A Balancing Act: PGRPs Preserve and Protect.
Dziarski Roman,Gupta Dipika
Cell host & microbe
How does the immune system maintain a balance between preserving a beneficial microbiome and protecting against pathogens while also inducing effective, yet not damaging, responses? In this issue of Cell Host & Microbe, Charroux et al. (2018) reveal that, in Drosophila, this task is performed by three isoforms of PGRP-LB, a peptidoglycan-hydrolyzing amidase.
10.1016/j.chom.2018.01.010
The regulatory isoform rPGRP-LC induces immune resolution via endosomal degradation of receptors.
Neyen Claudine,Runchel Christopher,Schüpfer Fanny,Meier Pascal,Lemaitre Bruno
Nature immunology
The innate immune system needs to distinguish between harmful and innocuous stimuli to adapt its activation to the level of threat. How Drosophila mounts differential immune responses to dead and live Gram-negative bacteria using the single peptidoglycan receptor PGRP-LC is unknown. Here we describe rPGRP-LC, an alternative splice variant of PGRP-LC that selectively dampens immune response activation in response to dead bacteria. rPGRP-LC-deficient flies cannot resolve immune activation after Gram-negative infection and die prematurely. The alternative exon in the encoding gene, here called rPGRP-LC, encodes an adaptor module that targets rPGRP-LC to membrane microdomains and interacts with the negative regulator Pirk and the ubiquitin ligase DIAP2. We find that rPGRP-LC-mediated resolution of an efficient immune response requires degradation of activating and regulatory receptors via endosomal ESCRT sorting. We propose that rPGRP-LC selectively responds to peptidoglycans from dead bacteria to tailor the immune response to the level of threat.
10.1038/ni.3536
Requirement for a peptidoglycan recognition protein (PGRP) in Relish activation and antibacterial immune responses in Drosophila.
Choe Kwang-Min,Werner Thomas,Stöven Svenja,Hultmark Dan,Anderson Kathryn V
Science (New York, N.Y.)
Components of microbial cell walls are potent activators of innate immune responses in animals. For example, the mammalian TLR4 signaling pathway is activated by bacterial lipopolysaccharide and is required for resistance to infection by Gram-negative bacteria. Other components of microbial surfaces, such as peptidoglycan, are also potent activators of innate immune responses, but less is known about how those components activate host defense. Here we show that a peptidoglycan recognition protein, PGRP-LC, is absolutely required for the induction of antibacterial peptide genes in response to infection in Drosophila and acts by controlling activation of the NF-kappaB family transcription factor Relish.
10.1126/science.1070216
Negative regulation by amidase PGRPs shapes the Drosophila antibacterial response and protects the fly from innocuous infection.
Paredes Juan C,Welchman David P,Poidevin Mickaël,Lemaitre Bruno
Immunity
Peptidoglycan recognition proteins (PGRPs) are key regulators of insect immune responses. In addition to recognition PGRPs, which activate the Toll and Imd pathways, the Drosophila genome encodes six catalytic PGRPs with the capacity to scavenge peptidoglycan. We have performed a systematic analysis of catalytic PGRP function using deletions, separately and in combination. Our findings support the role of PGRP-LB as a negative regulator of the Imd pathway and brought to light a synergy of PGRP-SCs with PGRP-LB in the systemic response. Flies lacking all six catalytic PGRPs were still viable but exhibited deleterious immune responses to innocuous gut infections. Together with recent studies on mammalian PGRPs, our study uncovers a conserved role for PGRPs in gut homeostasis. Analysis of the immune phenotype of flies lacking all catalytic PGRPs and the Imd regulator Pirk reveals that the Imd-mediated immune response is highly constrained by the existence of multiple negative feedbacks.
10.1016/j.immuni.2011.09.018
The Drosophila Immune Deficiency Pathway Modulates Enteroendocrine Function and Host Metabolism.
