Galleria mellonella as an infection model for viral pathogens

Lead Research Organisation: University of Exeter
Department Name: Biosciences

Abstract

(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 37oC. 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 focussed 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.

Technical Summary

Galleria mellonella have been used as an infection model for bacterial pathogens of humans since the 1980's. The model is now being used widely for research into bacterial and fungal infections and for antibacterial and antifungal drug screening. G. mellonella possess an innate immune system comprising cellular and humoral responses. The cellular response involves the production and mobilisation of hemocytes. Hemocytes share structural and functional similarity with mammalian phagocytic cells. Since the initial interaction with phagocytes often determines the outcome of infection, the galleria model provides information beyond that which could be obtained using cell cultures.

Mammalian infection models are frequently used to study viral disease, and to evaluate therapeutics. We will work with viruses which are insect-vectored. These viruses can replicate in the insect vector species, and there are reports of pathology and morbidity in infected insects. These findings have led to the suggestion by Shah et al., (Cell, 175, 1931-1945. 2018) that the "advantage of focusing on interactions conserved across viruses and hosts is that these interactions could serve as a starting point for broad-spectrum antiviral development with limited risk of viral resistance".

In this 12 month project we will build on our preliminary data showing that G. mellonella larvae are susceptible to Venezuelan Equine Encephalomyelitis (VEE) virus infection. We will evaluate whether this infection model shows morbidity or mortality in response to challenge with related viral pathogens (Western Equine Encephalomyelitis Virus, Eastern Equine Encephalomyelitis Virus, Semliki Forest Virus and Sindbis Virus). Our work will open new opportunities by providing a non-mammalian model for studying viral disease and for antiviral drug screening. This would allow a reduction in the number of studies involving regulated vertebrate models by replacing them with alternative insect infection models.

Publications

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