By studying the mycobacteria that cause tuberculosis, molecules with anti-inflammatory properties have been identified by the team led by Valérie Quesniaux in the Laboratoire Immunologie et Embryologie Moléculaires, working in collaboration with the Institut de Chimie Organique et Analytique (both based in the University of Orléans/CNRS). These molecules, as well as several new analogs, have been synthesized. Their anti-inflammatory activity has been confirmed, improved and demonstrated in the mouse, as reported in The Journal of Biological Chemistry on August 28, 2009.
The mycobacteria that cause tuberculosis (Mycobacterium tuberculosis) can remain silent for many years in man, thus eluding surveillance by the immune system. In 90% of individuals, the infection is controlled but not eradicated, and the mycobacterium can sometimes survive for several decades. Mycobacterium tuberculosis produces several complex proteins and glycolipids (a combination of sugars and lipids) that are capable of modulating the immune response.
Valérie Quesniaux's team has focused on the interactions between the mycobacterium and its host at the molecular scale, and on the resulting immune mechanisms. On the cell wall of the mycobacteria, the scientists identified low molecular mass glycolipids with very interesting anti-inflammatory properties, the PIM (Phosphatidyl Inositol Mannosides). They synthesized these PIM and reproduced their anti-inflammatory properties.
The team then turned to the synthesis of novel, analog molecules, thus considerably simplifying their synthesis. And indeed, the first example of this new family proved to be even more active than the natural or synthetic molecules tested hitherto. During their study, the researchers demonstrated the enhanced anti-inflammatory activity of these novel PIM molecules both in vitro and in an in vivo model of pulmonary inflammation.
Two patents have been filed in the context of this research. The use of such immunomodulating molecules of microbial origin for therapeutic purposes is seeing considerable growth. These new molecules could be used in the treatment of severe, chronic, inflammatory diseases such as rheumatoid arthritis, Crohn's disease or psoriasis.
- Emilie Doz, Stéphanie Rose, Nathalie Court, Sophie Front, Virginie Vasseur, Sabine Charron, Martine Gilleron, Germain Puzo, Isabelle Fremaux, Yves Delneste, François Erard, Bernhard Ryffel, Olivier R. Martin and Valerie F. J. Quesniaux. Mycobacterial Phosphatidylinositol Mannosides Negatively Regulate Host Toll-like Receptor 4, MyD88-dependent Proinflammatory Cytokines, and TRIF-dependent Co-stimulatory Molecule Expression. Journal of Biological Chemistry, 2009; 284 (35): 23187 DOI: 10.1074/jbc.M109.037846
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