Toll-8/Tollo Negatively Regulates Antimicrobial Response in the Drosophila Respiratory Epithelium

Abstract

Barrier epithelia that are persistently exposed to microbes have evolved potent immune tools to eliminate such pathogens. If mechanisms that control Drosophila systemic responses are well-characterized, the epithelial immune responses remain poorly understood. Here, we performed a genetic dissection of the cascades activated during the immune response of the Drosophila airway epithelium i.e. trachea. We present evidence that bacteria induced-antimicrobial peptide (AMP) production in the trachea is controlled by two signalling cascades. AMP gene transcription is activated by the inducible IMD pathway that acts non-cell autonomously in trachea. This IMD-dependent AMP activation is antagonized by a constitutively active signalling module involving the receptor Toll-8/Tollo, the ligand Spätzle2/DNT1 and Ect-4, the Drosophila ortholog of the human Sterile alpha and HEAT/ARMadillo motif (SARM). Our data show that, in addition to Toll-1 whose function is essential during the systemic immune response, Drosophila relies on another Toll family member to control the immune response in the respiratory epithelium. Invertebrates solely rely on innate immune responses for defense against microbial infections. Taking advantage of its powerful genetics, the fly Drosophila melanogaster has been extensively used as a model system to dissect the molecular mechanisms that control innate immunity. This work led to the discovery of the essential role of the Toll-1 receptor in triggering the systemic immune response in flies, and paved the way for the discovery of the function of members of the Toll-like receptor (TLR) family in mammalian immunity. Whereas all TLRs are implicated in the mammalian immune response, Toll-1 was, so far, the only Drosophila Toll family member to be involved in the regulation of the immune response. In the present study, we show that another Toll family member, Toll-8 (Tollo), plays an important role in controlling the respiratory epithelium immune response. Our data indicate that, by antagonizing the IMD pathway, Tollo is preventing over-activation of the antibacterial response in the airway epithelium.