Publications by authors named "Ivo Gomperts Boneca"

35 Publications

LpxT-Dependent Phosphorylation of Lipid A in Increases Resistance to Deoxycholate and Enhances Gut Colonization.

Front Microbiol 2021 4;12:676596. Epub 2021 May 4.

Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), Gif-sur-Yvette, France.

The cell surface of Gram-negative bacteria usually exhibits a net negative charge mostly conferred by lipopolysaccharides (LPS). This property sensitizes bacterial cells to cationic antimicrobial peptides, such as polymyxin B, by favoring their binding to the cell surface. Gram-negative bacteria can modify their surface to counteract these compounds such as the decoration of their LPS by positively charged groups. For example, in and , EptA and ArnT add amine-containing groups to the lipid A moiety. In contrast, LpxT enhances the net negative charge by catalyzing the synthesis of tri-phosphorylated lipid A, whose function is yet unknown. Here, we report that has the intrinsic ability to resist polymyxin B upon the simultaneous activation of the two component regulatory systems PhoPQ and PmrAB by intricate environmental cues. Among many LPS modifications, only EptA- and ArnT-dependent decorations were required for polymyxin B resistance. Conversely, the acquisition of polymyxin B resistance compromised the innate resistance of to deoxycholate, a major component of bile. The inhibition of LpxT by PmrR, under PmrAB-inducing conditions, specifically accounted for the acquired susceptibility to deoxycholate. We also report that the kinetics of intestinal colonization by the mutant was impaired as compared to wild-type in a mouse model of infection and that was upregulated at the temperature of the host. Together, these findings highlight an important function of LpxT and suggest that a tight equilibrium between EptA- and LpxT-dependent decorations, which occur at the same position of lipid A, is critical for the life style of .
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http://dx.doi.org/10.3389/fmicb.2021.676596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129183PMC
May 2021

Multifaceted modes of action of the anticancer probiotic Enterococcus hirae.

Cell Death Differ 2021 May 11. Epub 2021 May 11.

Gustave Roussy Cancer Campus (GRCC), Villejuif, France.

A deviated repertoire of the gut microbiome predicts resistance to cancer immunotherapy. Enterococcus hirae compensated cancer-associated dysbiosis in various tumor models. However, the mechanisms by which E. hirae restored the efficacy of cyclophosphamide administered with concomitant antibiotics remain ill defined. Here, we analyzed the multifaceted modes of action of this anticancer probiotic. Firstly, E. hirae elicited emigration of thymocytes and triggered systemic and intratumoral IFNγ-producing and CD137-expressing effector memory T cell responses. Secondly, E. hirae activated the autophagy machinery in enterocytes and mediated ATG4B-dependent anticancer effects, likely as a consequence of its ability to increase local delivery of polyamines. Thirdly, E. hirae shifted the host microbiome toward a Bifidobacteria-enriched ecosystem. In contrast to the live bacterium, its pasteurized cells or membrane vesicles were devoid of anticancer properties. These pleiotropic functions allow the design of optimal immunotherapies combining E. hirae with CD137 agonistic antibodies, spermidine, or Bifidobacterium animalis. We surmise that immunological, metabolic, epithelial, and microbial modes of action of the live E. hirae cooperate to circumvent primary resistance to therapy.
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http://dx.doi.org/10.1038/s41418-021-00753-8DOI Listing
May 2021

Cellular stress promotes NOD1/2-dependent inflammation via the endogenous metabolite sphingosine-1-phosphate.

EMBO J 2021 May 4:e106272. Epub 2021 May 4.

Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.

Cellular stress has been associated with inflammation, yet precise underlying mechanisms remain elusive. In this study, various unrelated stress inducers were employed to screen for sensors linking altered cellular homeostasis and inflammation. We identified the intracellular pattern recognition receptors NOD1/2, which sense bacterial peptidoglycans, as general stress sensors detecting perturbations of cellular homeostasis. NOD1/2 activation upon such perturbations required generation of the endogenous metabolite sphingosine-1-phosphate (S1P). Unlike peptidoglycan sensing via the leucine-rich repeats domain, cytosolic S1P directly bound to the nucleotide binding domains of NOD1/2, triggering NF-κB activation and inflammatory responses. In sum, we unveiled a hitherto unknown role of NOD1/2 in surveillance of cellular homeostasis through sensing of the cytosolic metabolite S1P. We propose S1P, an endogenous metabolite, as a novel NOD1/2 activator and NOD1/2 as molecular hubs integrating bacterial and metabolic cues.
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http://dx.doi.org/10.15252/embj.2020106272DOI Listing
May 2021

Acute monoarthritis in young children: comparing the characteristics of patients with juvenile idiopathic arthritis versus septic and undifferentiated arthritis.

Sci Rep 2021 Feb 9;11(1):3422. Epub 2021 Feb 9.

Department of General Pediatrics, Pediatric Internal Medicine, Rheumatology and Infectious Diseases, National Reference Centre for Rare Pediatric Inflammatory Rheumatisms and Systemic Autoimmune Diseases RAISE, Robert Debré University Hospital, Assistance Publique-Hôpitaux de Paris, 75019, Paris, France.

