A Thermodynamic Funnel Drives Bacterial Lipopolysaccharide Transfer in the TLR4 Pathway

Huber, Roland G.; Berglund, Nils; Kargas, Vasileios; Marzinek, Jan K.; Holdbrook, Daniel A.; Khalid, Syma; Piggot, Thomas J.; Schmidtchen, Artur; Bond, Peter J.

doi:10.1016/j.str.2018.04.007

Cited by 35 publications

(46 citation statements)

References 78 publications

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“…[60] developed a computational model to study the thermodynamics and affinity of the receptor complex in the process of LPS transfer to TLR4 and suggested that the lipid affinity increases along the TLR4 signaling cascade. The affinity for lipid A binding to CD14 (136 ± 13 kJ mol −1 ) is less than the affinity for MD2 (156 ± 11 kJ mol −1 ) and lipid A binding to the MD2/TLR4 complex (~400 kJ mol −1 ) is the most thermodynamically favored event [61]. Furthermore, Phe126 residue in MD2 is important for the transfer of LPS from CD14 to the TLR4-MD2 complex which acts as a hydrophobic switch to mediate the signaling at the TLR4 complex dimerization interface [60,61].…”

Section: Lps Recognition By Tlr4mentioning

confidence: 95%

“…The affinity for lipid A binding to CD14 (136 ± 13 kJ mol −1 ) is less than the affinity for MD2 (156 ± 11 kJ mol −1 ) and lipid A binding to the MD2/TLR4 complex (~400 kJ mol −1 ) is the most thermodynamically favored event [61]. Furthermore, Phe126 residue in MD2 is important for the transfer of LPS from CD14 to the TLR4-MD2 complex which acts as a hydrophobic switch to mediate the signaling at the TLR4 complex dimerization interface [60,61]. demonstrated that LPS binding leads to the dimerization of the TLR4/MD2-LPS complex, and LPS interacts with the hydrophobic pocket in MD-2 where five of six lipid chains are buried deep inside the pocket and one is exposed to the surface which interacts with a second TLR4 molecule.…”

Section: Lps Recognition By Tlr4mentioning

confidence: 95%

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Recent Advances in Lipopolysaccharide Recognition Systems

Mazgaeen

Gurung

2020

IJMS

231

156

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Lipopolysaccharide (LPS), commonly known as endotoxin, is ubiquitous and the most-studied pathogen-associated molecular pattern. A component of Gram-negative bacteria, extracellular LPS is sensed by our immune system via the toll-like receptor (TLR)-4. Given that TLR4 is membrane bound, it recognizes LPS in the extracellular milieu or within endosomes. Whether additional sensors, if any, play a role in LPS recognition within the cytoplasm remained unknown until recently. The last decade has seen an unprecedented unfolding of TLR4-independent LPS sensing pathways. First, transient receptor potential (TRP) channels have been identified as non-TLR membrane-bound sensors of LPS and, second, caspase-4/5 (and caspase-11 in mice) have been established as the cytoplasmic sensors for LPS. Here in this review, we detail the brief history of LPS discovery, followed by the discovery of TLR4, TRP as the membrane-bound sensor, and our current understanding of caspase-4/5/11 as cytoplasmic sensors.

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Section: Lps Recognition By Tlr4mentioning

confidence: 95%

Section: Lps Recognition By Tlr4mentioning

confidence: 95%

Recent Advances in Lipopolysaccharide Recognition Systems

Mazgaeen

Gurung

2020

IJMS

231

156

View full text Add to dashboard Cite

show abstract

“…15. This involved switching the GL0 and GL5 beads in our original E. coli LPS CG model and shortening the lengths of the carbon lipid tails (30). The initial CG model for S. aureus LTA was initially constructed based on an atomic model kindly provided by Dr. T. J. Piggot.…”

Section: Thrombin Fragments Aggregate Bacteria Molecular Dynamics Simmentioning

confidence: 99%

Thrombin-derived C-terminal fragments aggregate and scavenge bacteria and their proinflammatory products

