> Pathogénie microbienne moléculaire - INSERM U389
• Summary
• Saga Shigella
• Objectives
• Genetics
• Cell Biology
• Inflammation
• Vaccines
4 - Innate and adaptive immunity in bacillary dysentery.
Group leader: Armelle Phalipon.
Post-doctoral scientists: Maria-Isabel Fernandez-Martinez, Karine Le Barillec.
Graduate student: Joao Gamelas.
Technician: Audrey Thuizat.
The major role played by secretory IgA directed against bacterial LPS in the protection against invasion of the epithelium by Shigella has been demonstrated ( ), The current work is aimed at understanding the mechanisms of mucosal immune protection against Shigella, both in the course of the primary infection by the innate response, and in the course of an infection in an immune individual. The characteristics of the innate response observed in the course of Shigella infection and how they modulate the nature of the adaptive response are particularly studied.
The effectors involved in the eradication of primary infection are studied in collaboration with James Di Santo. Using a model of infection of Rag2/bC mice, it has been shown that NK and TCD4+(b/b) lymphocytes are both involved in eradication of the primary infection via the production of interferon bb( INF-b). In addition, it seems that Shigella, at the very early stages of primary infection, modulate INF-bbproduction. This may constitute a key step in the induction and orientation of the protective humoral response.
The humoral response, specific for the polysaccharidic part of LPS (O-Ag), is crucial for protection against re-infection. The anti-O-Ag IgG-mediated immune response may contribute to protection only if the response is induced at the mucosal level in order to ensure the production of the effectors at the site of bacterial infection. Concerning the secretory IgA (S-IgA)-mediated response required to protect the mucosal surface from bacterial infection, in collaboration with Blaise Corthésy, it has been shown that the secretory component is directly involved in the protective function of S-IgA by ensuring, through its glycosylated residues, the appropriate localization of IgA for optimal immune exclusion ( ).
Moreover, LPS internalized by epithelial cells activates NF-bB, although with a slower kinetics than that observed with the invasive bacterium. Interestingly, LPS-mediated NF-bB activation is inhibited by a monoclonal IgA antibody specific for LPS that intercepts it during, its transcytosis (Fernandez et al., submitted). This is a newly and unexpected anti-inflammatory protective function of S-IgA. Therefore, S-IgA-mediated mucosal protection seems to occur via a double mechanism comprising immune exclusion of bacteria from the epithelial surface and intracellular neutralization of pro-inflammatory bacterial products.