Kamareddine Layla,Robins William P,Berkey Cristin D,Mekalanos John J,Watnick Paula I
Cell metabolism
Enteroendocrine cells (EEs) are interspersed between enterocytes and stem cells in the Drosophila intestinal epithelium. Like enterocytes, EEs express components of the immune deficiency (IMD) innate immune pathway, which activates transcription of genes encoding antimicrobial peptides. The discovery of large lipid droplets in intestines of IMD pathway mutants prompted us to investigate the role of the IMD pathway in the host metabolic response to its intestinal microbiota. Here we provide evidence that the short-chain fatty acid acetate is a microbial metabolic signal that activates signaling through the enteroendocrine IMD pathway in a PGRP-LC-dependent manner. This, in turn, increases transcription of the gene encoding the endocrine peptide Tachykinin (Tk), which is essential for timely larval development and optimal lipid metabolism and insulin signaling. Our findings suggest innate immune pathways not only provide the first line of defense against infection but also afford the intestinal microbiota control over host development and metabolism.
10.1016/j.cmet.2018.05.026
Cytosolic and Secreted Peptidoglycan-Degrading Enzymes in Drosophila Respectively Control Local and Systemic Immune Responses to Microbiota.
Charroux Bernard,Capo Florence,Kurz C Léopold,Peslier Sabine,Chaduli Delphine,Viallat-Lieutaud Annelise,Royet Julien
Cell host & microbe
Gut-associated bacteria produce metabolites that both have a local influence on the intestinal tract and act at a distance on remote organs. In Drosophila, bacteria-derived peptidoglycan (PGN) displays such a dual role. PGN triggers local antimicrobial peptide production by enterocytes; it also activates systemic immune responses in fat-body cells and modulates fly behavior by acting on neurons. How these responses to a single microbiota-derived compound are simultaneously coordinated is not understood. We show here that the PGRP-LB locus generates both cytosolic and secreted PGN-cleaving enzymes. Through genetic analysis, we demonstrate that the cytosolic PGRP-LB isoforms cell-autonomously control the intensity of NF-κB activation in enterocytes, whereas the secreted isoform prevents massive and detrimental gut-derived PGN dissemination throughout the organism. This study explains how Drosophila are able to uncouple the modulation of local versus systemic responses to a single gut-bacteria-derived product by using isoform-specific enzymes.
10.1016/j.chom.2017.12.007
Phase I/II trial of gene therapy with autologous tumor cells modified with tag7/PGRP-S gene in patients with disseminated solid tumors: miscellaneous tumors.
Moiseyenko V M,Danilov A O,Baldueva I A,Danilova A B,Tyukavina N V,Larin S S,Kiselev S L,Orlova R V,Anisimov V V,Semenova A I,Shchekina L A,Gafton G I,Kochnev V A,Barchuk A S,Kanaev S V,Hanson K P,Georgiev G P
Annals of oncology : official journal of the European Society for Medical Oncology
BACKGROUND:The use of genetically modified autologous tumor cells appears to be a promising approach for cancer therapy. A phase I/II trial was undertaken to define the feasibility, safety and antitumor effects of the autologous vaccine prepared by transferring tag7/PGRP-S gene into malignant melanoma and renal cell carcinoma cells. PATIENTS AND METHODS:Twenty-one patients (17 with disseminated malignant melanoma and four with metastatic renal cell carcinoma) were enrolled in this study. Cytoreduction was performed in all cases prior to therapy. Autologous tumor cells were transfected with the tag7/PGRP-S gene, irradiated and injected intradermally every 3 weeks. RESULTS:Vaccinations were well tolerated by all patients, without clinically significant signs of toxicity. Delayed-type hypersensitivity was observed in 48% of cases. Antitumor immune response was observed in 95% of patients. There were no complete or partial responses; however, a minor response was achieved in one patient with renal cell carcinoma. The stabilization of neoplastic disease was observed in eight patients (seven with malignant melanoma and one with renal cell carcinoma). Median time to tumor progression was 3 months. CONCLUSIONS:The approach suggested here appears to be well tolerated and produces a number of durable clinical effects. Further studies are required to determine whether promising effects on immune activation will result in an actual clinical benefit for patients with malignant melanoma and renal cell carcinoma.
10.1093/annonc/mdi028
PGRP-LB minds the fort.