Acute arthritis is a common cause of consultation in pediatric emergency wards. Arthritis can be caused by juvenile idiopathic arthritis (JIA), septic (SA) or remain undetermined (UA). In young children, SA is mainly caused by Kingella kingae (KK), a hard to grow bacteria leading generally to a mild clinical and biological form of SA. An early accurate diagnosis between KK-SA and early-onset JIA is essential to provide appropriate treatment and follow-up. The aim of this work was to compare clinical and biological characteristics, length of hospital stays, duration of intravenous (IV) antibiotics exposure and use of invasive surgical management of patients under 6 years of age hospitalized for acute monoarthritis with a final diagnosis of JIA, SA or UA. We retrospectively analyzed data from < 6-year-old children, hospitalized at a French tertiary center for acute mono-arthritis, who underwent a joint aspiration. Non-parametric tests were performed to compare children with JIA, SA or UA. Bonferroni correction for multiple comparisons was applied with threshold for significance at 0.025. Among the 196 included patients, 110 (56.1%) had SA, 20 (10.2%) had JIA and 66 (33.7%) had UA. Patients with JIA were older when compared to SA (2.7 years [1.8-3.6] versus 1.4 [1.1-2.1], p < 0.001). Presence of fever was not different between JIA and SA or UA. White blood cells in serum were lower in JIA (11.2 × 10/L [10-13.6]) when compared to SA (13.2 × 10/L [11-16.6]), p = 0.01. In synovial fluid leucocytes were higher in SA 105.5 × 10 cells/mm [46-211] compared to JIA and UA (42 × 10 cells/mm [6.4-59.2] and 7.29 × 10 cells/mm [2.1-72] respectively), p < 0.001. Intravenous antibiotics were administered to 95% of children with JIA, 100% of patients with SA, and 95.4% of UA. Arthrotomy-lavage was performed in 66.7% of patients with JIA, 79.6% of patients with SA, and 71.1% of patients with UA. In children less than 6 years of age with acute mono-arthritis, the clinical and biological parameters currently used do not reliably differentiate between JIA, AS and UA. JIA subgroups that present a diagnostic problem at the onset of monoarthritis before the age of 6 years, are oligoarticular JIA and systemic JIA with hip arthritis. The development of new biomarkers will be required to distinguish JIA and AS caused by Kingella kingae in these patients.
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http://dx.doi.org/10.1038/s41598-021-82553-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873238PMC
February 2021

A Secreted NlpC/P60 Endopeptidase from Photobacterium damselae subsp. Cleaves the Peptidoglycan of Potentially Competing Bacteria.

mSphere 2021 02 3;6(1). Epub 2021 Feb 3.

Fish Immunology and Vaccinology Group, Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal

Peptidoglycan (PG) is a major component of the bacterial cell wall, forming a mesh-like structure enwrapping the bacteria that is essential for maintaining structural integrity and providing support for anchoring other components of the cell envelope. PG biogenesis is highly dynamic and requires multiple enzymes, including several hydrolases that cleave glycosidic or amide bonds in the PG. This work describes the structural and functional characterization of an NlpC/P60-containing peptidase from subsp. (), a Gram-negative bacterium that causes high mortality of warm-water marine fish with great impact for the aquaculture industry. PnpA ( lpC-like rotein ) has a four-domain structure with a hydrophobic and narrow access to the catalytic center and specificity for the γ-d-glutamyl--diaminopimelic acid bond. However, PnpA does not cleave the PG of or PG of several Gram-negative and Gram-positive bacterial species. Interestingly, it is secreted by the type II secretion system and degrades the PG of and This suggests that PnpA is used by to gain an advantage over bacteria that compete for the same resources or to obtain nutrients in nutrient-scarce environments. Comparison of the muropeptide composition of PG susceptible and resistant to the catalytic activity of PnpA showed that the global content of muropeptides is similar, suggesting that susceptibility to PnpA is determined by the three-dimensional organization of the muropeptides in the PG. Peptidoglycan (PG) is a major component of the bacterial cell wall formed by long chains of two alternating sugars interconnected by short peptides, generating a mesh-like structure that enwraps the bacterial cell. Although PG provides structural integrity and support for anchoring other components of the cell envelope, it is constantly being remodeled through the action of specific enzymes that cleave or join its components. Here, it is shown that subsp. , a bacterium that causes high mortality in warm-water marine fish, produces PnpA, an enzyme that is secreted into the environment and is able to cleave the PG of potentially competing bacteria, either to gain a competitive advantage and/or to obtain nutrients. The specificity of PnpA for the PG of some bacteria and its inability to cleave others may be explained by differences in the structure of the PG mesh and not by different muropeptide composition.
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http://dx.doi.org/10.1128/mSphere.00736-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7860986PMC
February 2021

NOD1 sensing of house dust mite-derived microbiota promotes allergic experimental asthma.

J Allergy Clin Immunol 2021 Jan 25. Epub 2021 Jan 25.

University of Lille, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale, Centre Hospitalier Universitaire Lille, Institut Pasteur de Lille, U1019-Unite Mixte de Recherche (UMR) 9017-Centre d'Infection et d'Immunité de Lille, Lille, France. Electronic address:

Background: Asthma severity has been linked to exposure to gram-negative bacteria from the environment that are recognized by NOD1 receptor and are present in house dust mite (HDM) extracts. NOD1 polymorphism has been associated with asthma.

Objective: We sought to evaluate whether either host or HDM-derived microbiota may contribute to NOD1-dependent disease severity.

Methods: A model of HDM-induced experimental asthma was used and the effect of NOD1 deficiency was evaluated. Contribution of host microbiota was evaluated by fecal transplantation. Contribution of HDM-derived microbiota was assessed by 16S ribosomal RNA sequencing, mass spectrometry analysis, and peptidoglycan depletion of the extracts.

Results: In this model, loss of the bacterial sensor NOD1 and its adaptor RIPK2 improved asthma features. Such inhibitory effect was not related to dysbiosis caused by NOD1 deficiency, as shown by fecal transplantation of Nod1-deficient microbiota to wild-type germ-free mice. The 16S ribosomal RNA gene sequencing and mass spectrometry analysis of HDM allergen, revealed the presence of some muropeptides from gram-negative bacteria that belong to the Bartonellaceae family. While such HDM-associated muropeptides were found to activate NOD1 signaling in epithelial cells, peptidoglycan-depleted HDM had a decreased ability to instigate asthma in vivo.

