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

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.

Zebrafish peptidoglycan recognition protein SC (zfPGRP-SC) mediates multiple intracellular signaling pathways

“…The report of Liu et al [12] showed that mouse PGRP-S inhibited phagocytosis and the oxidative burst in leukocytes, and inhibited cytokine induction in macrophages. The suppression of NF-kB activity by zfPGRP-SC in the present study may suggest that zfPGRP-SC has a negative regulatory function in the immune response, which is supported by the report of Liu et al [12] and Bischoff et al [41].…”

Bacterial strategies to overcome insect defences

“…A central role in gut tolerance to bacteria has been attributed to amidase PGRPs (PGRP-LB and PGRP-SC) as they abrogate the immunostimulatory activity of peptidoglycan fragments that are released by commensals 46,47 . It is also interesting to note the existence of specialization in the gut epithelium as only parts of the epithelium are immunoreactive, whereas bacteria are present throughout the midgut after infection 18,30,31 .…”

“…It is interesting to note that high titres of ingested Gram-negative bacteria, such as E. coli or E. c. carotovora 15 evf mutants, do not induce systemic AMP production, even though they are present in large numbers in the gut several hours after ingestion 36,37 . once again, this may be due to the presence of another type of PGRP with amidase activity that establishes a tolerance threshold level of bacteria in the gut by reducing the amount of active peptidoglycan fragments 46,47 . The absence of systemic AMP production despite a high level of non-infectious bacteria at early time points after ingestion indicates that the triggering of this systemic response by infectious bacteria such as E. c. carotovora 15 or P. entomophila either requires bacterial persistence and de novo synthesized peptidoglycan compounds, or depends on the detection of peptidoglycan molecules in a specific compartment of the gut.…”

“…It has been proposed that the systemic immune response that is induced during gut infection is mediated by the translocation of peptidoglycan fragments from the gut lumen to the haemolymph 46,47 .…”

Molecular and functional characterization of peptidoglycan-recognition protein SC2 (PGRP-SC2) from Nile tilapia (Oreochromis niloticus) involved in the immune response to Streptococcus agalactiae

“…PGLYRP-2 is homologous to mammal PGLYRP-2, while PGLYRP-5 and PGLYRP-6 are only found in teleost. However, the PGRP homolog of the SC2 type (PGRP-SC2), which was firstly discovered in fruit fly and proved to play an important role in regulation of innate immune response [23,24], has been reported only in tongue sole (Cynoglossus semilaevis) [25], and the study of fish PGRP-SC2 expression profiles and functional properties is rather limited.…”