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

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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

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Lapeyraque et al. N Engl J Med, May 2011

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Key questions we address

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Microbial host

species specificity

Microbial host invasion and

dissemination into tissues

Microbial and host

biodiversity

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• 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

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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

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• 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

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INRIA INSERM

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IRD

Microbial host invasionand dissemination into tissues

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• 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

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• 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)

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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

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Perspectives

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• 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