Conclusions: These data show that NOD1-dependent sensing of HDM-associated gram-negative bacteria aggravates the severity of experimental asthma, suggesting that inhibiting the NOD1 signaling pathway may be a therapeutic approach to treating asthma.
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http://dx.doi.org/10.1016/j.jaci.2020.12.649DOI Listing
January 2021

Effect of gut microbiota on depressive-like behaviors in mice is mediated by the endocannabinoid system.

Nat Commun 2020 12 11;11(1):6363. Epub 2020 Dec 11.

Perception and Memory Unit, CNRS UMR3571, Institut Pasteur, Paris, France.

Depression is the leading cause of disability worldwide. Recent observations have revealed an association between mood disorders and alterations of the intestinal microbiota. Here, using unpredictable chronic mild stress (UCMS) as a mouse model of depression, we show that UCMS mice display phenotypic alterations, which could be transferred from UCMS donors to naïve recipient mice by fecal microbiota transplantation. The cellular and behavioral alterations observed in recipient mice were accompanied by a decrease in the endocannabinoid (eCB) signaling due to lower peripheral levels of fatty acid precursors of eCB ligands. The adverse effects of UCMS-transferred microbiota were alleviated by selectively enhancing the central eCB or by complementation with a strain of the Lactobacilli genus. Our findings provide a mechanistic scenario for how chronic stress, diet and gut microbiota generate a pathological feed-forward loop that contributes to despair behavior via the central eCB system.
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http://dx.doi.org/10.1038/s41467-020-19931-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732982PMC
December 2020

Ileal immune tonus is a prognosis marker of proximal colon cancer in mice and patients.

Cell Death Differ 2021 May 1;28(5):1532-1547. Epub 2020 Dec 1.

Gustave Roussy Cancer Campus (GRCC), Villejuif, France.

Ileal epithelial cell apoptosis and the local microbiota modulate the effects of oxaliplatin against proximal colon cancer by modulating tumor immunosurveillance. Here, we identified an ileal immune profile associated with the prognosis of colon cancer and responses to chemotherapy. The whole immune ileal transcriptome was upregulated in poor-prognosis patients with proximal colon cancer, while the colonic immunity of healthy and neoplastic areas was downregulated (except for the Th17 fingerprint) in such patients. Similar observations were made across experimental models of implanted and spontaneous murine colon cancer, showing a relationship between carcinogenesis and ileal inflammation. Conversely, oxaliplatin-based chemotherapy could restore a favorable, attenuated ileal immune fingerprint in responders. These results suggest that chemotherapy inversely shapes the immune profile of the ileum-tumor axis, influencing clinical outcome.
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http://dx.doi.org/10.1038/s41418-020-00684-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167112PMC
May 2021

Cross-reactivity between tumor MHC class I-restricted antigens and an enterococcal bacteriophage.

Science 2020 08;369(6506):936-942

Department of Physics of Complex Systems, ELTE Eötvös Loránd University, Budapest, Hungary.

Intestinal microbiota have been proposed to induce commensal-specific memory T cells that cross-react with tumor-associated antigens. We identified major histocompatibility complex (MHC) class I-binding epitopes in the tail length tape measure protein (TMP) of a prophage found in the genome of the bacteriophage Mice bearing harboring this prophage mounted a TMP-specific H-2K-restricted CD8 T lymphocyte response upon immunotherapy with cyclophosphamide or anti-PD-1 antibodies. Administration of bacterial strains engineered to express the TMP epitope improved immunotherapy in mice. In renal and lung cancer patients, the presence of the enterococcal prophage in stools and expression of a TMP-cross-reactive antigen by tumors correlated with long-term benefit of PD-1 blockade therapy. In melanoma patients, T cell clones recognizing naturally processed cancer antigens that are cross-reactive with microbial peptides were detected.
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http://dx.doi.org/10.1126/science.aax0701DOI Listing
August 2020

Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer.

Nat Med 2020 06 25;26(6):919-931. Epub 2020 May 25.

Service de Chirurgie Digestive et Oncologique, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.

The prognosis of colon cancer (CC) is dictated by tumor-infiltrating lymphocytes, including follicular helper T (T) cells and the efficacy of chemotherapy-induced immune responses. It remains unclear whether gut microbes contribute to the elicitation of T cell-driven responses. Here, we show that the ileal microbiota dictates tolerogenic versus immunogenic cell death of ileal intestinal epithelial cells (IECs) and the accumulation of T cells in patients with CC and mice. Suppression of IEC apoptosis led to compromised chemotherapy-induced immunosurveillance against CC in mice. Protective immune responses against CC were associated with residence of Bacteroides fragilis and Erysipelotrichaceae in the ileum. In the presence of these commensals, apoptotic ileal IECs elicited PD-1 T cells in an interleukin-1R1- and interleukin-12-dependent manner. The ileal microbiome governed the efficacy of chemotherapy and PD-1 blockade in CC independently of microsatellite instability. These findings demonstrate that immunogenic ileal apoptosis contributes to the prognosis of chemotherapy-treated CC.
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http://dx.doi.org/10.1038/s41591-020-0882-8DOI Listing
June 2020

Study of the Operon Coding a Two-Component System and a Putative L,D-Carboxypeptidase in .

Front Microbiol 2020 3;11:156. Epub 2020 Mar 3.

PAM UMR, AgroSup Dijon, Université de Bourgogne Franche-Comté, Dijon, France.

