Fruit-fly offers new roads into studying fungal infections

Recent work from Dr Petros Ligoxygakis, a lecturer in the department, and colleagues in Aberdeen and Brighton has shown that the fruit-fly Drosophila melanogaster can provide insight into what happens when people become infected with opportunistic fungal pathogens like Candida albicans.

The model could offer a promising new approach to the identification of anti-fungal drug candidates.

Candida lives amongst the normal gut flora of many organisms without causing any disease.But if the host defence mechanisms become impaired, the fungus can spread into the blood and cause life-threatening systemic infection. Candida infection is a serious problem in hospitals, where susceptible patients include those who are immunocompromised or who have undergone major surgery.

Mice are currently the best model for studying how host and pathogen interact during Candida infection, but they are far from ideal – they are expensive to keep and large numbers are needed to derive statistically significant data. So Dr Ligoxygakis turned to the fruit-fly instead.

The gut from a Drosophila larva stained to show dead cells with fragmented DNA (larger green stains), cells with intact DNA (blue) and Candida (small green speckles)

The gut from a Drosophila larva stained to show dead cells with fragmented DNA (larger green stains), cells with intact DNA (blue) and Candida (small green speckles) (Click to enlarge)

To determine how useful a model Drosophila might be, a systematic study of how it responds to infection was needed.

Dr Ligoxygakis and colleagues first obtained a collection of clinically-isolated Candida strains whose virulence had been tested in mice, infected flies with these strains and followed their survival. They found that the virulence ranking correlated strongly with that in mice, indicating a similar host-pathogen interaction.

The next step was to see how Drosophila responded when challenged with Candida infection in the gut. The group established infection in Drosophila larvae by providing Candida-spiked food and monitored what happened to the infected cells, larvae survival and development to adults.

They observed that, as in humans and mice, the infection triggered excessive cell death in the gut and provoked a systemic immune response. From there, they were able to identify both host and pathogen factors which contributed to this.

The beauty of the Drosophila model is that it provides a simple and cheap way of studying an important aspect of infection - the host and pathogen factors affecting systemic response and pathogenesis.

'It's a nice system,' says Dr Ligoxygakis. 'It's the first time that you can start dissecting the pathways inside the pathogen that cause the systemic activation. It's much better than using mice if you have lots of Candida mutants to screen.'

Using the Drosophila model, it is possible to screen hundreds of Candida mutants at a time. Genes identified as being important for growth inside the host and for activation of systemic immunity are particularly interesting because they could potentially be targets for drug development.

'We could use this as a blueprint for studying other pathogens – emerging fungal infections that are most prominent in hospitals'

Some themes are already emerging from Dr Ligoxygakis' work in this area, such as mutants that cannot construct a normal cell wall and those defective in the movement of copper and iron, suggesting potentially interesting pathways to focus on.

He hopes that the model will identify pathogen-specific genes which could provide a pipeline of promising targets to test subsequently in mice.

To get a handle on the host factors involved, Dr Ligoxygakis is using a library of mutant Drosophila strains to screen for genes that affect susceptibility or tolerance to infection.

'We are screening the component of the Drosophila genome that has homology with human,' he explains. 'We've found a lot of host genes including those that have no assigned function either in Drosophila or humans but which we know are up-regulated in blood cells.' Since blood cells are involved in the innate immune system's fight against infection, these genes could be interesting ones to look at.

Looking beyond Candida, Dr Ligoxygakis believes that the model could have wider importance. 'We could use this as a blueprint for studying other pathogens – emerging fungal infections that are most prominent in hospitals.'

The two papers from the group have been published in a new journal from the Company of Biologists called Disease Models and Mechanisms (http://dmm.biologists.org). Open access from 2011, DMM has already proven to be the forum for researchers working on animal models of human disease.

References

  1. Glittenberg MT, Silas S, Maccallum DM, Gow NA, Ligoxygakis P (2011) Wild-type Drosophila melanogaster as an alternative model system for investigating the pathogenicity of Candida albicans. Dis Model Mech doi: 10.1242/dmm.006619
  2. Glittenberg M, Kounatidis I, Christensen D, Kostov M, Kimber S, Roberts I, Ligoxygakis P (2011) Pathogen and host factors are needed to provoke a host response to gastrointestinal infection of Drosophila larvae by Candida albicans. Dis Model & Mech doi: 10.1242/dmm.006627





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