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Ebola :Research at the heart of the african

tropical forestLEROY Eric• PhD & DVM• Research Director, UMR MIVEGEC (IRD224 / CNRS5291 / Université Montpellier 1)• Head of viral Emergent Diseases Unit, CIRMF, Gabon

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• 2000 human deaths

• > 10,000 deaths in gorillas and

chimpanzees: decline of 80%

Ebola virus: an emergent pathogen infecting humans and animals

Ebola virus: an emergent pathogenRecent discovery (1976)Unique form among virology world ~ highest lethal pathogens :

80 % mortality within days

Lancet 1997; J Infect Dis 1999; Science 2004 Lancet 2002; Clin Infect Dis 2006J Infect Dis 2011; Trans Roy Soc 2011

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Step 1: from the natural host to human

Step 2: from exposure to infection

2Step 3: from human to human3

The fundamentals of the pathogen Emergence

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Tracking Ebola: from field to lab

Outbreak Field investigations

In situ cohort studies: ~ 400 patients

Animal trapping

Molecular virology, immunological studies BSL4 lab, unique in sub saharian Africa WHO reference center for viral

haemorrhagic fevers in Central Africa

Field studies

Laboratory investigations

Human

Animal

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outbreak

direct contact

• Fruit bat species as Ebola virus reservoir as well as for Marburg virus

• Multi-emergence into great apes and/or humans with spill over events from bats

• Massive outbreaks in wild great ape populations with dramatic population decline

Step 1 to Emergence: From bats to humans

J Infect Dis 2004; Science 2004; Nature 2005 ; Emerg Infec Dis 2005Vect born Zoo Dis 2009; J Infect Dis 2010

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Before

Our study

Recombinant viruses

Lineage B

Lineage A

• Genetic characterization of 16 strains

among 18 known zaire ebolavirus

• Two lineages with ancient ancestor

• Long lasting circulation in Africa

• First evidence of recombination

• Viral strains in great apes

Tracking and following the Ebola virus history for the understanding of its Genomic evolution

Viral strains in animals

Step 2: From exposure to infection, virus evolution

J Gen Virol 2003; Science 2004Proc Natl Acad Sc USA 2008J Infect Dis 2011

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Host response: Deep defective immunity• Aberrant innate immunity :

"cytokine storm" & absence of IFN I responses

CD3+CD4+ CD3+CD8+

• Absence of adaptative immunity

0.7%

11.0%

51.9%

0.9%

72.6%

T8 CD95+T4 CD95+

Fas mechanism

Deep immunosuppression by

apoptosis of T cells

CTL

DCD

SURV

12.3% 5.4%

22.4%43.6%

T4 T8

46.2% 24.1

%

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Pathogenesis: virus replication and

superantigen activity ? -actin

V2

V5.1

V12

V11

V7

V6

V17

V16

V13.2

V19

Controls Fatal cases

Days before death

9 8 7 4 3 2 1 0

-actin

V2

V5.1

V12

V11

V7

V6

V17

V16

V13.2

V19

Controls Non fatal cases

Symptoms

begin middle end

Nat Med 1999; Clin Exp immunol 2001 PLoS Neg Trop Dis 2010J Virol 2011

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Step 3 of Emergence: From humans to humansRoutes of

transmission

From animals

From body fluids

At the hospitalTraditional

healer

Strategy to control outbreaks: Prevention only

Barriers nursing

Individual protection

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Human asymptomatic infection of Ebola virus

7 9 16 23

EBOV RNA+• EBOV RNA+ detection in PBMC for two weeks

• EBOV -IgG and -IgM detection three weeks post infection

• Identical viral strain as for survivors and deceased

• Strong and early inflammatory responses

• High overall EBOV -IgG

prevalence in Gabon

• Association with forested

areas

T cell memory responses

Real pathogenicity of Ebola

virus? Natural protective immunity? Exposure: fruits with saliva

from infected fruit bats ?

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Ebola

•Origin of massive and rapid apoptosis

•Vaccine and/or therapeutic development

Global surveillance of emergent diseases

•General survey, tracking of emergent diseases risk

•Search for animal reservoirs of viruses

International research networks and local plateforms

Perspectives