Development, evaluation and translation of next-generation sequencing tools to track MRSA transmission pathways

A bacterium called Staphylococcus aureus is often part of our normal body flora and is harmless for the majority of people, but may sometimes cause infection that ranges in severity from trivial (e.g. boils) to severe (e.g. infection of the heart valves or bones). Staphylococcus aureus is also the leading cause of infections that occur in people after admission to hospital for reasons other than infection. Some strains of Staphylococcus aureus have acquired resistance to an antibiotic (methicillin) that is otherwise the treatment of choice for infection caused by this organism. These methicillin-resistant Staphylococcus aureus (MRSA) are most often found in the hospital setting. Becoming a carrier of MRSA is the forerunner to infection, and development of carriage in a given patient occurs after transmission of the organism from another patient. Hospital infection control aims to prevent spread of these bacteria but can sometimes fail. One way to reveal how bacteria spread and pinpoint where preventive strategies require strengthening is to perform bacterial typing to determine if MRSA affecting two patients are highly related (suggesting that it passed from one person to another) or different. However, this is not straightforward since two particular strains of MRSA have become so successful that they are almost always the culprits (they are called EMRSA-15 and EMRSA-16). Two patients carrying or infected with one of these strains could have acquired it from each other or may have acquired it independently of each other, and current laboratory typing tools are unable to tell the two situations apart. We believe that it is now possible to develop a new generation of typing tools that distinguish between two strains based on the identification of single letter DNA changes in the bacterial genome. The objective of our study is to focus on MRSA strains that are important in the UK. We will undertake whole genome sequencing of numerous isolates each of EMRSA-15 and -16 obtained from across the country. The data generated will be examined to define those genetic differences that would prove most useful for defining clusters within the group. This will form the basis for the development of a new generation of typing technique that we aim to translate into the clinical setting where it will provide the capability to study the spread of MRSA transmission in the UK and beyond in such a way that has previously proved impossible.

Nosocomial pathogens represent one of the most significant challenges to the successful delivery of modern medical care. Revealing the routes of transmission and spread of nosocomial pathogens at local, regional, national and international levels is crucial to targeted control. This is severely constrained, however, by the inability to discern between strains of the same epidemiologically successful lineage. For example, two lineages of methicillin-resistant Staphylococcus aureus (MRSA) termed EMRSA-15 and -16 have become disseminated throughout the UK and cause most cases of MRSA infection, but current bacterial typing methods fail to distinguish between strains of the same lineage. This technology gap represents a major hindrance to the development of more effective infection control strategies since transmission of MRSA between patients and healthcare facilities cannot be differentiated from independent acquisition. We have developed a series of novel and synergistic tools to type, map and track nosocomial pathogens and to determine genetic events associated with shifts in patterns of transmission and infection. This involves the integrated use of whole genome sequence typing (which we have already shown to be capable of defining detailed phylogenetic structuring within a single MRSA lineage), a web-based interface that provides mapping and interactive tree building to place a given strain within its geographical and phylogenetic context, and a network model of patient movement between NHS facilities. The goal of this Consortium is to apply these tools to define transmission of ERMSA-15 and -16 at local and national levels in the UK, and to have demonstrated a clear role for this approach in disease control by the end of the grant. Our strategy is to build upon an existing grouping of internationally recognized scientists who have developed these tools, and to expedite their rapid introduction into UK healthcare systems. Our objectives are to undertake a 3-stage programme of research (development, evaluation and implementation) in which we refine and further develop these tools, conduct prospective macro- and micro-epidemiological evaluation studies, and seek to integrate this technology into the healthcare infrastructure. The detailed reconstruction of MRSA transmission pathways would be predicted to have a dramatic effect on future strategies for control and prevention of nosocomial MRSA infection. Furthermore, our model is adaptable to other existing and emerging pathogens, and will strengthen the capacity and resilience of healthcare networks to control and prevent a spectrum of current and future infectious disease threats.