Background: Airway epithelial cells not only constitute a physical barrier, but also the first line of defence against airborne pathogens. At the same time, they are constantly exposed to reactive oxygen species. Therefore, airway epithelia cells have to possess a sophisticated innate immune system and a molecular armamentarium to detoxify reactive oxygen species. It has become apparent that deregulation of epithelial innate immunity is a major reason for the development of chronic inflammatory lung diseases. To elucidate the molecular architecture of the innate immune system of airway epithelial cells, we choose the fruit fly Drosophila melanogaster as a model, because it has the simplest type of airways, consisting of epithelial cells only. Elucidating the structure of the innate immune system of this "airway epithelial cell culture" might enable us to understand why deregulatory processes in innate immune signalling cascades lead to long lasting inflammatory events.

The intestinal immune system is tailored to fight pathogens effectively while tolerating the indigenous microbiota. Impairments of this homeostatic interaction may contribute to the etiology of various diseases including inflammatory bowel diseases. However, the molecular architecture underlying this complex regulatory interaction is not well understood. Here, we show that the fruit fly Drosophila melanogaster has a multilayered intestinal immune system that ensures strictly localized antimicrobial responses. Enterocytes, a major cell population of the intestine, produced antimicrobial peptides (AMPs) in a FoxO- but not NF-κB-dependent manner. Consequently, animals impaired in FoxO-mediated signaling had a significantly lowered resistance to intestinal infections; they were unable to increase the expression of AMP genes and males showed an increased bacterial load in response to an infection. Conventional innate immune signaling converging onto NF-κB activation was operative in only a few regions of the intestine, comprising the proventriculus, copper cells, and intestinal stem cells. Taken together, our results imply that danger-mediated as well as conventional innate immune signaling constitute modules that contribute to the fruit fly's intestinal immune system. We propose that this special architecture ensures localized and efficient antimicrobial responses against invasive pathogens while preserving the microbiota.

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