The type I macrophage scavenger receptor binds to gram-positive bacteria and recognizes lipoteichoic acid.

Infections with gram-positive bacteria are a major cause of morbidity and mortality in humans. Opsonin-dependent phagocytosis plays a major role in protection against and recovery from gram-positive infections. Inborn and acquired defects in opsonin generation and/or recognition by phagocytes are associated with an increased susceptibility to bacterial infections. In contrast, the physiological significance of opsonin-independent phagocytosis is unknown. Type I and II class A scavenger receptors (SR-AI/II) recognize a variety of polyanions including bacterial cell wall products such as lipopolysaccharide (LPS) and lipoteichoic acid (LTA), suggesting a role for SR-AI/II in innate immunity to bacterial infections. Here, we show that SR-AI/II–deficient mice (MSR-A−/−) are more susceptible to intraperitoneal infection with a prototypic gram-positive pathogen, Staphylococcus aureus, than MSR-A+/+ control mice. MSR-A−/− mice display an impaired ability to clear bacteria from the site of infection despite normal killing of S. aureus by neutrophils and die as a result of disseminated infection. Opsonin-independent phagocytosis of gram-positive bacteria by MSR-A−/− macrophages is significantly decreased although their phagocytic machinery is intact. Peritoneal macrophages from control mice phagocytose a variety of gram-positive bacteria in an SR-AI/II–dependent manner. Our findings demonstrate that SR-AI/II mediate opsonin-independent phagocytosis of gram-positive bacteria, and provide the first evidence that opsonin-independent phagocytosis plays a critical role in host defense against bacterial infections in vivo.

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Streptococcus gordonii Type I Lipoteichoic Acid Contributes to Surface Protein Biogenesis

mSphere ◽

10.1128/msphere.00814-19 ◽

2019 ◽

Vol 4 (6) ◽

Cited By ~ 2

Author(s):

Bruno P. Lima ◽

Kelvin Kho ◽

Brittany L. Nairn ◽

Julia R. Davies ◽

Gunnel Svensäter ◽

...

Keyword(s):

Cell Surface ◽

Biofilm Formation ◽

Cell Envelope ◽

Surface Protein ◽

Lipoteichoic Acid ◽

Type I ◽

Streptococcus Gordonii ◽

Gram Positive ◽

Content Type ◽

Gram Positive Bacteria

ABSTRACT Lipoteichoic acid (LTA) is an abundant polymer of the Gram-positive bacterial cell envelope and is essential for many species. Whereas the exact function of LTA has not been elucidated, loss of LTA in some species affects hydrophobicity, biofilm formation, and cell division. Using a viable LTA-deficient strain of the human oral commensal Streptococcus gordonii, we demonstrated that LTA plays an important role in surface protein presentation. Cell wall fractions derived from the wild-type and LTA-deficient strains of S. gordonii were analyzed using label-free mass spectroscopy. Comparisons showed that the abundances of many proteins differed, including (i) SspA, SspB, and S. gordonii 0707 (SGO_0707) (biofilm formation); (ii) FtsE (cell division); (iii) Pbp1a and Pbp2a (cell wall biosynthesis and remodeling); and (iv) DegP (envelope stress response). These changes in cell surface protein presentation appear to explain our observations of altered cell envelope homeostasis, biofilm formation, and adhesion to eukaryotic cells, without affecting binding and coaggregation with other bacterial species, and provide insight into the phenotypes revealed by the loss of LTA in other species of Gram-positive bacteria. We also characterized the chemical structure of the LTA expressed by S. gordonii. Similarly to Streptococcus suis, S. gordonii produced a complex type I LTA, decorated with multiple d-alanylations and glycosylations. Hence, the S. gordonii LTA appears to orchestrate expression and presentation of cell surface-associated proteins and functions. IMPORTANCE Discovered over a half-century ago, lipoteichoic acid (LTA) is an abundant polymer found on the surface of Gram-positive bacteria. Although LTA is essential for the survival of many Gram-positive species, knowledge of how LTA contributes to bacterial physiology has remained elusive. Recently, LTA-deficient strains have been generated in some Gram-positive species, including the human oral commensal Streptococcus gordonii. The significance of our research is that we utilized an LTA-deficient strain of S. gordonii to address why LTA is physiologically important to Gram-positive bacteria. We demonstrate that in S. gordonii, LTA plays an important role in the presentation of many cell surface-associated proteins, contributing to cell envelope homeostasis, cell-to-cell interactions in biofilms, and adhesion to eukaryotic cells. These data may broadly reflect a physiological role of LTA in Gram-positive bacteria.