The cell surface is the primary recognition site between the bacterium and the host. An operon of three genes, LSEI_0219 (), LSEI_0220 (), and LSEI_0221 (), has been previously identified as required for the establishment of in the gut. The genes and encode a predicted two-component system (TCS) and a predicted D-alanyl-D-alanine carboxypeptidase which is a peptidoglycan (PG) biosynthesis enzyme. We explored the functionality and the physiological role of these three genes, particularly their impact on the bacterial cell wall architecture and on the bacterial adaptation to environmental perturbations in the gut. The functionality of CwaS/R proteins as a TCS has been demonstrated by biochemical analysis. It is involved in the transcriptional regulation of several genes of the PG biosynthesis. Analysis of the muropeptides of PG in mutants allowed us to re-annotate LSEI_0221 as a putative L,D-carboxypeptidase (LdcA). The absence of this protein coincided with a decrease of two surface antigens: LSEI_0020, corresponding to p40 or msp2 whose implication in the host epithelial homeostasis has been recently studied, and LSEI_2029 which has never been functionally characterized. The inactivation of each of these three genes induces susceptibility to antimicrobial peptides (hBD1, hBD2, and CCL20), which could be the main cause of the gut establishment deficiency. Thus, this operon is necessary for the presence of two surface antigens and for a suitable cell wall architecture.
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http://dx.doi.org/10.3389/fmicb.2020.00156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062640PMC
March 2020

Defective lytic transglycosylase disrupts cell morphogenesis by hindering cell wall de--acetylation in .

Elife 2020 02 5;9. Epub 2020 Feb 5.

Unité Biologie et Génétique de la Paroi Bactérienne, Institut Pasteur; Groupe Avenir, INSERM 75015, Paris, France.

Lytic transglycosylases (LT) are enzymes involved in peptidoglycan (PG) remodeling. However, their contribution to cell-wall-modifying complexes and their potential as antimicrobial drug targets remains unclear. Here, we determined a high-resolution structure of the LT, an outer membrane lipoprotein from species with a disordered active site helix (alpha helix 30). We show that deletion of the conserved alpha-helix 30 interferes with the integrity of the cell wall, disrupts cell division, cell separation, and impairs the fitness of the human pathogen during infection. Additionally, deletion of alpha-helix 30 results in hyperacetylated PG, suggesting this LtgA variant affects the function of the PG de-acetylase (Ape 1). Our study revealed that Ape 1 requires LtgA for optimal function, demonstrating that LTs can modulate the activity of their protein-binding partner. We show that targeting specific domains in LTs can be lethal, which opens the possibility that LTs are useful drug-targets.
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http://dx.doi.org/10.7554/eLife.51247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083599PMC
February 2020

HupA, the main undecaprenyl pyrophosphate and phosphatidylglycerol phosphate phosphatase in Helicobacter pylori is essential for colonization of the stomach.

PLoS Pathog 2019 09 5;15(9):e1007972. Epub 2019 Sep 5.

Institut Pasteur, Unité biologie et génétique de la paroi bactérienne, 28, rue du Docteur Roux, Paris, France.

The biogenesis of bacterial cell-envelope polysaccharides requires the translocation, across the plasma membrane, of sugar sub-units that are produced inside the cytoplasm. To this end, the hydrophilic sugars are anchored to a lipid phosphate carrier (undecaprenyl phosphate (C55-P)), yielding membrane intermediates which are translocated to the outer face of the membrane. Finally, the glycan moiety is transferred to a nascent acceptor polymer, releasing the carrier in the "inactive" undecaprenyl pyrophosphate (C55-PP) form. Thus, C55-P is generated through the dephosphorylation of C55-PP, itself arising from either de novo synthesis or recycling. Two types of integral membrane C55-PP phosphatases were described: BacA enzymes and a sub-group of PAP2 enzymes (type 2 phosphatidic acid phosphatases). The human pathogen Helicobacter pylori does not contain BacA homologue but has four membrane PAP2 proteins: LpxE, LpxF, HP0350 and HP0851. Here, we report the physiological role of HP0851, renamed HupA, via multiple and complementary approaches ranging from a detailed biochemical characterization to the assessment of its effect on cell envelope metabolism and microbe-host interactions. HupA displays a dual function as being the main C55-PP pyrophosphatase (UppP) and phosphatidylglycerol phosphate phosphatase (PGPase). Although not essential in vitro, HupA was essential in vivo for stomach colonization. In vitro, the remaining UppP activity was carried out by LpxE in addition to its lipid A 1-phosphate phosphatase activity. Both HupA and LpxE have crucial roles in the biosynthesis of several cell wall polysaccharides and thus constitute potential targets for new therapeutic strategies.
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http://dx.doi.org/10.1371/journal.ppat.1007972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748449PMC
September 2019

-Deacetylases required for muramic-δ-lactam production are involved in sporulation, germination, and heat resistance.

J Biol Chem 2018 11 28;293(47):18040-18054. Epub 2018 Sep 28.

From the EA4043 Unité Bactéries Pathogènes et Santé (UBaPS), Université Paris-Sud, Université Paris-Saclay, 92290 Châtenay-Malabry,. Electronic address:

Spores are produced by many organisms as a survival mechanism activated in response to several environmental stresses. Bacterial spores are multilayered structures, one of which is a peptidoglycan layer called the cortex, containing muramic-δ-lactams that are synthesized by at least two bacterial enzymes, the muramoyl-l-alanine amidase CwlD and the -deacetylase PdaA. This study focused on the spore cortex of , a Gram-positive, toxin-producing anaerobic bacterial pathogen that can colonize the human intestinal tract and is a leading cause of antibiotic-associated diarrhea. Using ultra-HPLC coupled with high-resolution MS, here we found that the spore cortex of the 630Δ strain differs from that of Among these differences, the muramic-δ-lactams represented only 24% in , compared with 50% in CD630_14300 and CD630_27190 were identified as genes encoding the -deacetylases PdaA1 and PdaA2, required for muramic-δ-lactam synthesis. In a mutant, only 0.4% of all muropeptides carried a muramic-δ-lactam modification, and muramic-δ-lactams were absent in the cortex of a double mutant. Of note, the mutant exhibited decreased sporulation, altered germination, decreased heat resistance, and delayed virulence in a hamster infection model. These results suggest a much greater role for muramic-δ-lactams in than in other bacteria, including In summary, the spore cortex of contains lower levels of muramic-δ-lactams than that of , and PdaA1 is the major -deacetylase for muramic-δ-lactam biosynthesis in , contributing to sporulation, heat resistance, and virulence.
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http://dx.doi.org/10.1074/jbc.RA118.004273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6254358PMC
November 2018

A step-by-step guide to bond cleavage and 1,6-anhydro-sugar product synthesis by a peptidoglycan-degrading lytic transglycosylase.

