Structural Immunology

Because living organisms are always in contact with microorganisms, they have developed a system of biological structures and processes that protects against disease. Physical barriers prevent microbes from entering the organism. If a microbe breaches these barriers, the innate immune system provides an immediate, but non-specific response. If microbes successfully evade the innate response, vertebrates possess a second layer of protection, the adaptive immune system, which is activated by the innate response. We are studying the mechanism of the innate immune response at molecular and structural levels. We have chosen to work on the Dorosophila model organism for the following reasons: the lack of adaptive immunity, the correspondence of some pathways with those found in human, the impressive number of genetic data accumulated on this organism.
We have focused our work on the activation of the synthesis of antimicrobial peptides upon infection. We are especially interested by the detection of microorganisms and by the subsequent signaling cascades. Our main objective is to characterize at biochemical level the molecules (proteins) involved in these processes, to define the way they interact and to study their tridimensional structure by X-ray crystallography. All together, the genetic, functional and structural data will allow a better understanding of the role of the different proteins. The exact definition of the molecules will help to establish a general overview of the innate immune response in Drosophila and will be used as a model to decipher some homologous mechanisms in Human.

In all living species, the first line of defense against microbial aggressions is constituted by innate immunity. During evolution, it appeared in invertebrates and plants, long before adaptive immunity emerged in vertebrates. The innate immune system comprises a variety of components and mechanisms that can discriminate between different microorganisms and mount specific responses to control pathogenic infections. One of the most significant model systems that is used to investigate the innate immune response is the fruit fly, Drosophila melanogaster. Drosophila is easy and inexpensive to rear in the laboratory, produces numerous progeny and has a short (about 10 days) generation time. As an invertebrate, Drosophila is considered as ethically acceptable animal model. Exploration of the differential immune response presented by Drosophila led to the discovery of important signaling events and transduction pathways that were thereafter shown to be specific for the type of infecting pathogen. These factors and pathways were subsequently found to have homologues in many other organisms, including those with adaptive immune responses. This is exemplified by the discovery of the involvement of the Drosophila Toll receptor in the immune response, which stimulated the identification of the Toll-like receptors in mammals.
Genetic studies of the Drosophila immune response bring a wealth of data and give a rather comprehensive view of the strategies used to detect foreign intrusions and to mount appropriate responses. However, intimate descriptions of the molecular mechanisms at work need deeper molecular inspections to exploit all the power of the Drosophila model. The main goal of the team is to provide biochemical and structural information on proteins involved in the immune response in order to decipher the molecular mechanisms at work.

• Alain ROUSSEL (DR2, CNRS) : Group leader
  • Hervé DARBON
  • Christine KELLENBERGER
  • Renaud VINCENTELLI
  • Marilyne BLEMONT
  • Philippe LEONE
  • Chloe ROUSTAN

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 Molecular mechanism of activation of the Drosophila Toll receptor
 Activation and regulation of the Drosophila Imd and JAK/STAT pathways
 Study of the TSSP protease and its role in the diabete