Unravelling post-transcriptional regulatory networks in pathogenic S. aureus

Antimicrobial medicines have saved millions of lives since the introduction of penicillin in the 1940s. But their overuse has resulted in the rise of multidrug-resistant bacteria at a rate that has outpaced the discovery of new antibiotics. The emergence of multi-drug resistant Staphylococcus aureus (such as MRSA) in particular is causing major healthcare problems world-wide as S. aureus skin and respiratory infections can be life-threatening and are becoming increasingly more difficult to treat.
Like all organisms, MRSA initially makes temporary copies of its genes, called messenger RNA (mRNA) molecules, which can subsequently be read, or translated, by a molecular machine called the ribosome to generate proteins. How much of a protein is made depends on how much of its mRNA is present and how well it accesses the translation machinery. Proteins enable the organism to survive and, for bacteria like S. aureus, to infect human cells. One reason why S. aureus is such a successful human pathogen is because it can quickly remove mRNAs that are no longer required and control which mRNAs are translated. This enables the organism to swiftly adapt to challenges from the immune system by changing the proteins that it makes. This mechanism is crucial for S. aureus survival during infection, but we know remarkably little about how it works. The goal of our research is to gain detailed molecular insights into this process, using innovative techniques that we have developed over the years. The results from our studies may help uncover new ways of battling infectious diseases.

The emergence and expansion of antibiotic-resistant Staphylococcus aureus (including methicillin-resistant S. aureus, MRSA) in hospitals and the community is a global public health concern. S. aureus is an extremely versatile pathogen, due in part to its capacity to rapidly alter its transcriptome in response to stress. While transcription factors dictate which genes are expressed during stress, substantial regulation also occurs post-transcriptionally. Regulatory RNAs (ncRNAs) and RNA-binding proteins are now recognized as key players in controlling virulence, host cell interactions and antibiotic resistance in bacterial pathogens. By directly binding to their mRNA target, they decide the fate of the molecule by control how efficiently the mRNA is translated and/or degraded. We hypothesize that riboregulators play a key role in shaping gene expression profiles during stress. However, for the majority of these factors we lack understanding of their function. To gain mechanistic insights into how MRSA rapidly alters gene expression during stress, we will map the landscape of post-transcriptional regulation in S. aureus during human infection using innovative high-throughput methods developed in my group and by our collaborators. Because immune evasion is critical for S. aureus survival in the early stages of infection, we will focus our analyses on post-transcriptional events during entry into the blood stream and in response to phagocytic cells. Our preliminary data have already uncovered many targets for 89 ncRNAs, including interactions with transcripts encoding toxins and multi-drug efflux pumps, demonstrating the feasibility of our approach. We envisage that the insights into post-transcriptional regulatory networks derived from this work may lead to the design of novel approaches for treating or preventing infectious diseases.

1) Benefits to the scientific community:
As this is a basic research project, the main beneficiaries of the outputs generated by the proposed work will be both the national and the international scientific community. The data that we will generate and the technologies that we have developed will be not only be of interest to the bacterial field but also to the RNA research community in general. To maximize our impact, we will be presenting our work at conferences and seminars, publish in open-access journals and train researchers how to successfully apply the techniques developed in my group.

2) Benefits to the UK society and economy:
Our lab is a good place to learn all about the latest high-throughput techniques in RNA biology. Therefore, we believe that our staff as well as our visitors will greatly benefit from the biochemical and computational skills that they learn in our lab as it enables them to tackle complex and technically challenging biological questions. As these skills are in high-demand, I believe that these training opportunities will significantly improve their future employability.
Our results are not only expected to increase the level of understanding how Staphylococcus aureus is such a successful human pathogen, but it may reveal promising targets for the development of antimicrobials. Therefore, in the longer-term our work may contribute to finding new approaches to battle S. aureus infections.

3) Benefits to industry:
We have been working with a UK company (UVO3) for several years now to develop new tools for RNA biology. UVO3 has indicated that it would be interested in developing new equipment with us and we will work closely with our Edinburgh Research and Innovation department to determine whether inventions arising from future collaborative efforts could be patented.

4) Benefits to the general public:
We will disseminate our results to the general public through our press office (Press Gang) as well as through public outreach. These channels provide a great opportunity to engage with public to discuss the importance of studying pathogenic bacteria, how this may lead to improved methods to treat infections and the importance of MRC funding in driving research in this area forward.