J Biol Chem 2018 04 26;293(16):6000-6010. Epub 2018 Feb 26.

From the Institut Pasteur, Département de Microbiologie, Unité Biologie et Génétique de la Paroi Bactérienne, 75015 Paris, France,

Lytic transglycosylases (LTs) are a class of enzymes important for the recycling and metabolism of peptidoglycan (PG). LTs cleave the β-1,4-glycosidic bond between -acetylmuramic acid (MurNAc) and GlcNAc in the PG glycan strand, resulting in the concomitant formation of 1,6-anhydro--acetylmuramic acid and GlcNAc. No LTs reported to date have utilized chitins as substrates, despite the fact that chitins are GlcNAc polymers linked via β-1,4-glycosidic bonds, which are the known site of chemical activity for LTs. Here, we demonstrate enzymatically that LtgA, a non-canonical, substrate-permissive LT from utilizes chitopentaose ((GlcNAc)) as a substrate to produce three newly identified sugars: 1,6-anhydro-chitobiose, 1,6-anhydro-chitotriose, and 1,6-anhydro-chitotetraose. Although LTs have been widely studied, their complex reactions have not previously been visualized in the crystalline state because macromolecular PG is insoluble. Here, we visualized the cleavage of the glycosidic bond and the liberation of GlcNAc-derived residues by LtgA, followed by the synthesis of atypical 1,6-anhydro-GlcNAc derivatives. In addition to the newly identified anhydro-chitin products, we identified trapped intermediates, unpredicted substrate rearrangements, sugar distortions, and a conserved crystallographic water molecule bound to the catalytic glutamate of a high-resolution native LT. This study enabled us to propose a revised alternative mechanism for LtgA that could also be applicable to other LTs. Our work contributes to the understanding of the mechanisms of LTs in bacterial cell wall biology.
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http://dx.doi.org/10.1074/jbc.RA117.001095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5912472PMC
April 2018

Lactobacillus paracasei feeding improves immune control of influenza infection in mice.

PLoS One 2017 20;12(9):e0184976. Epub 2017 Sep 20.

Bioaster, Paris, France.

Respiratory tract infections such as flu cause severe morbidity and mortality and are among the leading causes of death in children and adults worldwide. Commensal microbiota is critical for orchestrating tissue homeostasis and immunity in the intestine. Probiotics represent an interesting source of immune modulators and several clinical studies have addressed the potential beneficial effects of probiotics against respiratory infections. Therefore, we have investigated the mechanisms of protection conferred by L. paracasei CNCM I-1518 strain in a mouse model of influenza infection. Notably, local myeloid cells accumulation is generated in the lungs after seven days feeding with L. paracasei prior to viral infection. L. paracasei-fed mice showed reduced susceptibility to the influenza infection, associated with less accumulation of inflammatory cells in the lungs, faster viral clearance and general health improvement. Interestingly, Allobaculum was significantly increased in L. paracasei-fed mice 7 days after influenza infection, even if the gut microbiota composition was not altered overall. L. paracasei-purified peptidoglycan partially recapitulated the protective phenotype observed with the entire bacteria. Collectively, our results demonstrate that oral consumption of L. paracasei CNCM I-1518 modulates lung immunity was associated with an improved control of influenza infection. These results further extend the beneficial role for certain lactobacilli to alleviate the burden of respiratory tract infections.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0184976PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5607164PMC
October 2017

Regulation of bone mass by the gut microbiota is dependent on NOD1 and NOD2 signaling.

Cell Immunol 2017 Jul 19;317:55-58. Epub 2017 May 19.

Centre for Bone and Arthritis Research, Institute of Medicin, Sahlgrenska Academy at University of Gothenburg, SE-413 45 Gothenburg, Sweden. Electronic address:

Germ-free (GF) mice have increased bone mass that is normalized by colonization with gut microbiota (GM) from conventionally raised (CONV-R) mice. To determine if innate immune signaling pathways mediated the effect of the GM, we studied the skeleton of GF and CONV-R mice with targeted inactivation of MYD88, NOD1 or NOD2. In contrast to WT and Myd88 mice, cortical bone thickness in mice lacking Nod1 or Nod2 was not increased under GF conditions. The expression of Tnfα and the osteoclastogenic factor Rankl in bone was reduced in GF compared to CONV-R WT mice but not in Nod1 or Nod2 mice indicating that the effect of the GM to increase Tnfα and Rankl in bone and to reduce bone mass is dependent on both NOD1 and NOD2 signaling.
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http://dx.doi.org/10.1016/j.cellimm.2017.05.003DOI Listing
July 2017

Enhancing the clinical coverage and anticancer efficacy of immune checkpoint blockade through manipulation of the gut microbiota.

Oncoimmunology 2017;6(1):e1132137. Epub 2016 Feb 18.

Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), Villejuif, France; INSERM Unit U1015, Villejuif, France; Faculté de Médecine, Université Paris Sud, Université Paris-Saclay, Le Kremlin Bicêtre, France; INSERM Unit U932, Institut Curie, Paris Cedex 05, France; Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507, Villejuif, France.