Petrlova

Petruk

Huber

et al. 2020

Journal of Biological Chemistry

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Thrombin-derived C-terminal peptides (TCPs), including a major 11-kDa fragment (TCP96), are produced through cleavage by human neutrophil elastase and aggregate lipopolysaccharide (LPS) and the Gram-negative bacterium Escherichia coli. However, the physiological roles of TCP96 in controlling bacterial infections and reducing LPS-induced inflammation are unclear. Here, using various biophysical methods, in silico molecular modeling, microbiological and cellular assays, and animal models, we examined the structural features and functional roles of recombinant TCP96 (rTCP96) in the aggregation of multiple bacteria and the Toll-like receptor (TLR) agonists they produce. We found that rTCP96 aggregates both Gram-negative and Gram-positive bacteria, including Staphylococcus aureus and Pseudomonas aeruginosa, and their cell-wall components LPS, lipid A, and lipoteichoic acid (LTA). The Gram-negative bacteria E. coli and P. aeruginosa were particularly sensitive to aggregation-induced bacterial permeabilization and killing. As a proof of concept, we show that rTCP96 reduces LPS-induced NF-κB activation in human monocytes, as well as in mouse models of LPS-induced subcutaneous inflammation. Moreover, in a mouse model of subcutaneous inoculation with P. aeruginosa, rTCP96 reduced bacterial levels. Together, these results link TCP-mediated aggregation of endotoxins and bacteria in vitro to attenuation of inflammation and bacterial levels in vivo.

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“…to Toll-like receptor 4 (TLR4) and its co-receptor MD-2 on the cell surface, leading to activation of downstream inflammatory responses (11). In order to probe whether the presentation and hence, activity of LPS was altered by the interaction with S protein, we decided to study the pro-inflammatory effects of S with or without LPS using THP1-XBlue-CD14 cells.…”

Section: Effects Of Sars-cov-2 S Protein On Lps-induced Responses Inmentioning

confidence: 99%

SARS-CoV-2 Spike protein binds to bacterial lipopolysaccharide and boosts proinflammatory activity

Petruk

Puthia

Petrlova

et al. 2020

Preprint

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ABSTRACTThere is a well-known and established link between high lipopolysaccharide (LPS) levels in blood and the metabolic syndrome (MS). MS is a risk factor for developing severe COVID-19 and acute respiratory distress syndrome (ARDS). Here we define an interaction between SARS-CoV-2 Spike (S) protein and LPS and its link to aggravated inflammation in vitro and in vivo. Electrophoresis under native conditions demonstrated that SARS-CoV-2 S protein binds to Escherichia coli LPS, forming high molecular weight aggregates. Microscale thermophoresis analysis further defined the interaction, having a KD of ~47 nM, similar to the observed affinity between LPS and the human receptor CD14. Moreover, S protein, when combined with low levels of LPS, boosted nuclear factor-kappa B (NF-κB) and cytokine responses in monocytic THP-1 cells and human blood, respectively. In an experimental model of localized inflammation, employing NF-κB reporter mice and in vivo bioimaging, S protein in conjunction with LPS significantly increased the inflammatory response when compared with S protein and LPS alone. Apart from providing information on LPS as a ligand for S protein, our results are of relevance for studies on comorbidities involving bacterial endotoxins, such as the MS, or co-existing acute and chronic infections in COVID-19 patients.

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A Thermodynamic Funnel Drives Bacterial Lipopolysaccharide Transfer in the TLR4 Pathway

Cited by 35 publications

References 78 publications

Recent Advances in Lipopolysaccharide Recognition Systems

Recent Advances in Lipopolysaccharide Recognition Systems

Thrombin-derived C-terminal fragments aggregate and scavenge bacteria and their proinflammatory products

SARS-CoV-2 Spike protein binds to bacterial lipopolysaccharide and boosts proinflammatory activity

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