Refining the mouse model of footpad immunisation and infection

Research into understanding the immune response to vaccination and infectious disease often necessitates the use of animal models due to the complexity of the cellular interactions involved. Often, researchers have used the mouse rear footpad as a convenient site of immunisation or infection because this site is readily accessible for measuring inflammation and because the physiology of the site has been well-characterised. However, mice are predominantly weight-bearing in their rear feet and swelling in the footpad can be associated with lameness and discomfort. We plan to test whether injecting mice on the top of the rear foot represents a simple, scientifically-valid REFINEMENT to such animal tests. We will first characterise whether the induction of immune responses differ between these two sites before testing the potential of this site for parasite infection. Importantly, we will quantify the impact of this refinement by measuring any reduction in animal lameness and pain throughout infection. Together, these data will allow us to quantify any improvement in animal welfare, as well as to provide scientific validation for using this alternative model of infection.

Our aim is to REFINE the 'traditional' model of footpad immunisation and infection in order to improve animal welfare. We will use a combination of immunological and cutting-edge imaging methods to define the key parameters associated with the administration of antigens, cells or parasites in the dorsal aspect to the foot, comparing it to the established footpad model. We will also assess development of Leishmania infection at this alternative site to establish whether parasite growth and ease of monitoring lesion development are comparable. Critically, we will use a combination of methods to assess any improvement in animal welfare in order to determine whether our proposal truly represents a refinement to currently used methods.

With an overall aim to refine the mouse model of immunisation and infection, we anticipate several areas of potential impact for the proposed project:

Impact on the 3Rs:
By developing and validating a simple approach to minimise animal suffering and distress, we anticipate a significant impact on the use of animals for such studies, both within the PI's research group, across the University of Strathclyde and in the wider scientific community.

The proposed impact on the 3Rs will be quantified by gait analysis and application of the 'mouse grimace scale' at various stages of Leishmania infection or following immunisation. The success of this impact will be determined by analysis of annual reports to the Home Office for the relevant project licence and potentially a reduction in severity rating.

By sharing our methodology (as well as its impact on 3Rs) as outlined in the Communication Plan, we will seek to ensure that similar approaches are adopted in the laboratories of collaborators, as well as in other immunology and parasitology research groups in the UK. Additionally, by offering training for attendees at the Integrative Mammalian Biology summer school and other researchers working in the fields of imaging, modeling, immunology or parasitology, we will aim to disseminate the impact of our cutting-edge imaging approaches on the 3Rs.

Scientific impact:
We envisage that the results of experiments outlined in the Case for Support will also provide impact in further understanding the interaction between the site of Leishmania infection and the draining lymph node. We will seek to achieve this impact by sharing our findings through publication and presentations at local, national and international meetings (as outlined in the Communications Plan), as well as through engagement with networks such as the British Society for Immunology and the British Society of Parasitology - in both of which the PI plays an active role.

Economic impact:
This project seeks to refine a technique commonly used in in vivo pharmaceutical, toxicological and vaccine studies. Whilst the alternative site of injection may not have economic value itself, any improvement in animal welfare would have provide impact in terms of more reliable data derived from such studies.
This project is also expected to contribute to new knowledge of inflammation and parasitology, providing potential for therapeutic development in the future. The Research and Knowledge Exchange Services (RKES) and the Knowledge Exchange Hub at the University of Strathclyde have significant experience in sourcing funding for technology transfer and for the establishment of commercial spin-outs, involving both the Research Councils and the Scottish Government.

Societal impact:
The proposed project has the potential to generate impact through public engagement both through the 3Rs (and associated debate surrounding animal research) as well as the generation of outstanding scientific data and imagery. As outlined in the Communications plan, the team in the Centre for Biophotonics are actively involved in a number of Outreach activities including with schools, the Glasgow Science Centre, popular media and with artists. We will therefore seek to use these outcomes to continue to engage with the public, working with the MUSE initiative within the University of Strathclyde as well as external partners at the Centre for Contemporary Arts and the Glasgow School of Art.