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Streptococcus pneumoniae, S. mitis, and S. oralis produce a phosphatidylglycerol-dependent, ltaS-independent glycerophosphate-linked glycolipid

10.1101/2020.10.27.355933 ◽

2020 ◽

Author(s):

Yahan Wei ◽

Luke R. Joyce ◽

Ashley M. Wall ◽

Ziqiang Guan ◽

Kelli L. Palmer

Keyword(s):

Streptococcus Pneumoniae ◽

Lipoteichoic Acid ◽

Growth Defect ◽

Type I ◽

Gram Positive ◽

Gram Positive Bacteria ◽

Type Iv ◽

Biosynthetic Precursor ◽

Increased Sensitivity ◽

Host Microbe Interactions

AbstractLipoteichoic acid (LTA) is a cell surface polymer of Gram-positive bacteria. LTA participates in host-microbe interactions including modulation of host immune reactions. It was previously reported that the major human pathogen Streptococcus pneumoniae and the closely related oral commensals S. mitis and S. oralis produce Type IV LTAs. Herein, using liquid chromatography/mass spectrometry (LC/MS)-based lipidomic analysis, we found that in addition to Type IV LTA biosynthetic precursors, S. mitis, S. oralis, and S. pneumoniae also produce glycerophosphate (Gro-P)-linked dihexosyl-diacylglycerol (DAG), which is a biosynthetic precursor of Type I LTA. Mutants in cdsA and pgsA produce dihexosyl-DAG but lack (Gro-P)-dihexosyl-DAG, indicating that the Gro-P moiety is derived from phosphatidylglycerol (PG), whose biosynthesis requires these genes. S. mitis, but neither S. pneumoniae nor S. oralis, encodes an ortholog of the PG-dependent Type I LTA synthase, ltaS. By heterologous expression analyses, we confirmed that S. mitis ltaS confers poly-(Gro-P) synthesis in both Escherichia coli and Staphylococcus aureus, and that S. mitis ltaS can rescue the severe growth defect of a S. aureus ltaS mutant. However, despite these observations, we do not detect a poly-(Gro-P) polymer in S. mitis using an anti-Type I LTA antibody. Moreover, (Gro-P)-linked dihexosyl-DAG is still synthesized by a S. mitis ltaS mutant, demonstrating that S. mitis LtaS does not catalyze the transfer of Gro-P from PG to dihexosyl-DAG. Finally, a S. mitis ltaS mutant has increased sensitivity to human serum, demonstrating that ltaS confers a beneficial but currently undefined function in S. mitis. Overall, our results demonstrate that S. mitis, S. pneumoniae, and S. oralis produce a (Gro-P)-linked glycolipid via a PG-dependent, ltaS-independent mechanism.ImportanceLTA is an important cell wall component synthesized by Gram-positive bacteria. Disruption of LTA production can confer severe physiological defects and attenuation of virulence. We report here the detection of a biosynthetic precursor of Type I LTA, in addition to the previously characterized Type IV LTA, in the total lipid extracts of S. pneumoniae, S. oralis, and S. mitis. Our results indicate that a novel mechanism is responsible for producing the Type I LTA intermediate. Our results are significant because they identify a novel feature of S. pneumoniae, S. oralis, and S. mitis glycolipid biology.

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Gram-positive bacteria cell wall-derived lipoteichoic acid induces inflammatory alveolar bone loss through prostaglandin E production in osteoblasts

Scientific Reports ◽

10.1038/s41598-021-92744-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Tsukasa Tominari ◽

Ayumi Sanada ◽

Ryota Ichimaru ◽

Chiho Matsumoto ◽

Michiko Hirata ◽

...

