scholarly journals Toll-Like Receptor 2 Ligand Pretreatment Attenuates Retinal Microglial Inflammatory Response but Enhances Phagocytic Activity toward Staphylococcus aureus

2012 ◽  
Vol 80 (6) ◽  
pp. 2076-2088 ◽  
Author(s):  
Travis Kochan ◽  
Anuj Singla ◽  
Joaquin Tosi ◽  
Ashok Kumar
Keyword(s):  
Staphylococcus Aureus ◽  
Inflammatory Response ◽  
Phagocytic Activity ◽  
Toll Like Receptor ◽  
Innate Response ◽  
Content Type ◽  
Proinflammatory Mediators ◽  
Retinal Microglia ◽  
Tlr2 Ligand ◽  
Toll Like Receptor 2

ABSTRACTStaphylococcus aureusis a leading cause of severe endophthalmitis, which often results in vision loss in some patients. Previously, we showed that Toll-like receptor 2 (TLR2) ligand pretreatment prevented the development of staphylococcal endophthalmitis in mice and suggested that microglia might be involved in this protective effect (Kumar A, Singh CN, Glybina IV, Mahmoud TH, Yu FS. J. Infect. Dis. 201:255–263, 2010). The aim of the present study was to understand how microglial innate response is modulated by TLR2 ligand pretreatment. Here, we demonstrate thatS. aureusinfection increased the CD11b+CD45+microglial/macrophage population in the C57BL/6 mouse retina. Using cultured primary retinal microglia and a murine microglial cell line (BV-2), we found that these cells express TLR2 and that its expression is increased upon stimulation with bacteria or an exclusive TLR2 ligand, Pam3Cys. Furthermore, challenge of primary retinal microglia withS. aureusand its cell wall components peptidoglycan (PGN) and lipoteichoic acid (LTA) induced the secretion of proinflammatory mediators (tumor necrosis factor alpha [TNF-α] and MIP-2). This innate response was attenuated by a function-blocking anti-TLR2 antibody or by small interfering RNA (siRNA) knockdown of TLR2. In order to assess the modulation of the innate response, microglia were pretreated with a low dose (0.1 or 1 μg/ml) of Pam3Cys and then challenged with liveS. aureus. Our data showed thatS. aureus-induced production of proinflammatory mediators is dramatically reduced in pretreated microglia. Importantly, microglia pretreated with the TLR2 agonist phagocytosed significantly more bacteria than unstimulated cells. Together, our data suggest that TLR2 plays an important role in retinal microglial innate response toS. aureus, and its sensitization inhibits inflammatory response while enhancing phagocytic activity.

scholarly journals Staphylococcus aureus Releases Proinflammatory Membrane Vesicles To Resist Antimicrobial Fatty Acids

mSphere ◽  
2020 ◽  
Vol 5 (5) ◽  
Author(s):  
Arnaud Kengmo Tchoupa ◽  
Andreas Peschel
Keyword(s):  
Fatty Acids ◽  
Staphylococcus Aureus ◽  
Immune Responses ◽  
Membrane Vesicle ◽  
Membrane Vesicles ◽  
Innate Immune ◽  
Toll Like Receptor ◽  
Content Type ◽  
Healthy Humans ◽  
Toll Like Receptor 2

