Assessing the relevance of Galleria mellonella to antibiotic drug discovery for pulmonary infections

Why did we fund this project?

This award aims to establish Galleria mellonella in bacterial and fungal lung infection studies in seven laboratories at King’s College London as a replacement for some mouse models.

Galleria mellonella larvae are increasingly being used as a replacement for mice in infection studies. To study bacterial lung infections, agar beads embedded with bacteria are surgically introduced to the respiratory tract of the mouse under general anaesthetic. Galleria larvae have a number of technical advantages over other invertebrate models and murine models including being able to be maintained at 37oC. This allows infections to be studied at the same temperature as in humans, an important factor for cellular interactions and temperature-sensitive protein production. The larvae do not have lungs but do possess an innate immune system, including phagocytic cells, which shares similarities with that of humans. This makes the larvae a potentially suitable model for research examining the immune response to lung infection.

Dr James Mason and colleagues at King’s College London will collaborate with BioSystems Technology - a company that provides research grade Galleria larvae, to test whether the larvae can be used in research at King’s that would typically involve the use of mice. The study will focus on optimising for infection with Pseudomonas aeruginosa, a key lung bacterial species. James and colleagues will disseminate their experiences and act as a hub for international researchers who want to take up Galleria in their own laboratories.

What has this project achieved?

James and colleagues have worked in collaboration with Science Animated to produce a video describing their project and the replacement potential of Galleria mellonella.  

As we are all increasingly aware, the world faces the renewed threat of bacterial infections due to the rise in cases where bacteria are resistant to the antibiotics that are normally used to treat such infections. Ongoing efforts to counter this threat are wide-ranging but two key elements are: 1) the discovery of new classes of antibiotic and; 2) the understanding how bacteria adapt to both antibiotics and antiseptics so that appropriate responses can be devised and enacted.

The Institute of Pharmaceutical Science at King's College London is a hub of research activity in these two areas. Together with the National Infection Service of Public Health England and other partners, we have identified four new classes of antibiotic that have the potential to be effective against the most troubling, antibiotic resistant bacteria currently causing infections in patients. We have also taken steps to understand how these same bacteria adapt to antiseptics that are used in hospitals. We have shown that this can happen, but not whether it does and have not yet discovered if bacterial adaptation to antiseptics makes the bacteria tougher or weaker.

The key steps in moving this research from bench to bedside is to have effective infection models so we can test if your antibiotics are likely to work in patients or know if infections are likely to be more or less severe if bacteria adapt to antiseptics. Normally this work would be done in mice and we have tried and tested models of bacterial lung infection which simulate the kind of infections patients might get e.g. when ventilated in hospital.

Data from these models is widely regarded as robust and relevant to both human and other mammalian infections (hence they also have application in veterinary science). However, these models are expensive, require highly trained staff and their use for screening many compounds/conditions is inappropriate. Consequently there is a bottleneck in both research areas and an ethical, cost effective and predictive alternative that can be used even by laboratories that do not specialise in animal studies is highly desired. Caterpillars of the greater wax moth have been used by some groups elsewhere to replace mice in models of bacterial infection. Although many people are much more comfortable with the use of caterpillars for research rather than mice or other animals, of course caterpillars do not have lungs and so there is a perception that this model may not be relevant to lung infections in humans (or pets or livestock). Nevertheless, some early tests with caterpillars looked promising and have generated some excitement that caterpillars are indeed an appropriate model that can reduce testing in mice. However a further problem has arisen: often the bacteria that are the biggest problem in lung infections were too toxic to the caterpillars and the infection model for these key bacteria was not really useful.

This project aims to break down these perceived and real barriers to adoption of the caterpillar infection model. We will use a special research grade of caterpillar provided by a new company spun-out from Exeter University which is expected to give more reliable results. While establishing this technology at King's we will adapt it for our purposes by modifying how we grow bacteria and also getting bacteria accustomed to living in the caterpillar host. When we have done this we will act as a hub to share our know-how with our partners and other researchers worldwide.

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Skills and Knowledge Transfer grant

Status:

Active

Principal investigator

Dr James Mason

Institution

King's College London

Grant reference number

NC/T001240/1

Award date:

Jul 2019 - Jan 2020

Grant amount

£74,976