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BIOGRAPHY:
Dr. Sansonetti received his M.D. in 1979 from the University of Paris. From 1979 until 1981 he conducted research in the Department of Enteric Infections at the Walter Reed Army Institute of Research in the United States. He has been awarded the Chevalier de la Légion d'Honneur, the Prix d'Excellence Jacques Monod en Biologie Moléculaire, the Prix AGIR du Conseil Pasteur-Weitzmann, the Grand Prix de l'Académie de Médecine, the Prix Louis Jeantet de Médecine, and the Robert Koch Prize and Médaille. He is currently Professor at the Institute Pasteur and Head of the Unité de Pathogénie Microbienne Moléculaire (Unité Insern 389) at the Pasteur Institute of Paris. His HHMI-funded project is entitled "How Shigella Overwhelms the Innate Immune Response: A Model for Inflammatory Bowel Diseases?."
RESEARCH ABSTRACT SUMMARY:
How Shigella Overwhelms the Innate Immune Response: A Model for Inflammatory Bowel Diseases?
Interaction of Shigella flexneri with epithelial cells
involves contact with membrane rafts through engagement of CD44 and
release of Ipa proteins through an activatable, type III secretory
apparatus (i.e., Mxi/Spa). A cascade of signals elicited by GTPases of
the Rho family and by c-src causes rearrangements of the cytoskeleton,
allowing bacterial entry by macropinocytosis. Then the bacterium
initiates intracytoplasmic movement, due to assembly of actin filaments
caused by a surface protein, IcsA, which recruits N-WASP and Arp2/3.
This allows passage to adjacent cells via protrusions, which are
engulfed by a cadherin-dependent process. A paracrine pathway involving
secretion of ATP by hemiconnexions and calcium fluxes facilitates
cytoskeletal rearrangements, thus boosting entry and cell-to-cell
spread of bacteria.
In addition, epithelial cells are able to sense intracellular
bacteria through their peptidoglycan (PGN) by proteins of the NOD/CARD
family that are able to activate the NF-kappaB pathway in invaded
cells, thus reprogramming them to produce pro-inflammatory cytokines.
Global transcriptional analysis of infected cells reveals a typical
pattern of increased transcription of genes encoding pro-inflammatory
cytokines and other cytokines; transcription of the latter is dominated
by the massive expression of IL-8 mRNAs and correlated production of
this potent chemoattractant for polymorphonuclear cells. This is
particularly the case for epithelial Nod1/CARD4, which was shown to
specifically recognize PGN from gram-negative microorganisms. As an
increasing number of epithelial cells are invaded by Shigella,
the colonic epithelium becomes a major provider of IL-8, thereby
inducing massive recruitment of polymorphonuclear leukocytes that
account for the destructive inflammatory process that is characteristic
of shigellosis.
Photo: unknown, unknown
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