ABSTRACT Staphylococcus aureus is a major pathogen, which colonizes one in three otherwise healthy humans. This significant spread of S. aureus is largely due to its ability to circumvent innate immune responses, including antimicrobial fatty acids (AFAs) on the skin and in nasal secretions. In response to AFAs, S. aureus swiftly induces resistance mechanisms, which have yet to be completely elucidated. Here, we identify membrane vesicle (MV) release as a resistance strategy used by S. aureus to sequester host-specific AFAs. MVs protect S. aureus against a wide array of AFAs. Strikingly, beside MV production, S. aureus modulates MV composition upon exposure to AFAs. MVs purified from bacteria grown in the presence of linoleic acid display a distinct protein content and are enriched in lipoproteins, which strongly activate Toll-like receptor 2 (TLR2). Cumulatively, our findings reveal the protective capacities of MVs against AFAs, which are counteracted by an increased TLR2-mediated innate immune response. IMPORTANCE The nares of one in three humans are colonized by Staphylococcus aureus. In these environments, and arguably on all mucosal surfaces, bacteria encounter fatty acids with antimicrobial properties. Our study uncovers that S. aureus releases membrane vesicles (MVs) that act as decoys to protect the bacterium against antimicrobial fatty acids (AFAs). The AFA-neutralizing effects of MVs were neither strain specific nor restricted to one particular AFA. Hence, MVs may represent “public goods” playing an overlooked role in shaping bacterial communities in AFA-rich environments such as the skin and nose. Intriguingly, in addition to MV biogenesis, S. aureus modulates MV composition in response to exposure to AFAs, including an increased release of lipoproteins. These MVs strongly stimulate the innate immunity via Toll-like receptor 2 (TLR2). TLR2-mediated inflammation, which helps to fight infections, may exacerbate inflammatory disorders like atopic dermatitis. Our study highlights intricate immune responses preventing infections from colonizing bacteria.

scholarly journals Purified Streptococcus pneumoniae Endopeptidase O (PepO) Enhances Particle Uptake by Macrophages in a Toll-Like Receptor 2- and miR-155-Dependent Manner

2017 ◽  
Vol 85 (4) ◽  
Author(s):  
Hua Yao ◽  
Hong Zhang ◽  
Kai Lan ◽  
Hong Wang ◽  
Yufeng Su ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Streptococcus Pneumoniae ◽  
Host Defense ◽  
Defense Response ◽  
Dependent Manner ◽  
Toll Like Receptor ◽  
Content Type ◽  
Host Defense Response ◽  
Toll Like Receptor 2 ◽  
In Cells

ABSTRACT Insights into the host-microbial virulence factor interaction, especially the immune signaling mechanisms, could provide novel prevention and treatment options for pneumococcal diseases. Streptococcus pneumoniae endopeptidase O (PepO) is a newly discovered and ubiquitously expressed pneumococcal virulence protein. A PepO-mutant strain showed impaired adherence to and invasion of host cells compared with the isogenic wild-type strain. It is still unknown whether PepO is involved in the host defense response to pneumococcal infection. Here, we demonstrated that PepO could enhance phagocytosis of Streptococcus pneumoniae and Staphylococcus aureus by peritoneal exudate macrophages (PEMs). Further studies showed that PepO stimulation upregulated the expression of microRNA-155 (miR-155) in PEMs in a time- and dose-dependent manner. PepO-induced enhanced phagocytosis was decreased in cells transfected with an inhibitor of miR-155, while it was increased in cells transfected with a mimic of miR-155. We also revealed that PepO-induced upregulation of miR-155 in PEMs was mediated by Toll-like receptor 2 (TLR2)–NF-κB signaling and that the increased expression of miR-155 downregulated expression of SHIP1. Taken together, these results indicate that PepO induces upregulation of miR-155 in PEMs, contributing to enhanced phagocytosis and host defense response to pneumococci and Staphylococcus aureus.

scholarly journals Toll-Like Receptor 2 Modulates the Proinflammatory Milieu in Staphylococcus aureus-Induced Brain Abscess

2005 ◽  
Vol 73 (11) ◽  
pp. 7428-7435 ◽  
Author(s):  
Tammy Kielian ◽  
Anessa Haney ◽  
Patrick M. Mayes ◽  
Sarita Garg ◽  
Nilufer Esen
Keyword(s):  
Staphylococcus Aureus ◽  
Brain Abscess ◽  
Complex Nature ◽  
Interleukin 17 ◽  
Immune Recognition ◽  
Toll Like Receptor ◽  
Necrosis Factor Alpha ◽  
Proinflammatory Mediators ◽  
Brain Abscesses ◽  
Toll Like Receptor 2

