A Genetic Variation of Lipopolysaccharide Binding Protein Affects the Inflammatory Response and Is Associated with Improved Outcome during Sepsis.
Oliver KumpfKathleen GürtlerSaubashya SurMonalisa ParvinLena-Karoline ZerbeJana Kristin EckertAlexander N R WeberDjin-Ye OhLinn LundvallLutz HamannRalf R SchumannPublished in: ImmunoHorizons (2021)
LPS binding protein (LBP) is an important innate sensor of microbial cell wall structures. Frequent functionally relevant mutations exist and have been linked to influence susceptibility to and course of bacterial infections. We examined functional properties of a single nucleotide polymorphism resulting in an exchange of phenylalanine to leucine at position 436 of LBP (rs2232618) and compared the frequent variant of the molecule with the rare one in ligand binding experiments. We then stimulated RAW cells with bacterial ligands in the presence of serum obtained from individuals with different LBP genotypes. We, furthermore, determined the potential effects of structural changes in the molecule by in silico modeling. Finally, we analyzed 363 surgical patients for this genetic variant and examined incidence and course of sepsis following surgery. We found that binding of LBP to bacterial ligands was reduced, and stimulation of RAW cells resulted in an increased release of TNF when adding serum from individuals carrying the F436L variant as compared with normal LBP. In silico analysis revealed structural changes of LBP, potentially explaining some of the effects observed for the LBP variant. Finally, patients carrying the F436L variant were found to be similarly susceptible for sepsis. However, we observed a more favorable course of severe infections in this cohort. Our findings reveal new insights into LPS recognition and the subsequent activation of the innate immune system brought about by LBP. The identification of a genetic variant of LBP influencing the course of sepsis may help to stratify individuals at risk and thus reduce clinical complications of patients.
Keyphrases
- inflammatory response
- binding protein
- end stage renal disease
- acute kidney injury
- intensive care unit
- immune response
- ejection fraction
- induced apoptosis
- newly diagnosed
- chronic kidney disease
- prognostic factors
- peritoneal dialysis
- rheumatoid arthritis
- toll like receptor
- cell wall
- minimally invasive
- microbial community
- climate change
- lps induced
- oxidative stress
- early onset
- cell cycle arrest
- patient reported outcomes
- mass spectrometry
- single cell
- endoplasmic reticulum stress
- signaling pathway
- percutaneous coronary intervention
- cell death