Unit: Biology of viral emerging infections

Director: DEUBEL Vincent

The scientific team of the Pasteur Institute in Lyon belongs to the Unit "  Biologie des Infections Virales Emergentes (UBIVE) " which includes the National Reference Centers (NRC) for Arboviruses and for Viral Hemorrhagic Fevers (VHF), and the WHO Collaborative Center for Arboviruses and Hemorrhagic Fevers. UBIVE belongs to the Virology Department in Pasteur Institute in Paris and to the IFR128 " Biosciences Lyon-Gerland ". Most of the basic and applied research programs are carried out inside the Biosafety Level 4 (BSL-4) laboratory "Jean Mérieux".

UBIVE is involved in surveillance and research activities on emerging enzootic diseases developed within the International Network of Pasteur and Associated Institutes and is associated to three European networks dealing with the natural and provoked risk of diseases caused by class 3 and class 4 viruses. Basic researches of UBIVE are oriented on pathogenesis of VHF and emerging encephalitis to develop new diagnostics, therapeutics and vaccines.

Basic research activities in UBIVE are in majority focussed on Lassa, Nipa and yellow fever diseases to develop new diagnostic tools, potent therapies and safe vaccines. Expertise and reference activities are oriented on the surveillance of hemorrhagic fever with renal syndrome, Crimean Congo hemorrhagic fever, West Nile encephalitis and SARS.

I. Research activities

I.1. Lassa virus (S. Baize, H. Contamin, C. Faure, M.C. Georges-Courbot, P. Loth, P. Marianneau, D. Pannetier)

Lassa fever is endemic in sevral countries in West Africa. The viral causative agent is an arenavirus which belongs to the Arenaviridae family. The number of estimated cases is about 200,000 and 5,000 deaths. The onset of the disease is accompanied with flu-like symptoms which may be followed by diarrheas, vomitting, facial and cervical edema, and bleeding. Patients generally die with hypovolemic shock and respiratory distress. Lassa virus is listed A amoung the bioterrorim agents and should be manipulated in a BSL-4 laboratory.

Little is known about the immune response induced by Lassa virus, but it may be crucial in the disease outcome. We are interested to study the interactions of the virus with dendritic cells and macrophages derived from blood monocytes that are the primary target cells of infection. Our results show that the infection of these antigen-presenting cells are productive but not activated. The absence of cell maturation may be associated with altered inflammatory and cellular responses observed in severe Lassa virus infection.

Lassa virus is pathogenic for macaque monkeys who show a disease spectrum similar to that observed in humans. Cynomolgus macaques have been infected with Lassa virus to study the kinetics of virus infection and of immune responses. Virus replication in different tissues and cellular and humoral responses have been compared in moribond animals and in survivals. Results confirm the important role of the viral load and cellular response in disease outcome. This study is also important to establish an animal model for testing vaccine candidates that are developed in the Unit (Collaborations: IMTSSA Pharo Marseille, Michèle Chevallier).

I.2. Nipah virus (H. Contamin, M-C. Georges-Courbot, P. Loth)

Nipah virus belongs to the henipavirus genus in the Paramyxoviridae family. It has emerged in Malaysia in 1998 where it has caused an epidemics in pigs and in people in contact with the animals. The case fatality rate was about 40% in people who had presented acute encephalitis. The natural cycle of transmission involves bat reservoirs (Pteropus), and pigs as amplifying hosts. The virus is pleiotropic and induces necrosis of endothelial cells in vascular vessels, and neuronal damages. The virus is classified BSL-4.

Endothelial cells are presumably involved in vascular permeability leading to hypovolemic shock. We are presently studying the cell responses to Lassa virus infection.

In order to study the pathogenesis of Nipah encephalitis, we have identified the golden hamster as an appropriate animal model which shows tissue lesions similar to those observed in human cases. In addition, the animals vaccinated with recombinant vaccines producing Nipah virus envelope proteins have shown full protection against a fatal dose of Nipah virus. In addition, animals which received antibodies prepared against Nipah virus envelope proteins were passively protected against a lethal challenge. Chemotherapeutic approaches are also investigated.

(Collaborations : Christine Brisson, Robin Buckland, Michèle Chevallier, Vanessa Guillaume, Johan Neyts, Fabian Wild, Kum Thong Wong)

I. 3. Yellow fever virus (H. Contamin A. Lefeuvre, P. Loth, P. Marianneau)

Yellow fever remains a public health problem due to the endemic circulation of the virus and to recent post-vaccination adverse events. Yellow fever virus is a flavivirus in the family Flaviviridae. The yellow fever 17D virus vaccine was derived from its hepatotropic Asibi parental strain. Phenotypic and molecular markers of virus attenuation have been tested in HepG2 Human hepatoma cells by comparying the host cell responses to 17D and Asibi virus infections. These markers are being verified in macaque monkeys and will be evaluated and compared in HepG2 cells infected with chimeric viruses based on the 17D virus vector. (Collaborations : Aventis Pasteur, Michèle Chevallier)

I.4. SARS virus (H. Contamin, MC. Georges-Courbot, P. Loth, I. Marendat, P. Marianneau)

The human coronavirus responsible of the epidemic of SARS is highly pathogenic. We are contributing to research programs in Pasteur Institute in Paris by providing large amounts of purified viral antigens for the diagnosis and by testing several small animals for virus susceptibiliy. (Collaborations : W. Praiser, F. Tangy, Unité GMVR)

II. Activities of National Reference Centers and WHO Collaborating Center

II.1. Prédiction and prevention of Puumala virus causing hemorrhagic fever with renal syndrome (I. Marendat, S. Murri, S. Michel, I. Schuffenecker, H. Zeller)

Puumala virus is a hantavirus in the family Bunyaviridae transmited to human by the bank vole (Clethrionomys glareolus). The project includes the study of the reservoir, identification of circulating viruses, improvement of diagnostic tools, modelisation of virus/host interaction, and the study of risk factors in humans. (Collaborations : AFSSA Nancy, Comité Interdépartemental de Lutte contre la Rage, Université Lyon I, Ecole Nationale Vétérinaire de Lyon, and Unité postulante de Génétique des Bunyaviridés).

II.2. West Nile virus activity in France (I. Marendat, S. Michel, S. Murri, I. Schuffenecker, H. Zeller)

During the surveillance of West Nile activity in 2003 in the South East region of France, we have diagnosed several human cases of West Nile encephalitis at the end of the summer. The presence of West Nile circulation in horses was also evidenced.

II.3. Diagnostic activities (M-C. Georges-Courbot, S. Lacote, I. Marendat, P. Marianneau, S. Murri, H. Zeller)

Our activities deals with regular biological diagnosis of VHF and encephalitis in patients leaving in endemo/epidemic countries and in travelers suspected of tropical viral diseases. Molecular and standard tools are developed for rapid serological and virological diagnosis of class 3 (yellow fever, dengue, tick-borne and Japanese encephalitis, Rift Valley fever) and class 4 (Ebola, Marburg, Lassa, Crimean Congo hemorrhagic fever, Nipah) viruses. (Collaborations : C. Akoua-Koffi, L. Koivogui, E. Leroy, A. Sall, S. Günther)

Keywords: Viral hemorrhagic fever, Lassa, Nipah, yellow fever, SARS, West Nile, hepatocytes, dendritic cells, macrophages, animal model, pathophysiology

Activity Reports 2003 - Institut Pasteur

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