Girardin Stephen E,Philpott Dana J
Immunity
Peptidoglycan recognition proteins (PGRPs) are a class of molecules that play a critical role in Drosophila immunity. In this issue of Immunity, Zaidman-Rémy et al. (2006) show that PGRP-LB controls systemic immune responses as well as homeostasis at the barrier surfaces.
10.1016/j.immuni.2006.04.001
Defect in neutrophil killing and increased susceptibility to infection with nonpathogenic gram-positive bacteria in peptidoglycan recognition protein-S (PGRP-S)-deficient mice.
Dziarski Roman,Platt Kenneth A,Gelius Eva,Steiner Håkan,Gupta Dipika
Blood
Insect peptidoglycan recognition protein-S (PGRP-S), a member of a family of innate immunity pattern recognition molecules conserved from insects to mammals, recognizes bacterial cell wall peptidoglycan and activates 2 antimicrobial defense systems, prophenoloxidase cascade and antimicrobial peptides through Toll receptor. We show that mouse PGRP-S is present in neutrophil tertiary granules and that PGRP-S-deficient (PGRP-S-/-) mice have increased susceptibility to intraperitoneal infection with gram-positive bacteria of low pathogenicity but not with more pathogenic gram-positive or gram-negative bacteria. PGRP-S-/- mice have normal inflammatory responses and production of tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6). Neutrophils from PGRP-S-/- mice have normal phagocytic uptake of bacteria but are defective in intracellular killing and digestion of relatively nonpathogenic gram-positive bacteria. Therefore, mammalian PGRP-S functions in intracellular killing of bacteria. Thus, only bacterial recognition by PGRP-S, but not its effector function, is conserved from insects to mammals.
10.1182/blood-2002-12-3853
Peptidoglycan-Sensing Receptors Trigger the Formation of Functional Amyloids of the Adaptor Protein Imd to Initiate Drosophila NF-κB Signaling.
Kleino Anni,Ramia Nancy F,Bozkurt Gunes,Shen Yanfang,Nailwal Himani,Huang Jing,Napetschnig Johanna,Gangloff Monique,Chan Francis Ka-Ming,Wu Hao,Li Jixi,Silverman Neal
Immunity
In the Drosophila immune response, bacterial derived diaminopimelic acid-type peptidoglycan binds the receptors PGRP-LC and PGRP-LE, which through interaction with the adaptor protein Imd leads to activation of the NF-κB homolog Relish and robust antimicrobial peptide gene expression. PGRP-LC, PGRP-LE, and Imd each contain a motif with some resemblance to the RIP Homotypic Interaction Motif (RHIM), a domain found in mammalian RIPK proteins forming functional amyloids during necroptosis. Here we found that despite sequence divergence, these Drosophila cryptic RHIMs formed amyloid fibrils in vitro and in cells. Amyloid formation was required for signaling downstream of Imd, and in contrast to the mammalian RHIMs, was not associated with cell death. Furthermore, amyloid formation constituted a regulatable step and could be inhibited by Pirk, an endogenous feedback regulator of this pathway. Thus, diverse sequence motifs are capable of forming amyloidal signaling platforms, and the formation of these platforms may present a regulatory point in multiple biological processes.
10.1016/j.immuni.2017.09.011
Function of the drosophila pattern-recognition receptor PGRP-SD in the detection of Gram-positive bacteria.
Bischoff Vincent,Vignal Cécile,Boneca Ivo G,Michel Tatiana,Hoffmann Jules A,Royet Julien
Nature immunology
The activation of an immune response requires recognition of microorganisms by host receptors. In drosophila, detection of Gram-positive bacteria is mediated by cooperation between the peptidoglycan-recognition protein-SA (PGRP-SA) and Gram-negative binding protein 1 (GNBP1) proteins. Here we show that some Gram-positive bacterial species activate an immune response in a PGRP-SA- and GNBP1-independent manner, indicating that alternative receptors exist. Consistent with this, we noted that PGRP-SD mutants were susceptible to some Gram-positive bacteria and that a loss-of-function mutation in PGRP-SD severely exacerbated the PGRP-SA and GNBP1 mutant phenotypes. These data indicate that PGRP-SD can function as a receptor for Gram-positive bacteria and shows partial redundancy with the PGRP-SA-GNBP1 complex.
