1.2 ivo boneca
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CEA CHRU
CNRS CPU INRA
INRIA INSERM
INSTITUT PASTEUR
IRD
1CEA CHRU
CNRS CPU INRA
INRIA INSERM
INSTITUT PASTEUR
IRD
Bacterial infectious diseases:
The PG perspective
Ivo G BonecaGroup Biology and genetics of
the bacterial cell wallInstitut Pasteur, INSERM
Paris, France
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PGa key component of bacterial physiology
peptidoglycan
Bacterial shape/ physiology
Antibiotics resistance
Host/Microbeinteractions Mesenteric
Lymph Nodes
Peyer’s Patches
Cryptopatches LymphaticsILFs
Gram -
2
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Understanding PG structure and assembly
How do they work?How do they determine shape?
Model
PBP2
MreC
SID
116 226
PBP2 (588 aa)
N-ter C-ter MreC (248 aa)
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SID
116 226
PBP2 (588 aa)
N-ter C-ter MreC (248 aa)
Can the SID peptide be used as an inhibitor ?
SPTAT +SID
New therapeutic strategiesOvercome Resistance mechanisms
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PG is a signaling molecule
Homeostasis
Disease
M
A
G
G M
A
G
G
dA
•Adjuvant activity
•Maturation of intestinal lymphoid tissues
•Activation of neutrophils
•Induced slow-wave sleepEx: Streptococcuspneumoniae
•Gram-positive septic shock
•Induced arthritisEx: Staphylococcus aureus
•CytotoxicityEx: Bordetella pertussis
Girardin et al. 2003. J. Biol. Chem. 278(11):8869-72Girardin et al. 2003. J. Biol. Chem. 278(43):41702-8Girardin et al. 2003. Science. 300(5625):1584-7Nod1Nod2NF-kB
JNK
MAMPMAMP
IntracellularNod1
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Analysis of theHost response
DNA arrays
Understanding PG as a signaling molecule
Fine analysis of PG distribution
Structural analysis of circulating 3H-PG by HPLC
Analysis of circulating cells carrying 3H-PG by AutoMACs
Soluble 3H-PG
Homeostasis vs
Disease (IBD, sepsis)
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Studying the PG as a signaling molecule in vivo
time 24 h
Femur (0.02 cpm/mm2) Stomach (0.24 cpm/mm2)
Intestin (0.08 cpm/mm2)
1 h 6 h
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Perspectives•Diagnostics
•sepsis(PG detection)•sterile inflammation (Arthritis)
•Probiotics (Macho Fernandez et al. Gut. 2011. Apr 6. [Epub ahead of print])
•prevention of ulcerative colitis, Crohn’s disease (Nod2)•enhanced vaccination, etc. (Nod2)
•New innovative treatments •chronic inflammatory diseases (Nod1)•cancers associated with chronic inflammation (Nod1)•against antibiotic resistant bacteria (SID peptide)
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CEA CHRU
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peptidoglycan
Bacterial shape/ physiology
Antibiotics resistance
Host/Microbeinteractions
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