Although anticancer therapy with immune checkpoint blockers has seen unprecedented success, it fails to control neoplasia in most patients and often causes immune-related adverse events (irAEs). Our recent research shows the immunostimulatory and antitumor effects of CTLA-4 blockade depend on distinct species of the gut microbiota, signifying novel approaches to improve such immunotherapies.
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http://dx.doi.org/10.1080/2162402X.2015.1132137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5283646PMC
February 2016

Enterococcus hirae and Barnesiella intestinihominis Facilitate Cyclophosphamide-Induced Therapeutic Immunomodulatory Effects.

Immunity 2016 10 4;45(4):931-943. Epub 2016 Oct 4.

Department of Immunology and Pathology, Monash University, Alfred Hospital Precinct, Melbourne, Prahran, Victoria 3181, Australia.

The efficacy of the anti-cancer immunomodulatory agent cyclophosphamide (CTX) relies on intestinal bacteria. How and which relevant bacterial species are involved in tumor immunosurveillance, and their mechanism of action are unclear. Here, we identified two bacterial species, Enterococcus hirae and Barnesiella intestinihominis that are involved during CTX therapy. Whereas E. hirae translocated from the small intestine to secondary lymphoid organs and increased the intratumoral CD8/Treg ratio, B. intestinihominis accumulated in the colon and promoted the infiltration of IFN-γ-producing γδT cells in cancer lesions. The immune sensor, NOD2, limited CTX-induced cancer immunosurveillance and the bioactivity of these microbes. Finally, E. hirae and B. intestinihominis specific-memory Th1 cell immune responses selectively predicted longer progression-free survival in advanced lung and ovarian cancer patients treated with chemo-immunotherapy. Altogether, E. hirae and B. intestinihominis represent valuable "oncomicrobiotics" ameliorating the efficacy of the most common alkylating immunomodulatory compound.
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http://dx.doi.org/10.1016/j.immuni.2016.09.009DOI Listing
October 2016

Fine-Tuning Cancer Immunotherapy: Optimizing the Gut Microbiome.

Cancer Res 2016 08 29;76(16):4602-7. Epub 2016 Jul 29.

Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), Villejuif, France. INSERM Unit U1015, Villejuif, France. Université Paris Sud, Université Paris-Saclay, Faculté de Médecine, Le Kremlin Bicêtre, France. Center of Clinical Investigations CICBT1428, Gustave Roussy Cancer Campus, 94805, Villejuif, France.

The equilibrium linking the intestinal microbiota, the intestinal epithelium, and the host immune system establishes host health and homeostasis, with perturbations of this balance resulting in chronic inflammatory and autoimmune immunopathologies. The mutualistic symbiosis between gut microbiota and host immunity raises the possibility that dysbiosis of the intestinal content also influences the outcome of cancer immunotherapy. Here, we present our recent findings that specific gut-resident bacteria determine the immunotherapeutic responses associated with CTLA-4 checkpoint blockade. This new evidence hints that interindividual differences in the microbiome may account for the significant heterogeneity in therapeutic and immunopathologic responses to immune checkpoint therapies. We discuss how this new understanding could improve the therapeutic coverage of immune checkpoint inhibitors, and potentially limit their immune-mediated toxicity, through the use of adjunctive "oncomicrobiotics" that indirectly promote beneficial immune responses through optimizing the gut microbiome. Cancer Res; 76(16); 4602-7. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-16-0448DOI Listing
August 2016

Resistance Mechanisms to Immune-Checkpoint Blockade in Cancer: Tumor-Intrinsic and -Extrinsic Factors.

Immunity 2016 06;44(6):1255-69

Institut de Cancérologie, Gustave Roussy Cancer Campus, 94800 Villejuif, France; INSERM U1015, 94800 Villejuif, France; Faculté de Médecine, Université Paris Sud, Université Paris-Saclay, 94276 Le Kremlin Bicêtre, France; Center of Clinical Investigations CICBT1428, Gustave Roussy Cancer Campus, 94805 Villejuif Cedex 05, France. Electronic address:

Inhibition of immune regulatory checkpoints, such as CTLA-4 and the PD-1-PD-L1 axis, is at the forefront of immunotherapy for cancers of various histological types. However, such immunotherapies fail to control neoplasia in a significant proportion of patients. Here, we review how a range of cancer-cell-autonomous cues, tumor-microenvironmental factors, and host-related influences might account for the heterogeneous responses and failures often encountered during therapies using immune-checkpoint blockade. Furthermore, we describe the emerging evidence of how the strong interrelationship between the immune system and the host microbiota can determine responses to cancer therapies, and we introduce a concept by which prior or concomitant modulation of the gut microbiome could optimize therapeutic outcomes upon immune-checkpoint blockade.
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http://dx.doi.org/10.1016/j.immuni.2016.06.001DOI Listing
June 2016

Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota.

Science 2015 Nov 5;350(6264):1079-84. Epub 2015 Nov 5.

Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France. Laboratory of Immunomonitoring in Oncology, UMS 3655 CNRS/US 23 INSERM, GRCC, Villejuif, France.

Antibodies targeting CTLA-4 have been successfully used as cancer immunotherapy. We find that the antitumor effects of CTLA-4 blockade depend on distinct Bacteroides species. In mice and patients, T cell responses specific for B. thetaiotaomicron or B. fragilis were associated with the efficacy of CTLA-4 blockade. Tumors in antibiotic-treated or germ-free mice did not respond to CTLA blockade. This defect was overcome by gavage with B. fragilis, by immunization with B. fragilis polysaccharides, or by adoptive transfer of B. fragilis-specific T cells. Fecal microbial transplantation from humans to mice confirmed that treatment of melanoma patients with antibodies against CTLA-4 favored the outgrowth of B. fragilis with anticancer properties. This study reveals a key role for Bacteroidales in the immunostimulatory effects of CTLA-4 blockade.
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http://dx.doi.org/10.1126/science.aad1329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4721659PMC
November 2015

Paenibacillus faecis sp. nov., isolated from human faeces.

