Molecular Microbial Pathogenesis Unit
Team: "Shigella : manipulation of adaptive immunity and vaccine development"
Institut Pasteur 25-28 rue du docteur Roux, 75015 Paris
Research area of the Unit
Shigella is a Gram-negative enteroinvasive bacterium, responsible for shigellosis or bacillary dysentery, an acute recto-colitis. Over the years, our group has deciphered the targets and effectors of the humoral response induced in response to infection and discovered two novel molecular mechanisms of secretory IgA-mediated protection at mucosal surfaces. We are currently studying the impact of direct targeting of cells of the adaptive immunity by Shigella virulence effectors and the dynamics of the immune response by using two-photon laser microscopy for in vivo imaging. In addition, in collaboration with Dr. Laurence Mulard (Institut Pasteur), we have developed a parenterally administered subunit vaccine candidate. This chemically defined glycoconjugate vaccine is based on the use of synthetic oligosaccharides mimicking the protective serotype-specific determinants of the polysaccharide moiety (O-Ag) of lipopolysaccharide (LPS), the main protective Shigella antigen. Thanks to a recently funded European Consortium, a phase 1 clinical trial is ongoing to make the proof of concept in human.
Contribution to the programme
Recent technological developments now provide the opportunity to move from reductionist experimental systems into an era of integration of the biological processes taking place upon the encounter of a pathogen with its host. Of particular interest are the co-evolutionary mechanisms that allow the pathogen to counteract host immune defenses. Tapping into those escape strategies represents a substantial source of innovation in therapeutics and vaccine development. Our group wishes to contribute to this ambitious objective by focusing on the manipulation of the host adaptive response by Shigella. Starting from the recently obtained results of the impact of Shigella on the T cell response, the study will be extended to the other cell types critical for the adaptive response, i.e. B lymphocytes and dendritic cells. This approach is a step towards the understanding of Shigella-mediated immune responses, in particular the priming of the adaptive immunity and the events that lead to the absence of immunological memory characteristic of shigellosis.
References over the past 5 years
1. NATO F., A. PHALIPON, L.P. THI NGUYEN, T.T. DIEP, P.J. SANSONETTI, Y. GERMANI. Dipstick for rapid diagnosis of Shigella flexneri 2a in stool. Plos One, 2007, 2(4) e361.
2. VULLIEZ LE-NORMAND B., F. A. SAUL, A. PHALIPON, F. BELOT, C. GUEIRRERO, L. A. MULARD, G. A. BENTLEY. Structural studies of synthetic O-antigen fragments derived from serotype 2a Shigella flexneri lipopolysaccharide in complex with a protective monoclonal antibody.Proc. Natl. Acad. Sci., 2008, 105:9976-81.
3. BOULLIER S., M. TANGUY, K. KADAOUI, P. J. SANSONETTI, B. CORTHESY, A. PHALIPON. Secretory IgA-mediated neutralization of Shigella flexneri prevents intestinal tissue destruction by inhibiting inflammatory circuits. J. Immunol. 2009, 183 (9):5879-85.
4. PHALIPON A., M. TANGUY,C. GRANDJEAN, C. GUEIRREIRO, F. BELOT, D. COHEN, P. J. SANSONETTI, L. A. MULARD. 2009. A synthetic carbohydrate-protein conjugate vaccine against Shigella flexneri 2a infection. J. Immunol. 2009, 182 (4):2241-7.
5. SELLGE G., J. GAMELAS MAGALHAES, J. H. FRITZ, C. KONRADT, M. TANGUY, A. BANDEIRA, J. P. Di SANTO, P. J. SANSONETTI, A. PHALIPON. Th17 cells are the dominant T cell subtype primed by Shigella flexneri mediating protective immunity. J. Immunol., 2010, 184 (4):2076-86.
6. KONRADT C., FRIGIMELICA E., NOTHELFER K., PUHAR A., SALGADO-PABON W., DI BARTOLO V., SCOTT-ALGARA D., RODRIGUES C.D., SANSONETTI P.J., PHALIPON A. The Shigella flexneri type III secretion system effector IpgD inhibits T cell migration by manipulating host phosphoinositide metabolism. Cell Host Microbe. 2011, 21:263-72.
7. THEILLETF.X., CHASSAGNEP., DELEPIERREM., PHALIPONA., L.A. MULARD. Multidisciplinary approaches to study O-antigen:antibody recognition in support of the development of synthetic carbohydrate-based enteric vaccines. P. Kosma and S. Muller-Loennies (eds.), Anticarbohydrate Antibodies, Springer-Verlag/Wien 2012