Journal Article

Antibody WN1 222-5 mimics Toll-like receptor 4 binding in the recognition of LPS

Evans, Stephen V., Brooks, Cory L., Brade, Lore, Di Padova, Franco, Brade, Helmut, Müller-Loennies, Sven, Gomery, Kathryn, Kosma, Paul

2012

Overview

Escherichia coli infections, a leading cause of septic shock, remain a major threat to human health because of the fatal action to endotoxin (LPS). Therapeutic attempts to neutralize endotoxin currently focus on inhibiting the interaction of the toxic component lipid A with myeloid differentiating factor 2, which forms a trimeric complex together with Toll-like receptor 4 to induce immune cell activation. The 1.73-Å resolution structure of the unique endotoxin-neutralizing protective antibody WN1 222-5 in complex with the core region shows that it recognizes LPS of all E. coli serovars in a manner similar to Toll-like receptor 4, revealing that protection can be achieved by targeting the inner core of LPS and that recognition of lipid A is not required. Such interference with Toll-like receptor complex formation opens new paths for antibody sepsis therapy independent of lipid A antagonists.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Animals / antagonists / Antibodies / Antibodies - chemistry / Antibodies, Monoclonal - chemistry / Antigen-Antibody Complex / Antigens / Binding sites / Biological Sciences / Carbohydrates - chemistry / Crystal structure / E coli / Endotoxins / Endotoxins - metabolism / Epitopes / Escherichia coli / Escherichia coli - metabolism / Escherichia coli Infections - metabolism / human health / Hydrogen Bonding / Hydrogen bonds / Inner cores / Ligands / lipid A / Lipids / Lipids - chemistry / Lipopolysaccharides - chemistry / Mice / Mice, Inbred BALB C / Models, Chemical / Models, Molecular / neutralization / Polyclonal antibodies / Protein Binding / Sepsis / Septic shock / serotypes / Shock, Septic - metabolism / Sugars / therapeutics / Toll-like receptor 4 / Toll-Like Receptor 4 - chemistry / toxicity / Toxins