10.1038/ni1123
The Drosophila amidase PGRP-LB modulates the immune response to bacterial infection.
Zaidman-Rémy Anna,Hervé Mireille,Poidevin Mickael,Pili-Floury Sébastien,Kim Min-Sung,Blanot Didier,Oh Byung-Ha,Ueda Ryu,Mengin-Lecreulx Dominique,Lemaitre Bruno
Immunity
The Drosophila host defense against gram-negative bacteria is mediated by the Imd pathway upon sensing of peptidoglycan by the peptidoglycan recognition protein (PGRP)-LC. Here we report a functional analysis of PGRP-LB, a catalytic member of the PGRP family. We show that PGRP-LB is a secreted protein regulated by the Imd pathway. Biochemical studies demonstrate that PGRP-LB is an amidase that specifically degrades gram-negative bacteria peptidoglycan. In agreement with its amidase activity, PGRP-LB downregulates the Imd pathway. Hence, activation of PGRP-LB by the Imd pathway provides a negative feedback regulation to tightly adjust immune activation to infection. Our study also reveals that PGRP-LB controls the immune reactivity of flies to the presence of ingested bacteria in the gut. Our work highlights the key role of PGRPs that encode both sensors and scavengers of peptidoglycan, which modulate the level of the host immune response to the presence of infectious microorganisms.
10.1016/j.immuni.2006.02.012
PGRP-LC and PGRP-LE have essential yet distinct functions in the drosophila immune response to monomeric DAP-type peptidoglycan.
Kaneko Takashi,Yano Tamaki,Aggarwal Kamna,Lim Jae-Hong,Ueda Kazunori,Oshima Yoshiteru,Peach Camilla,Erturk-Hasdemir Deniz,Goldman William E,Oh Byung-Ha,Kurata Shoichiro,Silverman Neal
Nature immunology
Drosophila rely entirely on an innate immune response to combat microbial infection. Diaminopimelic acid-containing peptidoglycan, produced by Gram-negative bacteria, is recognized by two receptors, PGRP-LC and PGRP-LE, and activates a homolog of transcription factor NF-kappaB through the Imd signaling pathway. Here we show that full-length PGRP-LE acted as an intracellular receptor for monomeric peptidoglycan, whereas a version of PGRP-LE containing only the PGRP domain functioned extracellularly, like the mammalian CD14 molecule, to enhance PGRP-LC-mediated peptidoglycan recognition on the cell surface. Interaction with the imd signaling protein was not required for PGRP-LC signaling. Instead, PGRP-LC and PGRP-LE signaled through a receptor-interacting protein homotypic interaction motif-like motif. These data demonstrate that like mammals, drosophila use both extracellular and intracellular receptors, which have conserved signaling mechanisms, for innate immune recognition.
10.1038/ni1356
PGRP-SC2 promotes gut immune homeostasis to limit commensal dysbiosis and extend lifespan.
Guo Linlin,Karpac Jason,Tran Susan L,Jasper Heinrich
Cell
Interactions between commensals and the host impact the metabolic and immune status of metazoans. Their deregulation is associated with age-related pathologies like chronic inflammation and cancer, especially in barrier epithelia. Maintaining a healthy commensal population by preserving innate immune homeostasis in such epithelia thus promises to promote health and longevity. Here, we show that, in the aging intestine of Drosophila, chronic activation of the transcription factor Foxo reduces expression of peptidoglycan recognition protein SC2 (PGRP-SC2), a negative regulator of IMD/Relish innate immune signaling, and homolog of the anti-inflammatory molecules PGLYRP1-4. This repression causes deregulation of Rel/NFkB activity, resulting in commensal dysbiosis, stem cell hyperproliferation, and epithelial dysplasia. Restoring PGRP-SC2 expression in enterocytes of the intestinal epithelium, in turn, prevents dysbiosis, promotes tissue homeostasis, and extends lifespan. Our results highlight the importance of commensal control for lifespan of metazoans and identify SC-class PGRPs as longevity-promoting factors.
10.1016/j.cell.2013.12.018
The Drosophila peptidoglycan recognition protein PGRP-LF blocks PGRP-LC and IMD/JNK pathway activation.
