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2004 World Technology Awards Winners & Finalists
Please describe the work that you are doing that you consider to be the most innovative and of the greatest likely long-term significance.
Microbial infections are characterised by a continual dramatic interplay between pathogen and host: pathogens exploit an array of host cell functions during infection and their hosts respond with powerful immune responses. On the microbial side, this complex process involves the timely expression of virulence factors that mediate adhesion to the host surface, and eventually lead to colonization and persistence, thereby, causing tissue damage and disease. On the host side, sophisticated defence mechanisms are activated in response to infection that ususally clear the microbes. However, the complexity of host-pathogen interaction is underscored if one considers that “disease”, the focus of most researchers, is only one part of infectious process: pathogens often persist in the environment in reservoir species and are often transmitted by vectors. As the consequence, the overall biological complexity of host-pathogen interaction is poorly understood and scientists tend to focus their attention on discreet steps of the process. To comprehend host-pathogen interactions at the molecular level, both the host and pathogen should ideally be amenable to genetic analysis. My group has started to develop an “integrated” approach of host-pathogen analysis using the fruit fly, Drosophila melanogaster,as a model host. As illustrated by my pioneering work on the Toll receptor (see below), Drosophila provides a powerful model system for dissecting innate host defence mechanisms. Recently, we have identified bacterial and fungal pathogens that infect Drosophila naturally and with a high degree of specificity, indicating that these species have evolved mechanisms for exploiting Drosophila as a host. To study these mechanisms, we are now using molecular and genetic approaches to identify microbial virulence factors as well as their targets in Drosophila. A good example of the power of this approach is our work on a new bacterial species named Pseudomonas L48 that we identified for its capacity to colonize and kill flies after infection via the digestive tract (unpublished studies). An important project in the lab is now to characterize the different steps involved in the pathogenicity of Pseudomonas L48 during Drosophila infection. First, we have identified the bacterial factors that are required to infect, persist and provoke damage in the fly by using a genetic screen. This step was greatly facilitated by the complete sequence determination of the L48 genome that was done in collaboration with the Genoscope (Evry, France). Identification of L48 virulence factors will not only allow us to understand their role(s) in the different steps of the pathological process, but should also help us understand the mechanisms that limits interaction of pathogens with certain hosts. Second, we are currently analysing the effect of a natural infection on the fly transcriptome and, thereby, identify the fly genes that are specifically induced after L48 ingestion. The same analysis after infection by different types of L48 mutants will allow us to identify bacterial genes that may influence host responses. This project will be complemented by an extensive genetic screen for Drosophila factors required for L48 pathogenesis. We are especially interested in studying the “physiology of the host response”, or the sequential and coordinated activation of various immune defence reactions in multiple tissues, a process that is still poorly understood. Thus, this pathogenic bacterial strain and the Drosophila host together offer the possibility to study all phases of infection, from the initial interaction between the pathogen and its host, to the activation of the immune responses. The combination of these two systems should, for the first time, provide an integrated view of the interactions between an animal pathogen and its host. The sharing of infectious strategies between a wide range of prokaryotic pathogens, and the conservation of multiple aspects of innate immunity suggest that our analysis of host-pathogen interactions in Drosophila will have a global relevance. (For more information and description of other projects done in my lab, please visit: http://www.cnrs-gif.fr/cgm/immunity/enindex.html).
Brief Biography: I obtained my PhD in 1992 with Dario Coen at the University Pierre and Marie Curie (Paris) while studying mechanisms of P element transposition in Drosophila. Next, I joined the laboratory of Jules Hoffmann (CNRS, Strasbourg, France) as a research associate where I analysed the role of the Toll and Imd genes in the Drosophila immune response. In 1998, I started my own lab at the Centre Génétique Moléculaire (Gif-sur-Yvette, France).
Awards 1998 : ATIPE CNRS 2000 : Young Investigator Program (EMBO) 2001 : Prize Noury, Thorlet, Lazare from the French Academy of Sciences (personal prize) 2002 : First Prize of the Schlumberger Foundation 2003: William B. Coley Award for distinguished research in basic and tumor immunology (American Cancer Research Institute) (personal prize) 2004: Award from the Bettencourt-Schueller Foundation
In 1993, I joined Jules Hoffmann’s group at the University of Strasbourg. His laboratory was working on insect immune responses using molecular and biochemical approaches. I initiated the first genetic studies of insect immunity in order to elucidate the mechanisms that regulate antimicrobial peptide gene expression.
- immune deficiency and the antibacterial response pathway (Lemaitre et al. 1995, Proc. Natl. Acad. Sci. USA 92:9465-9469) I identified the first Drosophila mutation, immune deficiency (imd), that blocks both the expression of the genes that encode antibacterial peptides and confers high susceptibility to bacterial infection. This mutation defines a novel signaling pathway regulating Drosophila antibacterial responses.
Toll and the antifungal response pathway (Lemaitre et al., 1996, Cell 86:973-983) I demonstrated that the Toll signaling cascade that was known to regulate the NF-kB factor, Dorsal, during embryonic development, also regulates Drosophila antimicrobial responses. Our demonstration of Toll function in the antifungal immune response provided the first evidence that Toll receptors play an important role in animal host defence.
-Specificity of Drosophila immune responses (Lemaitre et al., 1997 Proc. Natl. Acad. Sci. USA 94: 14614-619) By using different bacteria and fungi, I revealed Drosophila’s ability to differentiate between pathogens and mount specific immune responses through the selective activation of either the Imd or Toll pathways. This work demonstrated that pathogen recognition leads to specific innate immune responses when Pattern recognition receptors are coupled to distinct signaling cascades.
These three studies sets the basis of the Toll and Imd model which still exerts a strong influence on the innate immunity field. A Perspective “The road to Toll” describing these studies will appear in July 2004 in Nature Review Immunology.
Since 1998, my team has continued these studies by the isolation of new components of the Imd and Toll pathways; by the characterization of the bacterial determinants that trigger the Toll and Imd pathways; by the identification of the first bacterial species that infects Drosophila via natural routes; and by extensive genomic analysis of Drosophila immune responses.
Impact of these studies My demonstration that Toll regulated Drosophila immune responses through a conserved signaling cascade inspired a search for mammalian Toll like proteins that also mediate host defense reactions. Medzhitov and Janeway, who were linked to the Hoffmann lab through a Human Frontiers Grant, were the first, in 1997, to implicate a Toll-related protein (TLR) in the activation of mammalian immune response (Nature 388:394-397). Subsequently, a series of remarkable studies demonstrated the crucial role of mammalian TLRs in the regulation of NF-_B, a central mediator of the mammalian innate immunity, in response to several microbial elicitors. For example, mice deficient for TLR4, TLR2 or TLR9 do not respond to Lipopolysaccharides, Peptidoglycans and bacterial DNA respectively. TLRs are now the focus of intense research. Therefore, our study has strongly stimulated the field of innate immunity and demonstrated the power of Drosophila as a model for dissecting these processes.
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