ABSTRACT Toll-like receptor 2 (TLR2) is a pattern recognition receptor (PRR) that plays an important role in innate immune recognition of conserved structural motifs on a wide array of pathogens, including Staphylococcus aureus. To ascertain the functional significance of TLR2 in the context of central nervous system (CNS) parenchymal infection, we evaluated the pathogenesis of S. aureus-induced experimental brain abscess in TLR2 knockout (KO) and wild-type (WT) mice. The expression of several proinflammatory mediators, including inducible nitric oxide synthase, tumor necrosis factor alpha, and macrophage inflammatory protein-2, was significantly attenuated in brain abscesses of TLR2 KO mice compared to WT mice during the acute phase of infection. Conversely, interleukin-17 (IL-17), a cytokine produced by activated and memory T cells, was significantly elevated in lesions of TLR2 KO mice, suggesting an association between innate and adaptive immunity in brain abscess. Despite these differences, brain abscess severity in TLR2 KO and WT animals was similar, with comparable mortality rates, bacterial titers, and blood-brain barrier permeability, implying a role for alternative PRRs. Expression of the phagocytic PRRs macrophage scavenger receptor type AI/AII and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) was increased in brain abscesses of both TLR2 KO and WT mice compared to uninfected animals. However, LOX-1 induction in brain abscesses of TLR2 KO mice was significantly attenuated compared to WT animals, revealing that the TLR2-dependent signal(s) influence LOX-1 expression. Collectively, these findings reveal the complex nature of gram-positive bacterial recognition in the CNS which occurs, in part, through engagement of TLR2 and highlight the importance of receptor redundancy for S. aureus detection in the CNS.

scholarly journals NOD2 Stimulation by Staphylococcus aureus-Derived Peptidoglycan Is Boosted by Toll-Like Receptor 2 Costimulation with Lipoproteins in Dendritic Cells

2014 ◽  
Vol 82 (11) ◽  
pp. 4681-4688 ◽  
Author(s):  
Holger Schäffler ◽  
Dogan Doruk Demircioglu ◽  
Daniel Kühner ◽  
Sarah Menz ◽  
Annika Bender ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Dendritic Cells ◽  
Immune System ◽  
Cytokine Secretion ◽  
Toll Like Receptor ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Murine Bone Marrow ◽  
J774 Cells ◽  
Toll Like Receptor 2

ABSTRACTMutations in the nucleotide-binding oligomerization domain-containing protein 2 (NOD2) play an important role in the pathogenesis of Crohn's disease. NOD2 is an intracellular pattern recognition receptor (PRR) that senses bacterial peptidoglycan (PGN) structures, e.g., muramyl dipeptide (MDP). Here we focused on the effect of more-cross-linked, polymeric PGN fragments (PGNpol) in the activation of the innate immune system. In this study, the effect of combined NOD2 and Toll-like receptor 2 (TLR2) stimulation was examined compared to single stimulation of the NOD2 receptor alone. PGNpol species derived from a lipoprotein-containingStaphylococcus aureusstrain (SA113) and a lipoprotein-deficient strain (SA113 Δlgt) were isolated. While PGNpol constitutes a combined NOD2 and TLR2 ligand, lipoprotein-deficient PGNpolΔlgtleads to activation of the immune system only via the NOD2 receptor. Murine bone marrow-derived dendritic cells (BMDCs), J774 cells, and Mono Mac 6 (MM6) cells were stimulated with these ligands. Cytokines (interleukin-6 [IL-6], IL-12p40, and tumor necrosis factor alpha [TNF-α]) as well as DC activation and maturation parameters were measured. Stimulation with PGNpolΔlgtdid not lead to enhanced cytokine secretion or DC activation and maturation. However, stimulation with PGNpol led to strong cytokine secretion and subsequent DC maturation. These results were confirmed in MM6 and J774 cells. We showed that the NOD2-mediated activation of DCs with PGNpol was dependent on TLR2 costimulation. Therefore, signaling via both receptors leads to a more potent activation of the immune system than that with stimulation via each receptor alone.

scholarly journals A Novel Class of Lipoprotein Lipase-Sensitive Molecules Mediates Toll-Like Receptor 2 Activation by Porphyromonas gingivalis

