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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)

3

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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

4

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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

7

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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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peptidoglycan

Bacterial shape/ physiology

Antibiotics resistance

Host/Microbeinteractions

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