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Jules Hoffmann was born in Luxembourg where he gained his bacchalaureate, after which he left for the University of Strasbourg to study biology and chemistry. He did his Ph.D. work with Professor Pierre Joly on the origins and roles of blood cells in the grasshopper Locustra migratoria, a major pest in Northern and Western Africa. J. Hoffmann has subsequently devoted his scientific life to the study of insects. Following his Ph.D. work, while still in Strasbourg, he X-ray treated the hematopoïetic tissue which he had discovered in grasshoppers and noted two dramatic effects which would thereafter orient his scientific career: (1) the X-ray treated insects failed to molt if the treatment was performed before a critical developmental period within the duration of the larval instars ; (2) the X-ray treated insects developed spontaneously a lethal septicemia involving various opportunistic microorganisms. The first effect pointed to a failure in the control of molting by the steroid hormone ecdysome, which had just been discovered by the great German biochemist Peter Karlson. J. Hoffmann went for an extended post-doctoral period to work with Karlson in Marburg (Germany) on steroid hormones in development and reproduction, and he continued this field of research with the renowned French chemist Guy Ourisson upon his return to Strasbourg. Eventually, the biosynthesis and metabolism of ecdysome were worked out and novel suicide-inhibitors were devised which were able to block the development of grasshoppers and other pests. In the course of these studies, J.Hoffmann and colleagues made the seminal discovery that massive ecdysone synthesis occurs in the ovaries of reproductively competent female grasshoppers and that a phosphoconjugate storage form is transferred to the oocyte and serves, after hydrolysis in the embryo, to control the cycles of embryonic cuticulogenesis. Whilst the studies on ecdysone had priority over many years in the group, experimental work on the immune system of grasshoppers continued by some of Hoffmann’s co-workers and culminated in the discovery in late 80ies of several novel inducible antimicrobial peptides in various insect species, namely the cysteine-rich defensins. In 1990, J.Hoffmann and his group decided to solely focus on the origin and role of these inducible antimicrobial peptides and to select Drosophila, as a genetically tractable model system, for their studies. In the early 90ies, J.Hoffmann and colleagues then succeeded in identifying in immunechallenged flies seven distinct families of inducible antimicrobial peptides produced by the fat body, an equivalent of the mammalian liver. Most of these peptides were found to be membrane-active and their activities were directed against either fungi (named drosomycin and metchnikowin by the group), Gram-positive bacteria (defensin) or Gram-negative bacteria (diptericin, drosocin, cecropin, attacin). J.Hoffmann and his colleagues next addressed the molecular regulation of the infection-induced expression of these antimicrobial peptides. A major breakthrough in the mid-nineties was the discovery that two distinct pathways regulate the response to infection at the transcriptional level. Remarkably, the pathway which responds to fungal and Gram-positive bacterial infection was shown by the group to involve part of a signaling cascade initially characterized for its role in the control of dorsoventral patterning in the embryo. The cascade is activated through a transmembrane receptor, called Toll. This receptor associates an extracellular domain similar to that of the by then known LPS-binding membrane linked protein CD14 and an intracellular domain homologous to that of the intracytoplasmic domain of the proinflammatory cytokine IL-1, which is a known activator of NF-B. Loss of function flies failed to induce the synthesis of antifungal peptides and were unable to resist fungal infections. The discovery that Toll was essential for innate resistance to fungi in adult flies anticipated, and directly led to the discovery of the innate immune sensing functions of the mammalian Toll-like receptors, and provoked a revolution in thought among immunologists throughout the world. As in the fly, the mammalian Toll-like receptors were shown to signal through NF-B family members and to lead to reprogramming of gene 1 expression. Significantly, many of the newly-expressed genes in mammals encode cytokines, co-stimulatory molecules, MHC proteins etc., which all concur to activate and orient the adaptive immune responses. Whereas in the pre-Toll era, defense to microorganisms was understood to be mediated primarily by phagocytosis or by the adaptive immune responses based on rearranging receptors of B- and T-lymphocytes, a novel facet has nom become apparent : a family of a dozen invariant Toll like receptors recognizes evolutionary conserved microbial molecules and in response activates expression of immune-response genes many of which are regulate efficient lymphocyte responses. Whereas in 1996 the Cell paper of the Hoffmann laboratory was the first and only study linking Toll receptors to a defined hostdefense, more than 6,500 papers have been published in this field since and innate immunity has now moved to the very forefront of immunology. Hoffmann and his colleagues continued their studies by using genetic methods to identify the component of the second immune