Why did we fund this project?
This award aims to determine if wax moths (Galleria mellonella) are susceptible to insect-borne viruses and whether the larvae could replace mammalian species used for modelling viral pathogenesis.
Galleria mellonella larvae are used as an infection model for bacterial and fungal pathogens but there are currently no publications reporting the use of Galleria as a model for viral infections. Viruses can only infect specific species (or hosts) so researchers use a range of mammalian species such as mice, rabbits and non-human primates dependent on the natural host of the virus. However, some viruses that infect humans replicate in insect vectors and Galleria may also be susceptible to these infections. Galleria provide a number of scientific, technical and ethical advantages over the use of other invertebrates, cell lines or murine models. The Galleria immune system contains hemocytes which, similarly to macrophages in humans, can engulf pathogens. This is an important infection stage to model in humans as it can be an indicator of the outcome of infection and cannot currently be modelled using in vitro methods. Galleria can also be infected and incubated at 37oC allowing infections to be studied at the same temperature as in humans, which is important for cellular kinetics and temperature-sensitive protein production.
Professor Richard Titball and colleagues have preliminary data showing Galleria are susceptible to Venezuelan Equine Encephalomyelitis (VEE), which causes disease in the larvae. This project will expand the pilot study by investigating the morbidity and mortality of related viral pathogens such as Western Equine Encephalomyelitis Virus, Eastern Equine Encephalomyelitis Virus, Semliki Forest Virus and Sindbis Virus.
This project grant was awarded under the 2019 highlight notice.
(Galleria mellonella) waxmoth larvae are now being used by laboratories to study diseases caused by fungal and bacterial pathogens. It has been one of the great success stories of the initiatives to replace experiments with mammals with alternative and more ethical alternatives. Last year there were 231 publications using this model, compared to 194 publications and 2017 and 141 publications in 2016.
The waxmoth larvae model is now used to study the ways in which fungi and bacteria cause disease and to test new ways of treating the diseases with drugs. There are several reasons why waxmoth larvae have become so widely used. First, they have an immune system, which resembles parts of the mammalian immune system, so they mimic the disease process much more effectively than, for example, cell culture models. Second, unlike many invertebrates they can be kept at 37°C. Finally, they are large enough to be handled easily and to be injected with exact doses of the microorganism and drugs.
However, waxmoth larvae have not yet been reported to be of value for the study of diseases caused by viruses. In part, this reflects the knowledge that viruses are very host specific. But we are also aware that some viruses can infect both insects and mammals. For example, many viruses are spread by mosquitos and ticks and cause disease in human and other mammals. Moreover, there is evidence that when these viruses infect insects they can have detrimental effects. For these viruses it may be feasible to use insects to study the infections.
In this short and focused project we will carry out a study to investigate whether a range of insect-borne viruses can cause disease in waxmoth larvae. We have already carried out a pilot study indicating that a virus called Venezuelan Equine Encephalomyelitis (VEE) virus causes disease in waxmoth larvae. We will extend our pilot study with VEE virus and also test whether related viruses can cause disease in waxmoth larvae. This would then open up opportunities to use this model to replace experiments with mammals.
If successful, we estimate that 50% of experiments using mammals could be replaced with studies using G. mellonella larvae. In addition, by carrying out preliminary studies in waxmoth larvae the design of any subsequent studies in mammals would be refined and the value of these experiments improved. Our work will stimulate other researchers to investigate whether other viruses are able to cause disease in waxmoth larvae allowing for further application of the model and a further reduction of animal use in the study of viruses.