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    Team: Innate immunity, Toll-like receptors and variability of the inflammatory respons

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    Team leader


    Despite major investigative efforts, severe sepsis is still a major healthcare problem. The immune response to microbial pathogens relies on both innate and adaptive components. Our goal is to elucidate some of the mechanisms underlying the variability of the innate immune response at the cellular and individual level. Indeed, whereas sepsis remains defined by a constellation of non-specific symptoms and biological parameters, accumulating evidence underlines the existence of qualitative and quantitative differences in the responses to a given pathogen.

    Recognition of PAMPs by an infected host is a critical determinant of an effective innate and adaptive immune response. Detection of PAMPS is mediated by cell surface receptors that include Toll-like receptors (TLRs). Whereas members of the TLR family can detect a diverse array of microbial ligands, the specificity of the cellular response to a defined pathogen remains a mystery. TLR2 is involved in innate immune responses to Gram-positive bacteria, mycobacteria, spirochetes and fungi.

    To investigate the role of TLR2 in the cell response to Gram-positive bacteria, our project combines (i) a proteomic approach to thoroughly characterize the molecular activation clusters of the innate response to synthetic ligands of TLRs as well as  S. aureus and S. pneumoniae,; (ii) a comprehensive analysis of the functional consequences of TLR2 polymorphisms; (iii) a large-scale evaluation of clinical consequences of polymorphisms of innate immunity genes on the susceptibility to- and the severity of pulmonary infections. This approach could not only allow for a more in-depth understanding of innate immunity in the lung, but might also dramatically change preventive and therapeutic strategies in these patients. As extensive elucidation of signaling pathways initiated upon microbial invasion is critical to a better understanding of sepsis, our perspectives include implementation of DNA microarray technology to investigate microbe-specific and organ-specific responses in ICU patients.