signaling pathway in flies (which they had named Imd, after a loss of function mutation resulting in immune-deficiency to Gram-negative bacteria). Their studies have in large part deciphered the molecular events that lead from the activation of the innate immune receptor to transcriptional control of gene expression. Of particular interest is their recent functional dissection of a family of peptidoglycan recognition receptors which bind to and are activated by various forms of peptidoglycan and direct the immune responses either via the Toll or the Imd pathway. Proteins homologous to these peptidoglycan recognition proteins have since been found in mammals where they appear to exert a bactericidal action. Further, in a manuscript in press in Cell, the laboratory now reports that proteases produced by invading filamentous fungi can also induce the Toll pathway by activating zymogens in the circulating blood of the flies. The induction of an immune response by microbial proteases is an important new concept which could prove in the future to be of paramount importance in host-pathogen interactions, as most microbes, including protozoan parasites, secrete proteases in their hosts. J.Hoffmann has recently extended his interests and those of some of his co-workers to antiviral defenses in Drosophila. So far, the results point to mechanisms distinct from those devoted to fighting fungal or bacterial infections. For one, RNA interference appears as a potent defense mechanism, which together with a STAT-JAK pathway dependent reprogramming of gene expression accounts for much of the resistance of the flies to viruses. The latter aspect can be regarded as a fac-simile of the mammalian interferon system. The impressive array of tools that the Hoffmann laboratory has developed are now being used to fully understand the antiviral response, which will also likely prove to be revealing for mammalian systems. With the purpose of applying the information gained on the Drosophila host defense to medically important vector insects, Hoffmann has recently started a new group on the postgenomic analysis on the immune defense of the mosquito Anopheles to the parasite Plasmodium. The group has recently documented that a mosquito equivalent of the Drosophila Toll pathway can abort infection by the malaria parasite in the mosquito. The group has identified a complement-like protein as a mediator of this immune response. These novel results are obviously of great potential and the molecular mechanisms of parasite killing are under intense studies in the laboratory. Hoffmann remains a highly active investigator in spite of his involvement in the French Academy of Sciences and in other national and international boards. He is at present particularly involved in the studies on antiviral and antiparasitic defenses of Drosophila and 2 Anopheles, respectively. In addition, Hoffmann has very recently built up a new group with three post-doctoral researchers which aims at studying at the genetic and biochemical levels the role of the Imd and Toll pathways in inflammation. New, mostly unpublished, data now indicate that the Imd pathway (and probably also the Toll pathway) is activated in the absence of any infection, in flies in which a neurodegenerative phenotype has been induced as well as in loss of function flies for the DNase genes (which scavenge DNA from apoptotic cells during development). These phenotypes are evocative of inflammatory reactions, an aspect not considered in flies to date. Hoffmann plans with this new group to make an indepth analysis of inflammation, using many of the tools and mutants which have been generated in the course of the studies on antimicrobial defenses. This area represents a novel frontier and given the parallels which exist between immune defenses of flies and mammals, these studies may help understand inflammation in mammalian systems. They could also bring significant insights into the crucial problem of identifying endogenous (non-microbial) inducers of inflammation. In conclusion, Hoffmann discovered the key pathways for resistance to infection in Drosophila and paved the way to a revolution in the science of innate immunity. He continues his work very actively to understand antiviral defense mechanisms and inflammatory reactions to abnormal non-infectious self. He is also strongly involved in extending the knowledge gained in immune defenses in Drosophila to the antiparasitic defense in the malaria vector Anopheles. Hoffmann is the founder of a school of internationally recognized group leaders, namely Bruno Lemaitre (Lausanne), Julien Royet (Marseille), Jean-Luc Imler, Dominique Ferrandon, Elena Levashina, Jean-Marc Reichhart, Charles Hetru and Maria Capovilla (Ferrara). He has authored or co-authored more than 250 papers, many of which appeared in Cell, Science, Nature, Nature Immunology, Immunity and other high ranking journals. He has received many awards, in particular the William Coley Award of the Cancer Research Institute (2003), the Koch Prize for Immunology of the Robert Koch Stiftung (2004) and the Grand Prix de la Fondation pour la Recherche Médicale (2004). He is the President of the French Academy of Sciences and a Member of the German Academy of Sciences Leopoldina, the Russian Academy of Sciences, the European Molecular Biology Organization, Academia Europaea, the American Academy of Arts and Sciences and the National Academy of the United States. 3