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Ebola - Ariis
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 CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD 1 Ebola virus: an emergent pathogen infecting humans and animals Ebola virus: an emergent pathogen ¾Recent discovery (1976) ¾Unique form among virology world ¾~ highest lethal pathogens : 80 % mortality within days • 2000 human deaths • > 10,000 deaths in gorillas and chimpanzees: decline of 80% Lancet 1997; J Infect Dis 1999; Science 2004 Lancet 2002; Clin Infect Dis 2006 J Infect Dis 2011; Trans Roy Soc 2011 CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD 2 The fundamentals of the pathogen Emergence Step 1: from the natural host to human 1 CEA CHRU CNRS 2 Step 3: from human to human 3 CPU INRA INRIA INSERM Step 2: from exposure to infection INSTITUT PASTEUR IRD Animal Tracking Ebola: from field to lab ¾ Field studies Outbreak Field Human investigations In situ cohort studies: ~ 400 patients Animal trapping ¾ Laboratory investigations Molecular virology, immunological studies BSL4 lab, unique in sub saharian Africa WHO reference center for viral haemorrhagic fevers in Central Africa CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD 4 Step 1 to Emergence: From bats to humans 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 J Infect Dis 2004; Science 2004; Nature 2005 ; Emerg Infec Dis 2005 Vect born Zoo Dis 2009; J Infect Dis 2010 CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD 5 Step 2: From exposure to infection, virus evolution Tracking and following the Ebola virus history for the understanding of its Genomic evolution Before • Genetic characterization of 16 strains among 18 known zaire ebolavirus • • • • Lineage A Two lineages with ancient ancestor Long lasting circulation in Africa First evidence of recombination Viral strains in great apes Our study Recombinant viruses Viral strains in animals Lineage B CEA CHRU J Gen Virol 2003; Science 2004 Proc Natl Acad Sc USA 2008 J Infect Dis 2011 CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD 6 Host response: Deep defective immunity • Aberrant innate immunity : • Absence of adaptative immunity "cytokine storm" & absence of IFN I responses Fas mechanism T4 Deep immunosuppression by T8 43.6% CTL T4 CD95+ T8 CD95+ 0.9% 0.7% 22.4% apoptosis of T cells CEA CHRU CNRS CD3+CD4+ SURV 46.2% 24.1% DCD 12.3% 5.4% CPU INRA INRIA INSERM 11.0% 51.9% 72.6% INSTITUT PASTEUR IRD 7 CD3+CD8+ Pathogenesis: virus replication and superantigen activity ? Controls Fatal cases β-actin Vβ2 Vβ5.1 Vβ6 Vβ7 Vβ11 Vβ12 Vβ13.2 Vβ16 Vβ17 Vβ19 9 8 7 4 3 2 1 0 Days before death Controls Non fatal cases β-actin Vβ2 Vβ5.1 Vβ6 Vβ7 Vβ11 Vβ12 Vβ13.2 Vβ16 Vβ17 Vβ19 begin middle end Recovery Symptoms Nat Med 1999; Clin Exp immunol 2001 PLoS Neg Trop Dis 2010 J Virol 2011 CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD 8 Step 3 of Emergence: From humans to humans Routes of transmission At the hospital From animals From body fluids Traditional healer Strategy to control outbreaks: Prevention only Individual protection Barriers nursing CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD 9 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 7 9 16 23 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 CEA CHRU CNRS CPU INRA INRIA INSERM Real pathogenicity of Ebola virus? Natural protective immunity? Exposure: fruits with saliva from infected fruit bats ? INSTITUT PASTEUR IRD 10 Perspectives 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 CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD 11