2013 ◽  
Vol 81 (4) ◽  
pp. 1277-1286 ◽  
Author(s):  
Sumita Jain ◽  
Stephen R. Coats ◽  
Ana M. Chang ◽  
Richard P. Darveau
Keyword(s):  
Lipoprotein Lipase ◽  
Porphyromonas Gingivalis ◽  
Lipid A ◽  
Bacterial Cells ◽  
Toll Like Receptor ◽  
Two Phase ◽  
Content Type ◽  
Tlr2 Ligand ◽  
Toll Like Receptor 2 ◽  
Major Factors

ABSTRACTInfection by the chronic periodontitis-associated pathogenPorphyromonas gingivalisactivates a Toll-like receptor 2 (TLR2) response that triggers inflammation in the host but also promotes bacterial persistence. Our aim was to define ligands on the surfaces of intactP. gingivaliscells that determine its ability to activate TLR2. Molecules previously reported as TLR2 agonists include lipopolysaccharide (LPS), fimbriae, the lipoprotein PG1828, and phosphoceramides. We demonstrate that these molecules do not comprise the major factors responsible for stimulating TLR2 by whole bacterial cells. First,P. gingivalismutants devoid of the reported protein agonists, PG1828 and fimbriae, activate TLR2 as strongly as the wild type. Second, two-phase extraction of whole bacteria resulted in a preponderance of TLR2 agonist activity partitioning to the hydrophilic phase, demonstrating that phosphoceramides are not a major TLR2 ligand. Third, analysis of LPS revealed that TLR2 activation is independent of lipid A structural variants. Instead, activation of TLR2 and TLR2/TLR1 by LPS is in large part due to copurifying molecules that are sensitive to the action of the enzyme lipoprotein lipase. Strikingly, intactP. gingivalisbacterial cells treated with lipoprotein lipase were attenuated in their ability to activate TLR2. We propose that a novel class of molecules comprised by lipoproteins constitutes the major determinants that confer toP. gingivalisthe ability to stimulate TLR2 signaling.

scholarly journals Contribution of Toll-Like Receptor 2 to the Innate Response against Staphylococcus aureus Infection in Mice

PLoS ONE ◽  
2013 ◽  
Vol 8 (9) ◽  
pp. e74287 ◽  
Author(s):  
Yimin ◽  
Masashi Kohanawa ◽  
Songji Zhao ◽  
Michitaka Ozaki ◽  
Sanae Haga ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Toll Like Receptor ◽  
Innate Response ◽  
Aureus Infection ◽  
Toll Like Receptor 2

scholarly journals Impact of Toll-Like Receptor 2 Deficiency on Immune Responses to Mycobacterial Antigens

2011 ◽  
Vol 79 (11) ◽  
pp. 4649-4656 ◽  
Author(s):  
Muhammad J. Rahman ◽  
Olga D. Chuquimia ◽  
Dagbjort H. Petursdottir ◽  
Natalia Periolo ◽  
Mahavir Singh ◽  
...  
Keyword(s):  
Immune Responses ◽  
Cellular Responses ◽  
Mouse Strains ◽  
Mycobacterial Antigen ◽  
Toll Like Receptor ◽  
Partial Explanation ◽  
Content Type ◽  
Tlr2 Ligand ◽  
Toll Like Receptor 2

ABSTRACTIn the present study, we addressed the question of whether Toll-like receptor 2 (TLR2)-mediated innate immunity can contribute to the development of acquired immune responses. We immunized TLR2−/−and wild-type (WT) mice three times subcutaneously with the mycobacterial antigen (Ag19kDa) (a TLR2 ligand) or Ag85A (not a TLR2 ligand). One week after the last immunization, sera and spleens were collected. To evaluate cellular responses, we measured gamma interferon (IFN-γ) afterin vitrorestimulation of spleen cells with antigen alone or antigen-pulsed bone marrow-derived macrophages (BMMAg) or pulmonary macrophages (PuMAg). Antibody responses were comparable in the two mouse strains, but we observed differences in the cellular responses. Recall responses to Ag85A were similar in the two strains, but responses to Ag19kDa given alone or presented by BMM or PuM were lower in TLR2−/−than in WT mice. The largest differences in cellular responses were observed when Ag19kDa was presented by PuM. To understand this, we analyzed phenotypic and functional differences between BMM and PuM upon stimulation with various ligands. Generally, PuM had a lower response to the TLR2 ligand Pam3Cys-Ser-(Lys)4trihydrochloride and to anti-CD40 than BMM, as measured by cytokine secretion and upregulation of costimulatory molecules. This might provide a partial explanation for the lower capacity of PuM when pulsed with Ag19kDa, also a TLR2 ligand. Altogether, our results revealed weaknesses in the T cell and antigen-presenting cell (APC) compartments of the Ag19kDa-immunized TLR2−/−mice but indicated that specific immune responses could be generated in the absence of TLR2 regardless of the characteristics of the antigen used.

