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SUMMARY:Bacterial Pathogeneie - Professor Sansonetti
DTSTART:20070131T163000Z
DTEND:20070131T173000Z
UID:TALK6118@talks.cam.ac.uk
CONTACT:Prof. Jonathan Heeney
DESCRIPTION:Rupture\, invasion and inflammatory destruction of the intesti
 nal epithelium by Shigella : War and Peace at mucosal surface.\nPhilippe S
 ansonetti\, Unité de Pathogénie Microbienne Moléculaire\, Unité INSERM
  786\, and Howard Hughes Medical Institute\, Institut Pasteur\, Paris\, Fr
 ance.\n\nShigella\, a gram-negative enteropathogenic bacteria cause the ru
 pture\, invasion and inflammatory destruction of the human rectal and colo
 nic epithelia. It is a major cause of mortality and morbidity among pediat
 ric populations in the most impoverished areas of the planet and an effici
 ent vaccine is still awaited. Understanding the molecular bases of the pat
 hogenic process of shigellosis is essntial to develop vaccine candidates a
 gainst dysentery. The invasive phenotype of Shigella is encoded by a large
  plasmid of 220 kb encoding a Type III Secretory System (TTSS) and cognate
  effector molecules that are injected by this TTSS into the membrane and c
 ytoplasm of eukaryotic cell targets in the course of the infectious proces
 s. Injected effectors can be subdivided into two major categories  (i) Ipa
  proteins that are mainly involved in the formation of the translocating s
 tructure of the TTSS\, and triggering of the massive actin cytoskeletal re
 arrangements that carry out the entry process via macropinocytosis. (ii) O
 sp and IpaH proteins whose genes are only transcribed when the TTSS is fun
 ctional. Ongoing work indicates that these proteins are major regulators o
 f the innate and adaptive immune responses of the mucosa to the invading p
 athogen. They act very specifically upon key steps of major signalling pat
 hways such as NF-B and MAPK\, through specific enzymatic activitie. Osp
 G\, for example\, is a kinase that binds a subgroup of E2 ubiquitine-ligas
 es\, thereby blocking ubiquitination of I-B and activation of the pro-i
 nflammatory genes that are under the control of this essential pathway. Os
 pF is a dual phosphatase that reaches the cell nucleus where it dephosphor
 ylates active Erk1/2 and P38\, thereby regulating histone phosphorylation\
 , chromatin compaction and the transcription of a set of inportant pro-inf
 lammatory genes including IL-8 \; this\, by the way\, being the first exam
 ple of epigenetic modification of gene transcription by a bacterial effect
 or. IpaH molecules correspond to a family of 10 proteins that share a comm
 on enzymatic activity of ubiquitine E3 ligase of the HECT type. It now rem
 ains to figure out how these effectors conjugate efforts to « carve » a 
 particular profile of immune genes transcription in their target cells\, i
 n which order it is performed\, and to  which extent it affects bacterial 
 colonisation and invasion capacity\, as well as the profiles of innate and
  adaptive responses. In order to achieve this\, we are developing imaging 
 tools to follow delivery of these effectors into cells in real time\, both
  in vitro and in vivo\, as well as humanized  transgenic mice able to deve
 lop shigellosis.\nThe process of individual cell invasion is considerably 
 amplified in epithelial cells by the capacity of Shigella that escape the 
 endocytic membrane to move intracellularly and pass from one cell to anoth
 er\, following surface activation of actin nucleation by an outer membrane
  protein\, IcsA. This highly regulated process of intercellular spread als
 o allows bacteria to resist host defenses mechanisms.\nBeyond the interest
  of deciphering the detailed mechanisms of a disease and of the host respo
 nse\, it is important to emphasize that tracing Shigella in its « journey
  » through the gut has also unravelled mechanisms of much broader interes
 t\, such as the Nod system of intracellular sensing of bacteria through th
 eir released muropeptides. We also hope to « harness » the effectors tha
 t regulate host immune responses to help develop new targets and drugs\, p
 articularly in the field of anti-inflammatory and immunomodulatory agents.
 \n
LOCATION:Lecture Theatre 1\, Department of Veterinary Medicine
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