Downregulation of the Drosophila Immune Response by Peptidoglycan-Recognition Proteins SC1 and SC2

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Abstract
Peptidoglycan-recognition proteins (PGRPs) are evolutionarily conserved molecules that are structurally related to bacterial amidases. Several Drosophila PGRPs have lost this enzymatic activity and serve as microbe sensors through peptidoglycan recognition. Other PGRP family members, such as Drosophila PGRP-SC1 or mammalian PGRP-L, have conserved the amidase function and are able to cleave peptidoglycan in vitro. However, the contribution of these amidase PGRPs to host defense in vivo has remained elusive so far. Using an RNA-interference approach, we addressed the function of two PGRPs with amidase activity in the Drosophila immune response. We observed that PGRP-SC1/2–depleted flies present a specific over-activation of the IMD (immune deficiency) signaling pathway after bacterial challenge. Our data suggest that these proteins act in the larval gut to prevent activation of this pathway following bacterial ingestion. We further show that a strict control of IMD-pathway activation is essential to prevent bacteria-induced developmental defects and larval death. It has long been known that the mammalian immune response needs to be kept under tight control. Responses that are delayed or of insufficient vigor can lead to a failure to control infection. However, excessive or inappropriate inflammation can be harmful or event fatal. Using the fruit fly as a model, evidence is presented that such an immuno-modulation is also essential in invertebrates and is mediated by peptidoglycan-recognition proteins (PGRPs). PGRPs are evolutionarily conserved molecules derived from enzymes that cleave bacterial peptidoglycan. It has been shown previously that some PGRPs have lost this enzymatic activity and function as sensors of bacteria upstream of the Drosophila immune pathways. The contribution of PGRPs which have maintained enzymatic activity to host defense has remained elusive so far. Here, the authors investigate in vivo data on the role of Drosophila PGRPs with enzymatic activity. Their results suggest that these proteins are required in the larval gut to negatively regulate the immune response, thus preventing bacterially induced developmental defects and death.