scholarly journals Staphylococcal Superantigen-Like Protein 3 Binds to the Toll-Like Receptor 2 Extracellular Domain and Inhibits Cytokine Production Induced by Staphylococcus aureus, Cell Wall Component, or Lipopeptides in Murine Macrophages

2012 ◽  
Vol 80 (8) ◽  
pp. 2816-2825 ◽  
Author(s):  
Ryosuke Yokoyama ◽  
Saotomo Itoh ◽  
Go Kamoshida ◽  
Takemasa Takii ◽  
Satoshi Fujii ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Sialic Acid ◽  
Extracellular Domain ◽  
Raw 264.7 Cells ◽  
Raw 264.7 ◽  
Toll Like Receptor ◽  
Content Type ◽  
Toll Like Receptor 2 ◽  
Binding Residues ◽  
Tlr2 Ligands

ABSTRACTStaphylococcal superantigen-like proteins (SSLs) are a family of exoproteins sharing structural similarity with superantigens, but no superantigenic activity. Corresponding host target proteins or receptors against a portion of SSLs in the family have been identified. In this study, we show that SSL3 specifically binds to Toll-like receptor 2 (TLR2) and inhibits the stimulation of macrophages by TLR2 ligands. An approximately 100-kDa protein was recovered by using recombinant His-tagged SSL3-conjugated Sepharose from the lysate of porcine spleen, and the protein was identified as porcine TLR2 by peptide mass fingerprinting analysis. The SSL3-conjugated Sepharose recovered human and mouse TLR2 but not TLR4 from human neutrophils and mouse macrophage RAW 264.7 cells, as well as a recombinant TLR2 extracellular domain chimera protein. The production levels of interleukin 12 (IL-12) from mouse macrophages treated with heat-killedStaphylococcus aureusand of tumor necrosis factor alpha (TNF-α) from RAW 264.7 cells induced by peptidoglycan or lipopeptide TLR2 ligands were strongly suppressed in the presence of SSL3. The mutation of consensus sialic acid-containing glycan-binding residues in SSL3 did not abrogate the binding ability to TLR2 or inhibitory activity on TLR2, indicating that the interaction of SSL3 with TLR2 was independent of the sialic acid-containing glycan-binding residues. These findings demonstrate that SSL3 is able to bind the extracellular domain of TLR2 and interfere with TLR2 function. The present study provides a novel mechanism of SSL3 in immune evasion ofS. aureusvia interfering with its recognition by innate immune cells.

scholarly journals Heterozygous Toll-Like Receptor 2 Polymorphism Does Not Affect Lipoteichoic Acid-Induced Chemokine and Inflammatory Responses

2004 ◽  
Vol 72 (3) ◽  
pp. 1828-1831 ◽  
Author(s):  
Sonja von Aulock ◽  
Nicolas W. J. Schröder ◽  
Stephanie Traub ◽  
Katja Gueinzius ◽  
Eva Lorenz ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Inflammatory Response ◽  
Inflammatory Responses ◽  
Lipoteichoic Acid ◽  
Cytokine Response ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Functional Allele ◽  
Polymorphic Gene ◽  
Toll Like Receptor 2

ABSTRACT While transfection of tlr2 conveyed responsiveness to lipoteichoic acid (LTA), the Arg753Gln polymorphic gene could not. LTA induced a stronger chemokine and anti-inflammatory response than lipopolysaccharides did. Blood from heterozygous polymorphic and wild-type donors reacted uniformly to LTA and Staphylococcus aureus. Thus, one functional allele for Toll-like receptor 2 suffices for full cytokine response.

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