Keyword(s):

Cell Wall ◽

Bone Loss ◽

Alveolar Bone ◽

Osteoclast Differentiation ◽

Lipoteichoic Acid ◽

Alveolar Bone Loss ◽

Gram Negative Bacteria ◽

Gram Positive ◽

Gram Negative ◽

Gram Positive Bacteria

AbstractPeriodontitis is an inflammatory disease associated with severe alveolar bone loss and is dominantly induced by lipopolysaccharide from Gram-negative bacteria; however, the role of Gram-positive bacteria in periodontal bone resorption remains unclear. In this study, we examined the effects of lipoteichoic acid (LTA), a major cell-wall factor of Gram-positive bacteria, on the progression of inflammatory alveolar bone loss in a model of periodontitis. In coculture of mouse primary osteoblasts and bone marrow cells, LTA induced osteoclast differentiation in a dose-dependent manner. LTA enhanced the production of PGE2 accompanying the upregulation of the mRNA expression of mPGES-1, COX-2 and RANKL in osteoblasts. The addition of indomethacin effectively blocked the LTA-induced osteoclast differentiation by suppressing the production of PGE2. Using ex vivo organ cultures of mouse alveolar bone, we found that LTA induced alveolar bone resorption and that this was suppressed by indomethacin. In an experimental model of periodontitis, LTA was locally injected into the mouse lower gingiva, and we clearly detected alveolar bone destruction using 3D-μCT. We herein demonstrate a new concept indicating that Gram-positive bacteria in addition to Gram-negative bacteria are associated with the progression of periodontal bone loss.

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Mixed liposomes containing gram-positive bacteria lipids: Lipoteichoic acid (LTA) induced structural changes

Colloids and Surfaces B Biointerfaces ◽

10.1016/j.colsurfb.2020.111551 ◽

2021 ◽

Vol 199 ◽

pp. 111551

Author(s):

Bhavesh Bharatiya ◽

Gang Wang ◽

Sarah E. Rogers ◽

Jan Skov Pedersen ◽

Stephen Mann ◽

...

Keyword(s):

Structural Changes ◽

Lipoteichoic Acid ◽

Gram Positive ◽

Gram Positive Bacteria

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Type I and Type II mechanisms of antimicrobial photodynamic therapy: An in vitro study on gram-negative and gram-positive bacteria

Lasers in Surgery and Medicine ◽

10.1002/lsm.22045 ◽

2012 ◽

Vol 44 (6) ◽

pp. 490-499 ◽

Cited By ~ 168

Author(s):

Liyi Huang ◽

Yi Xuan ◽

Yuichiro Koide ◽

Timur Zhiyentayev ◽

Masamitsu Tanaka ◽

...

Keyword(s):

Photodynamic Therapy ◽

In Vitro Study ◽

Vitro Study ◽

Type I ◽

Antimicrobial Photodynamic Therapy ◽

Type Ii ◽

Gram Positive ◽

Gram Negative ◽

Gram Positive Bacteria

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The Macrophage Scavenger Receptor Type A Is Expressed by Activated Macrophages and Protects the Host Against Lethal Endotoxic Shock

Journal of Experimental Medicine ◽

10.1084/jem.186.9.1431 ◽

1997 ◽

Vol 186 (9) ◽

pp. 1431-1439 ◽

Cited By ~ 202

Author(s):

Richard Haworth ◽

Nick Platt ◽

Satish Keshav ◽

Derralynn Hughes ◽

Elisabeth Darley ◽

...

