Relish is pickled to protect flies from immunogenic havoc

A fruit fly (Drosophila melanogaster, male) photo: Max Westby (CC-BY-NC-SA)

Two proteins called Pickle and Relish help to keep fruit flies healthy, a new study shows.

Scientists at The Institute of Cancer Research, London, identified a protein called Pickle that helps to establish a balanced immune response, ensuring effective protection from invading pathogens while enabling beneficial interactions between the host and microbes in its environment.

In fruit flies, Pickle trains the immune response to tolerate some forms of bacteria while fighting others.

When the researchers silenced Pickle, they found that fruit flies showed greater short-term resistance to bacteria. But this came at a cost as chronic hyper-activation of the immune system led to shorter lifespans.

Although inflammation helps to repair damage and resolve toxic conditions, it is now clear that chronic inflammation is intimately linked with cancer, so understanding these processes better will help to improve treatment.

The study was published in the Journal Cell Host & Microbe and was funded by Cancer Research UK, Breast Cancer Now and the Biotechnology and Biological Sciences Research Council.

A similar immune system to humans

The immune system in fruit flies has many similarities to humans, and can help to understand the complex biological signals that occur when tissues respond to damage or infection.

Immune responses must be tightly controlled to react quickly to threats in the body, while avoiding damaging healthy cells by acting too aggressively.

In fruit flies, the protein Relish is a member of a family of transcription factors called NF-κB that regulate inflammation as part of the immune response, but how they are switched on and off in cells is not well understood.

ICR scientists used genetic screening techniques to find proteins that interact with Relish, and identified a new protein they called Pickle, which restrains Relish activity and prevents from signalling too much.

Pickle belongs to the IκB protein family, and they found that Pickle inhibits genes that are promoted by Relish, to help balance the flies’ immune response to infection.

In flies infected with bacteria, suppressing Pickle caused Relish-dependent genes to become overactive, leading to heightened resistance to pathogens.

But loss of Pickle also reduced the lifespan of fruit flies, compared with cells where both Pickle and Relish were present.

'Wounds that don't heal'

This may have been caused by the immune system attacking the microbe environment in the gut, causing damage and premature death.

Professor Pascal Meier, Leader of the Cell Death and Inflammation Team at the ICR, said: “Cancer has been described as wounds that don’t heal, and chronic and deregulated inflammation has been identified as one of the founding causes of the disease. A better understanding of the principles that regulate inflammation could be key to harnessing these processes to improve cancer treatment.

Our study provides physiological evidence that the immune system needs to be balanced to maintain healthy tissues. We found a protein called Pickle in fruit flies that is required to help prevent hyper-activation of the immune response, which can be detrimental to their overall health. In humans, hyper-activation of inflammatory signalling forms a hot-bed for cancer. ”