The role of commensal organisms as pro-infectious agents in Staphylococcus aureus infection dynamics.

Staphylococcus aureus is an important human pathogen that causes significant death and disease around the world. The problem is exacerbated by the spread of antibiotic resistant strains such as Methicillin Resistant S. aureus (MRSA). MRSA is generally a hospital-associated infection but recently community acquired MRSA has increased in the apparent absence of antibiotic selection. Thus there is a constant need to develop new control regimes for S. aureus, as this organism has begun to show resistance even to new antibiotics such as linezolid and no vaccine is available. To win this battle we must not only produce new treatments and preventative measures but also to understand the complexities of how S. aureus causes disease and thus how interventions can be best utilised, to reduce the disease burden and to minimise the development and spread of resistance to antibiotics. How do humans get infected with S. aureus? We have made the astonishing discovery that relatively harmless skin organisms and even their component cell walls are able to cause significant exacerbation of S. aureus infection, allowing disease to occur with a hugely reduced infectious dose. The most common route of human infection is via a wound and of course this will occur with whatever material gets in, including S. aureus. We have named the material that can augment S. aureus infection as "pro-infectious agents". We have opened a window on natural infection and in doing so provide novel avenues for trying to understand disease and how we may prevent it. The current application takes an interdisciplinary approach to understand how infection is initiated, the nature of material and organisms that can act as pro-infectious agents, how infection progresses and how such knowledge may be utilized to prevent and/or cure disease. Our background work and that proposed necessitates an integrated team led by a microbiologist and a clinician with research expertise in innate immunity. This combined expertise, coupled with important partners around the world, provides a proven network to underpin our ambitious proposal. Our work is underpinned by the use of animal models of infection, as this complex process cannot be recapitulated in vitro without understanding of what happens in vivo. We have uniquely developed the vertebrate zebrafish embryo as a model of S. aureus systemic disease. This provides a high-throughput, genetically tractable system where host:pathogen interaction can be observed in a living host. The importance of this model is that it has not only provided important insights into pathogenesis but has also informed our use of a mammalian system thus replacing many mouse experiments directly, reducing the numbers of mammals used and refining our approach. We will use a combination of animal models, together with in vitro analysis to determine the breadth of material that can augment S. aureus infection and the cellular and molecular mechanisms underlying this effect. Infection will then be mapped from initiation to endpoint in order to identify bottlenecks as sites for the development on novel intervention strategies. We will use a variety of approaches including state-of-the-art intravital microscopy in all models to determine the pathway of infection. The application provides an integrated package that will further our understanding of disease mechanisms and how this information may be used to inform clinical practice.

Overview

Grant agreement 027FCA23-6711-407E-A392-020B8329DDAB