Int J Syst Evol Microbiol 2015 Dec 18;65(12):4621-4626. Epub 2015 Sep 18.

Département de Microbiologie F-75015, Institut Pasteur, Collection de l'Institut Pasteur, Paris, France.

A spore-forming, rod-shaped Gram-strain-positive bacterium, strain 656.84T, was isolated from human faeces in 1984. It contained anteiso-C15 : 0 as the major cellular fatty acid, meso-diaminopimelic acid was found in the cell wall peptidoglycan, the polar lipid profile consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol and aminophospholipids as the major components, and the predominant menaquinone was MK-7. The DNA G+C content was 52.9 mol%. The results of comparative 16S rRNA gene sequence studies placed strain 656.84T within the genus Paenibacillus. Its closest phylogenetic relatives were Paenibacillus barengoltzii and Paenibacillus timonensis. Levels of DNA-DNA relatedness between strain 656.84T and Paenibacillus timonensis CIP 108005T and Paenibacillus barengoltzii CIP 109354T were 17.3 % and 36.8 %, respectively, indicating that strain 656.84T represents a distinct species. On the basis of phenotypic and genotypic results, strain 656.84T is considered to represent a novel species within the genus Paenibacillus, for which the name Paenibacillus faecis sp. nov. is proposed; the type strain is 656.84T ( = DSM 23593T = CIP 101062T).
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http://dx.doi.org/10.1099/ijsem.0.000622DOI Listing
December 2015

The biology of bacterial peptidoglycans and their impact on host immunity and physiology.

Cell Microbiol 2014 Jul 2;16(7):1014-23. Epub 2014 Jun 2.

Institut Pasteur, Biology and genetics of the bacterial cell wall Unit, Paris, 75724, France; INSERM, Avenir group, Paris, 75015, France.

Peptidoglycans (PGN) are a constituent of the bacterial cell wall, and are shed as bacteria divide. The presence of PGN is therefore a marker of bacterial activity that has been exploited by both plants and animals to induce defence mechanisms. Pattern recognition receptors that recognize PGN are extremely well conserved throughout evolution and shown to play important and diverse role in the development, homeostasis and activation of the immune system. In addition, PGN can be detected beyond mucosal surfaces, and their receptor can be expressed in tissues and cells that are far from the niches where bacteria reside. Thus, PGN affects not only the host's immunity, but also more generally the host's physiology. In this review, we discuss the biochemistry and biology of PGN, and their intriguing effects on the development of the immune system and the host physiology.
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http://dx.doi.org/10.1111/cmi.12304DOI Listing
July 2014

CCL17 production by dendritic cells is required for NOD1-mediated exacerbation of allergic asthma.

Am J Respir Crit Care Med 2014 Apr;189(8):899-908

1 Pulmonary Immunity, Institut National de la Santé et de la Recherche Médicale, Lille, France.

Rationale: Pattern recognition receptors are attractive targets for vaccine adjuvants, and polymorphisms of the innate receptor NOD1 have been associated with allergic asthma.

Objectives: To elucidate whether NOD1 agonist may favor allergic asthma in humans through activation of dendritic cells, and to evaluate the mechanisms involved using an in vivo model.

Methods: NOD1-primed dendritic cells from allergic and nonallergic donors were characterized in vitro on their phenotype, cytokine secretion, and Th2 polarizing ability. The in vivo relevance was examined in experimental allergic asthma, and the mechanisms were assessed using transfer of NOD1-conditioned dendritic cells from wild-type or CCL17-deficient mice.

Measurements And Main Results: NOD1 priming of human dendritic cells promoted a Th2 polarization profile that involved the production of CCL17 and CCL22 in nonallergic subjects but only CCL17 in allergic patients, without requiring allergen costimulation. Moreover, NOD1-primed dendritic cells from allergic donors exhibited enhanced maturation that led to abnormal CCL22 and IL-10 secretion compared with nonallergic donors. In mice, systemic NOD1 ligation exacerbated allergen-induced experimental asthma by amplifying CCL17-mediated Th2 responses in the lung. NOD1-mediated sensitization of purified murine dendritic cells enhanced production of CCL17 and CCL22, but not of thymic stromal lymphopoietin and IL-33, in vitro. Consistently, adoptive transfer of NOD1-conditioned dendritic cells exacerbated the Th2 pulmonary response in a CCL17-dependent manner in vivo.

Conclusions: Data from this study unveil a deleterious role of NOD1 in allergic asthma through direct induction of CCL17 by dendritic cells, arguing for a need to address vaccine formulation safety issues related to allergy.
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http://dx.doi.org/10.1164/rccm.201310-1827OCDOI Listing
April 2014

The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide.

Science 2013 Nov;342(6161):971-6

Institut National de la Santé et de la Recherche Médicale, U1015, Equipe labellisée Ligue Nationale Contre le Cancer, Institut Gustave Roussy, Villejuif, France.

Cyclophosphamide is one of several clinically important cancer drugs whose therapeutic efficacy is due in part to their ability to stimulate antitumor immune responses. Studying mouse models, we demonstrate that cyclophosphamide alters the composition of microbiota in the small intestine and induces the translocation of selected species of Gram-positive bacteria into secondary lymphoid organs. There, these bacteria stimulate the generation of a specific subset of "pathogenic" T helper 17 (pT(H)17) cells and memory T(H)1 immune responses. Tumor-bearing mice that were germ-free or that had been treated with antibiotics to kill Gram-positive bacteria showed a reduction in pT(H)17 responses, and their tumors were resistant to cyclophosphamide. Adoptive transfer of pT(H)17 cells partially restored the antitumor efficacy of cyclophosphamide. These results suggest that the gut microbiota help shape the anticancer immune response.
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http://dx.doi.org/10.1126/science.1240537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4048947PMC
November 2013

Peptidoglycan sensing by the receptor PGRP-LE in the Drosophila gut induces immune responses to infectious bacteria and tolerance to microbiota.

