Study Title:

Snacking Interferes with Immunity

Study Abstract

The innate immune system represents an ancient host defence mechanism that protects against invading microorganisms. An important class of immune effector molecules to fight pathogen infections are antimicrobial peptides (AMPs) that are produced in plants and animals1. In Drosophila, the induction of AMPs in response to infection is regulated through the activation of the evolutionarily conserved Toll and immune deficiency (IMD) pathways2. Here we show that AMP activation can be achieved independently of these immunoregulatory pathways by the transcription factor FOXO, a key regulator of stress resistance, metabolism and ageing. In non-infected animals, AMP genes are activated in response to nuclear FOXO activity when induced by starvation, using insulin signalling mutants, or by applying small molecule inhibitors. AMP induction is lost in foxo null mutants but enhanced when FOXO is overexpressed. Expression of AMP genes in response to FOXO activity can also be triggered in animals unable to respond to immune challenges due to defects in both the Toll and IMD pathways. Molecular experiments at the Drosomycin promoter indicate that FOXO directly binds to its regulatory region, thereby inducing its transcription. In vivo studies in Drosophila, but also studies in human lung, gut, kidney and skin cells indicate that a FOXO-dependent regulation of AMPs is evolutionarily conserved. Our results indicate a new mechanism of cross-regulation of metabolism and innate immunity by which AMP genes can be activated under normal physiological conditions in response to the oscillating energy status of cells and tissues. This regulation seems to be independent of the pathogen-responsive innate immunity pathways whose activation is often associated with tissue damage and repair. The sparse production of AMPs in epithelial tissues in response to FOXO may help modulating the defence reaction without harming the host tissues, in particular when animals are suffering from energy shortage or stress.

From press release:

Bonn researchers have discovered an elementary mechanism which regulates vital immune functions in healthy people. In situations of hunger which mean stress for the body's cells, the body releases more antimicrobial peptides in order to protect itself. The scientists will publish their results in the journal Nature.

T cells, B cells, antibodies are known as the 'SWAT team' of our immune system that intervenes when viruses and bacteria make us ill. With 'heavy molecular artillery' they wipe out intruders effectively. However, at the same time the defence systems cause collateral damage in the body's own tissue, which has to be repaired first.

In order for the immune system not to be consistently in a state of red alert and possibly cause chronic inflammation this way, there is a second defence system switched in series between body and outside world. This is absolutely necessary because on the barrier tissue such as lungs and skin there are trillions of bacteria. The majority of these microorganisms have been living with our body's cells as good neighbours for millions of years. There's more to come: the complex symbiosis of very different microorganisms supplies us with important natural substances such as vitamin B12.

Good germs, bad germs

At the same time there are always a few mischief-makers among the numerous peaceful bacteria which can make us sick. In this situation, even before the pathogenic germs invade our body, a mechanism is set in motion which acts completely independently of the classic immune defence systems. The biomedical researchers from the LIMES Institute at the University of Bonn have been able to show in fruit flies but also in human tissue that this natural immune defence system is linked directly to the metabolic status via the insulin signalling pathway.

If we have not eaten for a while or have to climb many stairs, the energy level of our cells drops and with it the level of insulin. The researchers from Bonn have now discovered that in the case of a low insulin level the FOXO transcription factor is activated. A transcription factor can switch genes on and off. FOXO switches genes for immune defence proteins on when energy is needed. These antimicrobial peptides (AMP) -- not to be confused with antibodies -- are subsequently jettisoned by the body's cells. They destroy possible pathogens by dissolving their cell walls.

'This happens every minute every day,' the director of studies Prof. Michael Hoch from the LIMES Institute explains. 'What is fascinating about this is that a function of the immune system directly depends on how much and what we eat.' In situations of hunger which mean stress for the body cells, the body releases antimicrobial peptides as a precaution in order to protect itself. 'The barrier between body and outside world is apparently fortified in a potentially dangerous situation in which we have too little energy,' Professor Hoch presumes.

Ancient defence mechanism helps us to get old?

FOXO and the antimicrobial peptide genes which it switches on occur in almost all groups of animals. That is why the researchers believe that the direct link between the food supply and the immunological defence probably developed during the early stage of evolution of metazoan organisms.

The research of the Bonn biologists could also be clinically relevant. For a number of common diseases such as type II diabetes or obesity (adiposity) are the result of an increased intake of calories. Furthermore, such diseases are accompanied by increased inflammation of the barrier tissue, a disturbed immune system and an overall reduced life span. 'Our results present new starting points for understanding of these diseases,' Professor Joachim Schultze from the LIMES Institute, who also is involved in the research project, says.

The scientists at LIMES will concentrate next on the relationship between calorie intake and life span. Examinations of nematodes, fruit flies and mice have shown that a reduced calorie intake can increase life span. Professor Hoch says: 'We now want to find out whether this is due to an foxo-dependent improvement of the barrier functions of the natural immune system.'

From press release:

Study Information

Thomas Becker, Gerrit Loch, Marc Beyer, Ingo Zinke, Anna C. Aschenbrenner, Pilar Carrera, Therese Inhester, Joachim L. Schultze & Michael Hoch.
FOXO-dependent regulation of innate immune homeostasis.
2010 January
Development, Genetics & Molecular Physiology Unit and .Molecular Immune & Cell Biology Unit, LIMES Institute, University of Bonn, Carl-Troll-Strasse 31, D-53115 Bonn, Germany.

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