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CEA CHRU
CNRS
CPU INRA
INRIA INSERM
INSTITUT PASTEUR
IRD
1CEA CHRU
CNRS
CPU INRA
INRIA INSERM
INSTITUT PASTEUR
IRD
Studying host-pathogen interactions with a clinical perspective
Marc LECUIT, MD PhDInstitut Pasteur, InsermHôpital Necker-Enfants malades, Université Paris-Descartes
CEA CHRU
CNRS
CPU INRA
INRIA INSERM
INSTITUT PASTEUR
IRD
Studying host-pathogen interactionsis critically needed on a clinical standpoint
• Ongoing outbreak of Hemolytic-Uremic Syndrome in Germany
• Shiga toxin-producing E. coli O104:H4– STX recognizes Gb3Cer/CD77 receptor
– Species- and tissue-specific
– Expressed on human endothelial cells
– STX blocks protein synthesis
– Endothelial cell damages, cell death
– Activation of complement cascade
– Coagulopathy, leading to HUS
• Therapeutic options– Antimicrobial therapy: the outbreak strain is multi-resistant (ESBL-producing strain)
– Targeted therapy: blockade of complement cascade with an anti-C5 monoclonal antibody
2
Lapeyraque et al. N Engl J Med, May 2011
CEA CHRU
CNRS
CPU INRA
INRIA INSERM
INSTITUT PASTEUR
IRD
Key questions we address
3
Microbial host
species specificity
Microbial host invasion and
dissemination into tissues
Microbial and host
biodiversity
CEA CHRU
CNRS
CPU INRA
INRIA INSERM
INSTITUT PASTEUR
IRD
• Most pathogens are species-specific– STEC, C. diphtheriae, Neisseria, Shigella, Salmonella, Streptococcus pyogenes, …– Poliovirus, Measles virus, HIV, HCV, …
• Species specificity of Listeria monocytogenes, and its molecular basis
Guinea pigRabbit
MouseRat
Human
L. monocytogenes
Microbial species specificity
4
Lecuit et al, EMBO J 1999Khelef et al, Cell Microbiol 2006
Microbial host
species specificity
Microbial host invasion and
dissemination into tissues
Microbial and host
biodiversity
CEA CHRU
CNRS
CPU INRA
INRIA INSERM
INSTITUT PASTEUR
IRD
Microbial species specificity
5
• Critical issue for the human relevance of in vitro and in vivo investigations
• Rational design of relevant animal models for human infectious diseases– Humanized models (transgenesis, knock-in), naturally permissive species – Overcome species specificity, discover new ones, iterative process
Lecuit et al, Science 2001Disson et al, Nature 2008
Guinea pigRabbit
HumanGerbil
E16PmEcad
Humanized E16P mouse
Microbial host
species specificity
Microbial host invasion and
dissemination into tissues
Microbial and host
biodiversity
L. monocytogenes
CEA CHRU
CNRS
CPU INRA
INRIA INSERM
INSTITUT PASTEUR
IRD
Microbial host invasionand dissemination into tissues
6
• Microbial crossing of host barriers– Listeria monocytogenes
• Intestinal barrier (InlA-Ecad)• Placental barrier (InlA-Ecad, InlB-Met)
– Group B streptococcus• ST-17 clone hypervirulence• Enhanced crossing of intestinal and blood-brain barriers (HvgA)
• Translation to emerging infections– Chikungunya virus
• Animal model• CHIKV organ, tissue and cell tropisms• Species-specific host response: non-hematopoietic type-I IFN• Treatment: passive immunotherapy (CHIKVIgs), antivirals (RNAi)
Lecuit et al, Science 2001Disson et al, Nature 2008
Tazi et al, J Exp Med 2010Couderc et al, PLoS Path 2008
Schilte et al, J Exp Med 2010Couderc et al, J Infect Dis 2009
Microbial host species
specificity
Microbial host invasion and
dissemination into tissues
Microbial and host
biodiversity
Lm Lm
GBS
CEA CHRU
CNRS
CPU INRA
INRIA INSERM
INSTITUT PASTEUR
IRD
• Microbial diversity– Laboratory, environmental vs. clinical strains– National Reference Centers– Whole genome sequencing of hundreds of isolates– Genomic and transcriptomic signatures of pathogenicity
• Host diversity– Population exposed: susceptible vs. resistant host– Genome: high throughput whole-exome sequencing– Microflora and resulting effects on pathogens and tissues
• Age: neonates vs. elderly• Treatment: antibiotherapy, immunosuppressive therapy
• Prospective studies– Ongoing case-control study on listeriosis (MONALISA)
7
Microbial and host biodiversityMicrobial
host species specificity
Microbial host invasion and
dissemination into tissues
Microbial and host
biodiversity
Ragon et al, PLoS Path 2008Chenal-Francisque, Emerg Infect Dis 2011
CEA CHRU
CNRS
CPU INRA
INRIA INSERM
INSTITUT PASTEUR
IRD
Perspectives
8
• Holistic view of the infectious process– Microbial side– Host side– Environment (microbial and non-microbial)
• Classical and emerging pathogens– Listeria monocytogenes, Group B streptococcus– Chikungunya and emerging pathogens to come…– Pathogen discovery program (PathoDisc)
• Basic understanding of biological principles
• Diagnosis, biomarkers, treatment, prevention
Hôpital Necker-Enfants malades
Microbial host
species specificity
Microbial host invasion and
dissemination into tissues
Microbial and host
biodiversity