Keyword(s):

Host Defense ◽

Bacterial Infections ◽

Endotoxic Shock ◽

Scavenger Receptor ◽

Type A ◽

Lipoteichoic Acid ◽

Protective Role ◽

Infection Model ◽

Macrophage Scavenger Receptor ◽

Tnf Α

During gram-negative bacterial infections, lipopolysaccharide (LPS) stimulates primed macrophages (Mφ) to release inflammatory mediators such as tumor necrosis factor (TNF)-α, which can cause hypotension, organ failure, and often death. Several different receptors on Mφ have been shown to bind LPS, including the type A scavenger receptor (SR-A). This receptor is able to bind a broad range of polyanionic ligands such as modified lipoproteins and lipoteichoic acid of gram-positive bacteria, which suggests that SR-A plays a role in host defense. In this study, we used mice lacking the SR-A (SRKO) to investigate the role of SR-A in acquired immunity using a viable bacillus Calmette Guérin (BCG) infection model. We show that activated Mφ express SR-A and that this molecule is functional in assays of adhesion and endocytic uptake. After BCG infection, SRKO mice are able to recruit Mφ to sites of granuloma formation where they become activated and restrict BCG replication. However, infected mice lacking the SR-A are more susceptible to endotoxic shock and produce more TNF-α and interleukin-6 in response to LPS. In addition, we show that an antibody which blocks TNF-α activity reduces LPS-induced mortality in these mice. Thus SR-A, expressed by activated Mφ, plays a protective role in host defense by scavenging LPS as well as by reducing the release by activated Mφ of proinflammatory cytokines. Modulation of SR-A may provide a novel therapeutic approach to control endotoxic shock.

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L-Ficolin Specifically Binds to Lipoteichoic Acid, a Cell Wall Constituent of Gram-Positive Bacteria, and Activates the Lectin Pathway of Complement

The Journal of Immunology ◽

10.4049/jimmunol.172.2.1198 ◽

2004 ◽

Vol 172 (2) ◽

pp. 1198-1202 ◽

Cited By ~ 186

Author(s):

Nicholas J. Lynch ◽

Silke Roscher ◽

Thomas Hartung ◽

Siegfried Morath ◽

Misao Matsushita ◽

...

Keyword(s):

Cell Wall ◽

Lipoteichoic Acid ◽

Lectin Pathway ◽

Gram Positive ◽

Gram Positive Bacteria ◽

Cell Wall Constituent ◽

A Cell

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Mechanism of Gram-positive Shock: Identification of Peptidoglycan and Lipoteichoic Acid Moieties Essential in the Induction of Nitric Oxide Synthase, Shock, and Multiple Organ Failure

Journal of Experimental Medicine ◽

10.1084/jem.188.2.305 ◽

1998 ◽

Vol 188 (2) ◽

pp. 305-315 ◽

Cited By ~ 164

Author(s):

Ken M. Kengatharan ◽

Sjef De Kimpe ◽

Caroline Robson ◽

Simon J. Foster ◽

Christoph Thiemermann

Keyword(s):

Nitric Oxide ◽

Multiple Organ Failure ◽

Organ Failure ◽

Lipoteichoic Acid ◽

Interferon Γ ◽

Multiple Organ ◽

Organ Injury ◽

Gram Positive ◽

Gram Positive Bacteria ◽

No Formation

The incidence of septic shock caused by gram-positive bacteria has risen markedly in the last few years. It is largely unclear how gram-positive bacteria (which do not contain endotoxin) cause shock and multiple organ failure. We have discovered recently that two cell wall fragments of the pathogenic gram-positive bacterium Staphylococcus aureus, lipoteichoic acid (LTA) and peptidoglycan (PepG), synergize to cause the induction of nitric oxide (NO) formation, shock, and organ injury in the rat. We report here that a specific fragment of PepG, N-acetylglucosamine-β-[1→ 4]-N-acetylmuramyl-l-alanine–d-isoglutamine, is the moiety within the PepG polymer responsible for the synergism with LTA (or the cytokine interferon γ) to induce NO formation in the murine macrophage cell line J774.2. However, this moiety is also present in the PepG of the nonpathogenic bacterium Bacillus subtilis. We have discovered subsequently that S. aureus LTA synergizes with PepG from either bacterium to cause enhanced NO formation, shock, and organ injury in the rat, whereas the LTA from B. subtilis does not synergize with PepG of either bacterium. Thus, we propose that the structure of LTA determines the ability of a particular bacterium to cause shock and multiple organ failure (pathogenicity), while PepG acts to amplify any response induced by LTA.

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