Bruce Beutler et Jules Hoffmann

États-Unis et France/Luxembourg

Prix Balzan 2007 pour l'immunité innée

Projet de recherche 

Endogenous Activators of Inflammation in Insects and Mammals

Bruce Beutler is Professor and Chairman of the Department of Genetics at Scripps Research Institute in La Jolla, California. Jules A. Hoffmann is Distinguished Class Research Director (Emeritus) at the Centre National de la Recherche Scientifique of the Institute of Molecular and Cellular Biology in Strasbourg. The second half of the Balzan Prize to Bruce Beutler and Jules Hoffmann encouraged joint efforts regarding the establishment of a model of inflammation in insects and mammals. The parallel study on inflammation in the absence of germs in the fruit fly (Drosophila) and in mice could lead to the future discovery of the causes by which, in humans, antibodies of endogenous origin are also activated in the absence of the pathogenic germs they are supposed to fight, thus producing autoimmune diseases. The two Prizewinners hired young researchers and supervised research work in their respective laboratories, which led to a comparative analysis of the IMD (fly) and TNFTLR (mouse) proinflammatory, signalling pathways in infection and development.

In La Jolla, Dr. Michael Berger screened peptidomimetic libraries for activators of TLR signalling. These studies, designed to identify molecules that could cause unconventional activation of TLR signalling, were performed as a collaboration with the laboratory of Professor Dale Boger at the Scripps Research Institute. Dr. Oren Milstein searched for immune activating functions of peptides that do not exist in the mouse proteome. Dr. Philippe Krebs studied mutations that cause inflammatory disease and their attenuation by mutations that disrupt TLR signalling. Particularly significant was his demonstration that signalling via TLRs drives the lethal in- flammatory disorder observed in mice with deficiency of the inositol polyphosphate 5 phosphatase, SHIP-1. Drs. Sungyong Won and Lei Sun worked jointly to develop a technique for cloning mice from fibroblasts, with the goal of screening these cells en masse for ex vivo phenotypes (including spontaneous inflammatory phenotypes) before regenerating mice from them and positionally cloning the causative mutations. Dr. Carrie Arnold initiated a screen for defects in the adaptive immune response, and succeeded in identifying eleven mutations to date. Dr. Amanda Blasius identified a key molecule for the responses of plasmacytoid dendritic cells to nucleic acids.

In Strasbourg, Dr. Hidehiro Fukuyama pursued a biochemical strategy to identify proteins that interact with components of the stands for immune-deficiency pathway (IMD, homologous to mammalian TNF) in Drosophila to limit inflammation caused by endogenous stimuli. Dr. Anne Kaukinen made a functional analysis of some of the proteins isolated by Dr. Fukuyama, and namely addressed their potential roles in activating antimicrobial peptide gene expression following stimulation by a bacterial pathogen. Exciting new data point to a significant role of the IMD signalling pathway in the defence of flies against several viral pathogens. The Balzan funds for Professor Hoffmann’s group concentrated on developing this new line of research. Professor Hoffmann gave a lecture entitled Gene Expression and Signalling in the Immune System at the sixth Cold Spring Harbor meeting in April 2012.

Fukuyama H, Ndiaye S, Hoffmann J, Rossier J, Liuu S, Vinh J, Verdier Y. 2012. On-bead tryptic proteolysis: An attractive procedure for LC-MS/MS analysis of the Drosophila caspase protein complex during immune response against bacteria. Journal of Proteomics. DOI:10.1016/j.jprot.2012.03.003.

Liu X, Sano T, Guan Y, Nagata S, Hoffmann JA, Fukuyama H. 2012. Drosophila EYA Regulates the Immune Response against DNA through an Evolutionarily Conserved Threonine Phosphatase Motif. Journal PLos One. PLoS ONE 7(8): e42725. DOI:10.1371/journal.pone.0042725 (15.08.2012).

Excerpt from the: The Balzan Prizewinners’ Research Projects: An Overview 2018