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Several episodes of haemorrhagic fevers and of viral encephalitis have alerted the organisms of public health and collaborating reference centres this last decade: Ebola, Marburg, dengue haemorrhagic fever, yellow fever, Rift Valley fever, Crimean-Congo haemorrhagic fever, West Nile… There is a crucial need of treatments and vaccines against these viruses that are highly pathogenic for humans. One of the difficulties to reach this task is the high risk to manipulate these viruses that require BSL-3 or BSL-4 containements. The only BSL-4 in Europe has recently been opened in Lyon. This laboratory built up under the initiative of Dr Charles Mérieux belongs to Mérieux Foundation that maintains permanent logistic and biosecurity supports. A newly created association between Mérieux Foundation and Pasteur Institute, named Mérieux-Pasteur Research Centre in Lyon (MPRCL), has been the starter of new research topics dedicated to molecular diagnostics for the identification of P4 agents and to study of the biology of these agents. These researches will help to the development of potent therapy and prophylaxis. Over this academic research on emerging pathogens, the MPRCL represents a model of delocalisation of a Pasteur Institute research unit in Lyon. This Centre profits of the highest scientific environment provided by the IFR74 "Immunology and virology of emerging viruses" directed by INSERM, by the Ecole Normale Supérieure, by the Institute of Chemistry and Biology of Proteins, by the University Claude Bernard Lyon II… Finally, formation and teaching of professionals and information of a larger public about emerging viral diseases and their pathogens are part of the missions of the research and biosecurity teams of the MPRCL.
Research programmes of the MPRCL are oriented to the study of the pathophysiology of Lassa fever, a haemorrhagic disease caused by Lassa virus, genus Arenavirus of the family Arenaviridae. Like all Arenaviruses, the virus is maintained in nature by transmission of a persistently-infected Mastomys rodent to another rodent. Humans are infected by contact or inhalation of secretions of infected rodents (urine, feces, saliva) and can be the source of inter-human contamination. The endemic zone of Lassa virus is located in western Africa with an estimated number of cases of about 300,000 with 5000 deaths. Few days after contamination, the fever increases and flue-like symptoms appear. Severe disease is accompanied with diarrhea, vomiting, facial and cervical oedema, conjonctiva haemorrhages and sometimes bleedings. Patients generally die of hypovolaemic shock and respiratory distress.
In one project, the causes of the increase of vascular permeability during Lassa virus infection are studied. Changes in the biology and functions of human endothelial cells either infected or cultured with infected macrophages are analysed. In another project, the sensitivity of dendritic cells and macrophages to Lassa virus infection is studied. These cells are presumed to be the major targets for Lassa virus and may be involved in the regulation of the immune responses that seem down-regulated in severe cases. Activation and differentiation of blood monocytes-derived cells are studied after Lassa virus infection. These research programmes are developed in the BSL-4 facility in Lyon.
These studies will provide a better knowledge of the mechanisms of host cell response to Lassa virus infection and of the involvement of vascular and immune systems in the pathogenesis of the disease. These researches are necessary to develop further a prophylaxis against Lassa fever.
In addition, one of the tasks of the MPRCL, in connection with the National Reference Centre for Arboviruses and Haemorrhagic Fevers, is to provide rapid diagnosis for haemorrhagic fevers performed on samples received from patients living in countries with epidemics of VHF and from patients after they have returned from these countries. Lassa, Ebola, Marburg, Crimean-Congo haemorrhagic fever and Nipah virus genome amplification by RT-PCR has been established. Molecular tools are being developed to avoid the use of the BLS-4 laboratory for the preparation of antigens and for the diagnostics. Recombinant virus envelope and nucleocapsid proteins are produced using the baculovirus system. Reagents will then be available for laboratories of the International network of Pasteur Institutes, and for other collaborating laboratories located in endemic and epidemic zones.
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