Cell Host Microbe 2012 Aug;12(2):153-65

Institut de Biologie du Développement de Marseille-Luminy, CNRS UMR, Aix-Marseille Université, France.

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.
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http://dx.doi.org/10.1016/j.chom.2012.06.002DOI Listing
August 2012

Penicillin binding proteins as danger signals: meningococcal penicillin binding protein 2 activates dendritic cells through Toll-like receptor 4.

PLoS One 2011 27;6(10):e23995. Epub 2011 Oct 27.

INSERM U643, Nantes, CHU de Nantes, IUN, Nantes, Université de Nantes, UMR 643, Nantes, France.

Neisseria meningitidis is a human pathogen responsible for life-threatening inflammatory diseases. Meningococcal penicillin-binding proteins (PBPs) and particularly PBP2 are involved in bacterial resistance to β-lactams. Here we describe a novel function for PBP2 that activates human and mouse dendritic cells (DC) in a time and dose-dependent manner. PBP2 induces MHC II (LOGEC50 = 4.7 µg/ml ± 0.1), CD80 (LOGEC50 = 4.88 µg/ml ± 0.15) and CD86 (LOGEC50 = 5.36 µg/ml ± 0.1). This effect was abolished when DCs were co-treated with anti-PBP2 antibodies. PBP2-treated DCs displayed enhanced immunogenic properties in vitro and in vivo. Furthermore, proteins co-purified with PBP2 showed no effect on DC maturation. We show through different in vivo and in vitro approaches that this effect is not due to endotoxin contamination. At the mechanistic level, PBP2 induces nuclear localization of p65 NF-kB of 70.7 ± 5.1% cells versus 12 ± 2.6% in untreated DCs and needs TLR4 expression to mature DCs. Immunoprecipitation and blocking experiments showed thatPBP2 binds TLR4. In conclusion, we describe a novel function of meningococcal PBP2 as a pathogen associated molecular pattern (PAMP) at the host-pathogen interface that could be recognized by the immune system as a danger signal, promoting the development of immune responses.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0023995PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3203111PMC
March 2012

Anti-inflammatory capacity of selected lactobacilli in experimental colitis is driven by NOD2-mediated recognition of a specific peptidoglycan-derived muropeptide.

Gut 2011 Aug 6;60(8):1050-9. Epub 2011 Apr 6.

Bactéries Lactiques et Immunité des Muqueuses, Centre d'Infection et d'Immunité de Lille, Institut Pasteur de Lille, 1 rue du Pr Calmette, 59019 Lille Cedex, France.

Background And Aims: Inflammatory bowel disease (IBD) has been linked to a loss of tolerance towards the resident microflora. Therapeutic use of probiotics is known to be strain specific, but precise mechanisms remain unclear. The role of NOD2 signalling and the protective effect of Lactobacillus peptidoglycan (PGN) and derived muropeptides in experimental colitis were evaluated.

Methods: The anti-inflammatory capacity of lactobacilli and derived bacterial compounds was evaluated using the 2,4,6-trinitrobenzene sulfonic acid (TNBS) colitis model. The role of NOD2, MyD88 and interleukin 10 (IL-10) in this protection was studied using Nod2(-/-), MyD88(-/-) and Il10-deficient mice, while induction of regulatory dendritic cells (DCs) was monitored through the expansion of CD103(+) DCs in mesenteric lymph nodes or after adoptive transfer of bone marrow-derived DCs. The development of regulatory T cells was investigated by following the expansion of CD4(+)FoxP3(+) cells. High-performance liquid chromatography and mass spectrometry were used to analyse the PGN structural differences.

Results: The protective capacity of strain Lactobacillus salivarius Ls33 was correlated with a local IL-10 production and was abolished in Nod2-deficient mice. PGN purified from Ls33 rescued mice from colitis in an IL-10-dependent manner and favoured the development of CD103(+) DCs and CD4(+)Foxp3(+) regulatory T cells. In vitro Ls33 PGN induced IL-10-producing DCs able to achieve in vivo protection after adoptive transfer in a NOD2-dependent way. This protection was also correlated with an upregulation of the indoleamine 2,3-dioxygenase immunosuppressive pathway. The protective capacity was not obtained with PGN purified from a non-anti-inflammatory strain. Structural analysis of PGNs highlighted in Ls33 the presence of an additional muropeptide, M-tri-Lys. The synthesised ligand protected mice from colitis in a NOD2-dependent but MyD88-independent manner.

Conclusions: The results indicated that PGN and derived muropeptides are active compounds in probiotic functionality and might represent a useful therapeutic strategy in IBD.
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http://dx.doi.org/10.1136/gut.2010.232918DOI Listing
August 2011

Bacteria and MAMP-induced morphogenesis of the immune system.

Curr Opin Immunol 2010 Aug 25;22(4):448-54. Epub 2010 Jun 25.

Institut Pasteur, Development of Lymphoid Tissues Unit, Paris 75724, France.

To metazoans, bacteria are more than just potential pathogens. Many examples now document the role of bacterial symbionts in complementing the host for its full development and increasing its digestive and protective functions. Here, we discuss the role of Gram-negative bacteria in the development of intestinal lymphoid tissues and the impact of Segmented Filamentous Bacteria and Bacteroides on intestinal immunity and homeostasis. Furthermore, we discuss the potentially beneficial role of Helicobacter pylori on immunity of the stomach and beyond, even though this bacteria is primarily known for its pathogenicity. Altogether, these and other symbiotic bacteria may manipulate the host and the host immune system through the shedding of MAMPs that cross not only the epithelial barriers, but also permeate the circulation and impact every tissue and function of the host.
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http://dx.doi.org/10.1016/j.coi.2010.06.002DOI Listing
August 2010