1. The document discusses Ebola virus as an emergent pathogen that infects humans and animals in Africa, with a mortality rate of around 80%. 2. It describes tracking the virus through field investigations of outbreaks and laboratory studies to understand its transmission from bats to great apes to humans, evolution, and pathogenesis. 3. It examines routes of human-to-human transmission and strategies to control outbreaks through prevention, as well as perspectives on developing vaccines and therapies and improving global disease surveillance.

1. Ebola : Research at the heart of the african tropical forest LEROY Eric PhD & DVM Research Director, UMR MIVEGEC (IRD224 / CNRS5291 / Université Montpellier 1) Head of viral Emergent Diseases Unit, CIRMF, Gabon CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD

2. 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 pathogen Recent 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 2006 J Infect Dis 2011; Trans Roy Soc 2011

3. The fundamentals of the pathogen Emergence 1 Step 1: from the natural host to human Step 2: from exposure to infection 2 Step 3: from human to human 3

4. 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

5. 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 2005 Vect born Zoo Dis 2009; J Infect Dis 2010

6. 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 2004 Proc Natl Acad Sc USA 2008 J Infect Dis 2011 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

7. 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%

8. Pathogenesis: virus replication and superantigen activity ? Nat Med 1999; Clin Exp immunol 2001 PLoS Neg Trop Dis 2010 J Virol 2011  -actin V  2 V  5.1 V  12 V  1 1 V  7 V  6 V  17 V  16 V  13.2 V  19 Controls Fatal cases Days before death 9 8 7 4 3 2 1 0

9. Step 3 of Emergence: From humans to humans Routes of transmission From animals From body fluids At the hospital Traditional healer Strategy to control outbreaks: Prevention only Barriers nursing Individual protection

10. Human asymptomatic infection of Ebola virus 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 Real pathogenicity of Ebola virus? Natural protective immunity? Exposure: fruits with saliva from infected fruit bats ? 7 9 16 23 High overall EBOV -IgG prevalence in Gabon Association with forested areas T cell memory responses

11. 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