Transmembrane and Circulating Peptidoglycan Recognition Proteins are Involved in the Recognition of Bacteria

Peptidoglycan recognition proteins (PGRPs) are a highly conserved family of proteins. Proteins in the PGRP family have been classified into long (PGRP-L) or short (PGRP-S) forms. Both forms include membrane-bound and secreted proteins. (For a review of PGRP structure and activity, see Werner et al. 2000; Steiner 2004.) Both types recognize bacterial peptidoglycan (PGN) and contain a C-terminal domain that bears similarity to N-acetylmuramoyl-l-alanine amidases. It is believed that this amidase activity acts as a scavenger to degrade free PGN and limit an immune response (Mellroth et al. 2003). Several PGRPs have been identified as receptors in immune-responsive tissues. PGRP recognition of PGN leads to a cellular response of phagocytosis by hemocytes, or a humoral response, with the synthesis of antimicrobial peptides (AMPs) by the fat body.

One family member, PGRP-LC, was originally identified for its role in the humoral immune response. This receptor acts upstream of the Imd signaling pathway and triggers the production of AMPs such as diptericin in response to infection by Gram-negative bacteria (Choe et al. 2002; Gottar et al. 2002; Ramet et al. 2002; Kaneko et al. 2004). RNAi of PGRP-LC in S2 cells partially inhibits phagocytosis of E. coli, decreasing uptake by up to 40%. PGRP-LC mutants were also reported in this study to have an increased susceptibility to infection by E. coli, but not by S. aureus (Ramet et al. 2002). It is unclear if this is due to the phagocytic defect, as the PGRP-LC mutation also affects the humoral response. The PGRP-LC mutant, ird7, has been found to phagocytose both E. coli and S. aureus in vivo (Garver et al. 2006). One possible reason for the different findings in vitro and in vivo may be because of PGRP-LE. PGRP-LE appears to play a role both redundant and complementary to PGRP-LC in the recognition of Gram-negative peptidoglycan, and it is not expressed in hemocytes or S2 cells (Kaneko et al. 2006). Hence this may be the reason why a phagocytosis phenotype can be seen in S2 cells, but not in vivo.

Two short PGRP family members have also been implicated in the cellular immune response to Gram-positive bacteria. PGRP-SA (semmelweis) mutants exhibited a marked and specific decrease (~75% of animals showing no phagocytosis) in phagocytosis of S. aureus (Garver et al. 2006). Similarly, the PGRP-SC1a mutant picky is also specifically impaired in its ability to phagocytose S. aureus. Flies carrying the picky mutation failed to take up fluorescently-labeled S. aureus into their hemocytes and exhibited increased susceptibility to S. aureus infection. Furthermore, expression level of Drosomycin, the AMP target gene of the Toll pathway was virtually undetectable. PGRP-SA mutants showed similar humoral response impairments (Michel et al. 2001). This suggested that PGRP-SA and PGRP-SC1a are both important for Toll signaling and phagocytosis. The phagocytosis of S. aureus and survival to infection depended upon the amidase activity of PGRP-SC1a, suggesting that, in addition to a scavenger function, the amidase activity may be important for clearance of S. aureus and the ability to survive infection. The amidase activity may allow PGRP-SC1a to opsonize Gram-positive bacteria, or perhaps cleavage of PGN polymers into smaller units is necessary to trigger recognition of the bacteria (Garver et al. 2006). PGN monomers are effective activators of the humoral immune response (Kaneko et al. 2004), so PGN cleavage may be a prerequisite or play a role in activating the Toll and Imd signaling pathways (Filipe et al. 2005).

It is particularly interesting that these PGRPs are important for activity in both humoral and cellular immune responses and that these responses are specific to either Gram-positive or Gram-negative bacteria. These proteins may act in recognition events upstream of both phagocytosis and the AMP signaling pathways; alternatively, there may be an interdependence between these two branches of the innate immune system, with an optimal AMP response depending on a cellular immune response.

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