Peptidoglycan Sensing by the Receptor PGRP-LE in the Drosophila Gut Induces Immune Responses to Infectious Bacteria and Tolerance to Microbiota

Abstract

Gut epithelial cells contact both commensal and pathogenic bacteria, and proper responses to these bacteria require a balance of positive and negative regulatory signals. In the Drosophila intestine, peptidoglycan-recognition proteins (PGRPs), including PGRP-LE, play central roles in bacterial recognition and activation of immune responses, including induction of the IMD-NF-κB pathway. We show that bacteria recognition is regionalized in the Drosophila gut with various functional regions requiring different PGRPs. Specifically, peptidoglycan recognition by PGRP-LE in the gut induces NF-κB-dependent responses to infectious bacteria but also immune tolerance to microbiota through upregulation of pirk and PGRP-LB, which negatively regulate IMD pathway activation. Loss of PGRP-LE-mediated detection of bacteria in the gut results in systemic immune activation, which can be rescued by overexpressing PGRP-LB in the gut. Together these data indicate that PGRP-LE functions as a master gut bacterial sensor that induces balanced responses to infectious bacteria and tolerance to microbiota.

Friend, foe or food? Recognition and the role of antimicrobial peptides in gut immunity and Drosophila –microbe interactions

“…As in the systemic response, both the transmembrane receptor PGRP-LC and intracellular PGRP-LE recognize peptidoglycan in the gut and induce the Imd pathway cascade [31,32]. However, whereas both receptors are associated with fat body cells in the haemocoel, in the gut the activity of these receptors is regionalized, with PGRP-LC being localized to the fore-and hindgut, while PGRP-LE is restricted to the midgut [32].…”

“…The Imd pathway, which is similar to the mammalian TNF and TIR-domaindependent TLR pathway, recognizes diaminopimelic acid (DAP)-type peptidoglycan found in Gram-negative bacteria and Gram-positive Bacilli, as well as peptidoglycan monomers (also referred to as TCT, for tracheal cytotoxin) of Gram-negative bacteria. The surface-bound receptor PGRP-LC and cytosolic receptor PGRP-LE are the main Imd receptors in the fat body and, as described in more detail below, are also found in the gut [29][30][31][32][33].…”

“…AMPs are most highly expressed in the anterior midgut [67,89,90], where they are thought to reduce or eliminate potential pathogens ingested with the food. The gut also employs several negative regulators that downregulate Imd pathway activity, which are expressed in the posterior midgut and proposed to reduce the expression of AMPs in this region to support the persistence and colonization of the microbiota [28,31,35] (figure 1c). Though initially explored in the context of infection, where they adjust the level of immune activation to severity of infection, negative regulators also dampen the host response to gut microbiota and dietary microbes [31,74,91,92].…”

The Drosophila Imd Signaling Pathway

“…There are two parallel systems in Drosophila that control this host-microbe homeostasis: the DUOX pathway(s) (106) and the Imd pathway. The Imd pathway is activated upon PGN binding by PGRP-LC and, specifically in the gut, by PGRP-LE (41,107). Evidently, mechanisms for controlling the immune response play a major role in maintaining homeostasis.…”

Exploring host–microbiota interactions in animal models and humans

“…In flies, the recognition of peptidoglycan occurs through peptidoglycan recognition proteins (PGRPs), which can induce either the Toll or immune deficiency (IMD) pathways, leading to release of antimicrobial peptides (AMPs) and reactive oxygen species (ROS) Ha et al 2005), However it is vital that flies have the capacity to negatively regulate this immune response because of the endogenous microbes they harbor (Zaidman-Ré my et al 2006;Ryu et al 2008;Paredes et al 2011). While some members of the PGRP family can initiate an immune response, other members of this family can act as negative regulators of the IMD pathway (Zaidman-Ré my et al 2006;Lhocine et al 2008;Paredes et al 2011;Bosco-Drayon et al 2012). Mutation of PGRPs such as PGRP-LB, the PGRP-SC family, or the interacting partner PIMS (PGRP-LC-interacting inhibitor of Imd signaling) results in aberrantly high levels of AMPs in the presence of their resident microbiota and higher fly mortality when colonized by relatively innocuous Gram-negative bacteria (Lhocine et al 2008;Paredes et al 2011).…”