Maillet Frédéric,Bischoff Vincent,Vignal Cécile,Hoffmann Jules,Royet Julien
Cell host & microbe
Eukaryotic peptidoglycan recognition proteins (PGRPs) are related to bacterial amidases. In Drosophila, PGRPs bind peptidoglycan and function as central sensors and regulators of the innate immune response. PGRP-LC/PGRP-LE constitute the receptor complex in the immune deficiency (IMD) pathway, which is an innate immune cascade triggered upon Gram-negative bacterial infection. Here, we present the functional analysis of the nonamidase, membrane-associated PGRP-LF. We show that PGRP-LF acts as a specific negative regulator of the IMD pathway. Reduction of PGRP-LF levels, in the absence of infection, is sufficient to trigger IMD pathway activation. Furthermore, normal development is impaired in the absence of functional PGRP-LF, a phenotype mediated by the JNK pathway. Thus, PGRP-LF prevents constitutive activation of both the JNK and the IMD pathways. We propose a model in which PGRP-LF keeps the Drosophila IMD pathway silent by sequestering circulating peptidoglycan.
10.1016/j.chom.2008.04.002
The Innate Immune Receptor PGRP-LC Controls Presynaptic Homeostatic Plasticity.
Harris Nathan,Braiser Daniel J,Dickman Dion K,Fetter Richard D,Tong Amy,Davis Graeme W
Neuron
It is now appreciated that the brain is immunologically active. Highly conserved innate immune signaling responds to pathogen invasion and injury and promotes structural refinement of neural circuitry. However, it remains generally unknown whether innate immune signaling has a function during the day-to-day regulation of neural function in the absence of pathogens and irrespective of cellular damage or developmental change. Here we show that an innate immune receptor, a member of the peptidoglycan pattern recognition receptor family (PGRP-LC), is required for the induction and sustained expression of homeostatic synaptic plasticity. This receptor functions presynaptically, controlling the homeostatic modulation of the readily releasable pool of synaptic vesicles following inhibition of postsynaptic glutamate receptor function. Thus, PGRP-LC is a candidate receptor for retrograde, trans-synaptic signaling, a novel activity for innate immune signaling and the first known function of a PGRP-type receptor in the nervous system of any organism.
10.1016/j.neuron.2015.10.049
Peptidoglycan sensing by the receptor PGRP-LE in the Drosophila gut induces immune responses to infectious bacteria and tolerance to microbiota.
Bosco-Drayon Virginie,Poidevin Mickael,Boneca Ivo Gomperts,Narbonne-Reveau Karine,Royet Julien,Charroux Bernard
Cell host & microbe
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.
10.1016/j.chom.2012.06.002
PGRP-SD, an Extracellular Pattern-Recognition Receptor, Enhances Peptidoglycan-Mediated Activation of the Drosophila Imd Pathway.
Iatsenko Igor,Kondo Shu,Mengin-Lecreulx Dominique,Lemaitre Bruno
Immunity
Activation of the innate immune response in Metazoans is initiated through the recognition of microbes by host pattern-recognition receptors. In Drosophila, diaminopimelic acid (DAP)-containing peptidoglycan from Gram-negative bacteria is detected by the transmembrane receptor PGRP-LC and by the intracellular receptor PGRP-LE. Here, we show that PGRP-SD acted upstream of PGRP-LC as an extracellular receptor to enhance peptidoglycan-mediated activation of Imd signaling. Consistent with this, PGRP-SD mutants exhibited impaired activation of the Imd pathway and increased susceptibility to DAP-type bacteria. PGRP-SD enhanced the localization of peptidoglycans to the cell surface and hence promoted signaling. Moreover, PGRP-SD antagonized the action of PGRP-LB, an extracellular negative regulator, to fine-tune the intensity of the immune response. These data reveal that Drosophila PGRP-SD functions as an extracellular receptor similar to mammalian CD14 and demonstrate that, comparable to lipopolysaccharide sensing in mammals, Drosophila relies on both intra- and extracellular receptors for the detection of bacteria.
10.1016/j.immuni.2016.10.029