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Bacterial surface molecule of dog bite infections more significant than expected

As a normal inhabitant of the mucous membrane of the mouth, the usually harmless bacterium Capnocytophaga canimorsus is adapted to its host, the dog. Should it, however, get into the human blood circulation through a dog bite wound, it can trigger rare but severe inflammatory reactions, which can, in some cases, lead to life threatening multi-organ failure. A scientific collaboration headed by Prof. Guy Cornelis, from the Biozentrum of the University of Basel, reveals in the journal PLoS Pathogens, that not only the surface molecule lipid A, as previously assumed, but also a second component plays an important role in this process.

The healthy organism is densely populated by bacteria. Most live with the host organism without causing it any harm.  This is the case with the bacterium Capnocytophaga canimorsus, a natural component of the bacterial flora in the mouth of the dog. This bacterium can be transmitted to man through small bites or even simply scratches but in some patients this can cause dramatic immune reactions, which can even lead to death. In collaboration with scientists in Hamburg and Lausanne, the research group of Guy Cornelis has refuted the conventional dogma, that lipid A, a specific part of the bacterial surface, is responsible for this strong immune reaction.

Effective lipid A and core region complex

Like any gram-negative bacteria, C. canimorsus bacteria release lipopolysaccharide molecules (LPS) – complex chemical compounds from their outer cell membrane.   During evolution, LPS has become one of the main signatures of a bacterial infection, triggering the innate immune system. LPS is made up of three main components; lipid A, a core region and various further sugar chains. As lipid A alone can bind to specific receptors on the innate immunity cells, it was previously assumed that it was only this component which caused an immune response to bacterial infections. The scientists working with Cornelis have now been able to demonstrate, that the core region also plays an important role. Investigations in structural biology, computer modeling and experiments with human cells and receptors, showed that lipid A from C. canimorsus alone causes only a slight stimulation of the immune cells.  It was only able to evoke a full immune response, in combination with the core region. «This finding throws a new light on the mechanism, which was long believed to be explained.» said Simon Ittig, first author of the study. «According to this, the core region helps lipid A to bind optimally to the respective receptors of the immune cells.»

New approaches to improve treatment

While the immune system of most individuals usually copes with an infection caused by C. canimorsus, in some patients such an infection often takes a very serious course. Until now, the pharmaceutical approach to bring the immune cells under alarm was to use active substances analogous to lipid A. The researchers‘ new evidence offers a further strategy to improve the design of such receptor-antagonists. The effectiveness of these drugs can be potentially improved by attaching a core region to the lipid A substance.
 
Original article:
Simon Ittig, Buko Lindner, Marco Stenta, Pablo Manfredi, Evelina Zdorovenko, Yuriy A Knirel, Matteo Dal Peraro, Guy R Cornelis, Ulrich Zähringer (2012). The Lipopolysaccharide from Capnocytophaga canimorsus Reveals an Unexpected Role of the Core region-Oligosaccharide in MD-2 Binding. PLoS Pathogens, Published online May 3rd, 2012.

Contact: Communications, Katrin Bühler