating mechanism of molecular piracy will be the focus of the current project.

Planned Impact

The development of novel hypervirulent strains from formerly avirulent or only weakly virulent strains is dramatically fuelled by the acquisition of mobile elements carrying virulence factors. A case in point is the emergence of the notorious O157:H7 strains of E. coli and their relatives, whose genomes are nearly twice as large as those of the common garden varieties of E. coli, and in which the increase consists entirely of acquired mobile genetic elements (MGEs). Closer to home, staphylococcal and streptococcal superantigens are clearly related and have recently had a major role in several fulminant diseases (necrotizing fasciitis, necrotizing pneumonia, etc.). Many of the genes encoding these virulence factors are carried by highly mobile elements, and we would not be surprised to discover that intergeneric transfer of these genes has had an important role in the development of superantigenic strains. Even more to the point is the emergence of the hypervirulent community-acquired MRSA, typified by USA300 and its relatives, whose hypervirulence is largely attributable to virulence-enhancing genes acquired via the horizontal transfer of MGEs. In spite of its relevance in bacterial pathogenesis, the mechanisms underlying gene transfer among bacteria remain, in most cases, unidentified.
In this project we will try to establish novel pathways by which bacteria exchange genetic information. Although this project is a basic science project, and as such may not immediately result in translational output, understanding how bacterial pathogens exchange genetic information and adapt to new hosts is essential if we are to both predict and model the spread and emergence of new virulent clones. Consequently, the expected impact of this project is broad and involves the following areas:
- This project will contribute to the progress of maintaining health and treating diseases by generating a highly needed knowledge base concerning the principles and consequences of MGE transfer in one of the most important pathogens, Staphylococcus aureus, and by facilitating the transfer of this knowledge to human and veterinary clinicians.
- Combating infections: Since some antibiotic treatments increase the transfer and spread of MGE-encoded virulence, the identification of molecules that could block the packaging and transfer of virulence genes would prevent the emergence of new virulent clones.
- Phage therapy: This project highlights that there are unexplored mechanism of phage- and pathogenicity island-mediated gene transfer that have to be characterised in order to safely utilise phages to combat infections. Without this understanding, it is possible that some phage treatments may facilitate the emergence of novel virulent clones.
- Currently, >75% of bacteriophage and pathogenicity island genes are annotated as hypothetical. This application thus responds to the generally recognised need to translate genome data, and the latest developments in Systems Biology, into sustainable practical applications for medical and veterinary research and treatment.
- This project will unravel a fundamental understanding of the link between MGEs and disease. Besides Staphylococcus aureus, this is of general value, because MGEs play a central role for many pathogenic microorganisms, and SaPI-like elements are widespread in nature.
In summary, a better understanding of the biology of the different MGEs involved in bacterial virulence is urgently required. The data generated by the experiments proposed here will provide more information on the mechanisms underlying the apparition, spread and emergence of novel bacterial pathogens.

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