Clotting Agent Fragments Help Reduce Sepsis Risk

Small fragments of the coagulating protein thrombin may reduce the likelihood of bacterial wound infection leading to sepsis

Cancer cells, cilia development, air pollution, photonic devices, Micro-lens, mosquito-borne infections, Microbiota, bone repair, 3D printing, neurodegenerative disease, cancer treatments, biological research, sepsis, foot and mouth disease, cytometry, batteries, Influenza A virus, vascular diseases, New Cancer Drugs, RNA molecules, polymers, antimicrobial resistance, Aging White Blood Cells, microviscosity, Transplant Drug, Nanophotonics, photonics, Built-In Nanobulbs, cerebral cortex, cancer cells, nanowires, optoelectronic, solar energy, gold nanowires, Chikungunya virus, concrete, glaucoma, light-emitting diode, Proteomics, nanostructures, nickel catalyst, Ultrafast lasers, liver capsular macrophages, obesity, cancer, lignin polymer, liver capsular macrophages, Ultrafast lasers, monocyte cells, cancer treatments, antibody drug, gene mutations, quantum-entangled photons, gut microbes, skin aging, stroke, machine learning, Cloned tumors, cancer, Rare Skin Disease, terahertz lasers, silicon-nanostructure pixels, oral cancer, heart muscle cells, cancer, cancer stem cells, gastric cancer, microelectromechanical systems, data storage, silicon nanostructures, Drug delivery, cancer, muscle nuclei, Lithography, silicon nanostructures, Quantum matter, robust lattice structures, potassium ions, Photothermal therapy, Photonic devices, Optical Components, retina, allergy, immune cells, catalyst, Nanopositioning devices, mold templates, lung cancer, cytoskeletons, hepatitis b, cardiovascular disease, memory deficits, Photonics, pre-eclampsia treatment, hair loss, nanoparticles, mobile security, Fluid dynamics, MXene, Metal-assisted chemical etching, nanomedicine, Colorectal cancer, cancer therapy, liver inflammation, cancer treatment, Semiconductor lasers, zika virus, catalysts, stem cells, fetal immune system, genetic disease, liver cancer, cancer, liver cancer, RNA editing, obesity, Microcapsules, genetic disease, Piezoelectrics, cancer, magnesium alloy, Quantum materials, therapeutic antibodies, diabetes, 2D materials, lithium-ion batteries, obesity, lupus, surfactants, Sterilization, skin on chip, Magnetic Skyrmions, cyber-security, wound infections, human genetics, immune system, eczema, solar cells, Antimicrobials, joint disorder, genetics, cancer

The protein thrombin is vital for ensuring blood coagulates in a wound, but new research suggests small fragments of it, called thrombin-derived C-terminal peptides (TCPs), could also decrease the risk of sepsis in response to bacterial contamination.

In collaboration with researchers in Singapore, Sweden, and Copenhagen, scientists at the A*STAR Bioinformatics Institute have conducted computer modeling and experiments to explore the role played by TCPs, less than 20 amino acids long, that are formed when thrombin is cleaved as part of the blood clotting process.

“Biology is not wasteful, and when this protein is cleaved, the bits have lots of other functions other than just being a bystander in the clotting process,” says Peter Bond, from the A*STAR Bioinformatics Institute.

TCPs are known to bind to lipid molecules found on the surface of bacteria, called lipopolysaccharides. Bacterial lipopolysaccharides are key triggers for the over-active immune response that can lead to the potentially fatal blood infection, sepsis. By forming aggregates with the lipopolysaccharides, the short-chain thrombin peptides effectively mop them up and neutralize them.

However, the mechanism by which they do this is not well understood, and there is evidence to suggest that the TCPs do more than simply get rid of excess bacterial lipopolysaccharides.

In this study, the researchers used a range of techniques, including nuclear magnetic resonance spectroscopy and mass spectrometry, to work out the three-dimensional structure of the HVF18 thrombin peptide and lipopolysaccharide aggregates. With this information, Bond and his team were able to model a TCP and its interactions with lipopolysaccharides to better understand how they bind together and aggregate.

They found that TCPs appear to interact with a receptor called CD14, found on the surface of immune cells. CD14 is known to bind to bacterial lipopolysaccharides in a process that initiates an inflammatory immune response, and potentially also triggers sepsis.

The modeling suggests that TCPs somehow block the functioning of CD14 associated with the bacterial lipopolysaccharides, and therefore help to avoid an extreme immune response.

“That’s the interesting thing about all these peptides; it seems as though nature develops not just one kind of weapon, but a whole range of weapons with lots of different functionalities,” Bond says. “On the one hand, they’re serving to kill the bacteria, on the other hand they’re serving to protect the immune system from over-inflammation.”

By better understanding the structure and function of these small-chain peptides, the hope is to use them to develop better anti-infective treatments.

The A*STAR-affiliated researchers contributing to this research are from the Bioinformatics Institute.  For more information about the team’s research, please visit the Biomolecular Modelling and Design Division webpage.