Unit: Biology of viral emerging infections

Director: Fabian WILD (par intérim)

The Pasteur Unit, " Biology of emerging viral infections " (UBIVE) is responsible for the National Reference Centres for arboviruses and that of haemorrhagic viral fevers (HVF) and is also a WHO collaborative centre for arboviruses and HVF.The UBIVE is a member of both the Pasteur Virology Department (Paris) and the Federative Research Institute (IFR 128) " Biosciences Lyon-Gerland " created in January 2003. Its principal activities involving, surveillance, diagnosis and research are conducted in the P3 laboratory and the " Jean Mérieux " P4 high security laboratory.

The UBIVE participates in surveillance and research of emerging diseases and zoonoses in the Pasteur Institutes overseas network and three European networks both naturel and provoked risks by class 3 and 4 biological agents. The major research activities include studies on the pathogenesis of HVF (Lassa, yellow fever) and encephalitis induced by emerging viruses (Nipah) for which diagnostic tools, therapeutic and prophylatic solutions have been developed.

The principal fundamental research activities in the UBIVE involve the study of the pathology of Lassa, yellow fever and Nipah viruses and developing new approaches to diagnosis, therapeutics and prophylactics for these infections.

Research Activity

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

Lassa fever is endemic in several West African countries. The virus is an arenavirus which belongs to the family Arenaviridae. The WHO estimate that there are several hundred thousand cases of Lassa fever and 5,000 deaths annually. The disease starts with flu-like symptoms followed by more severe clinical - diarrhoea, vomiting, facial and cervical odema and occasionally bleeding. The patients normally die from hypovolemic shock and respiratory distress. There is no vaccine against this disease. The virus is one of the agents included on the list of potential bioterrorist targets and its manipulation requires a high level security (P4) laboratory.

The immune response induced by Lassa fever is little known, but is probably decisive in the survival of the patient. We have studied the interaction of Lassa virus with dendritic cells and macrophages derived from blood monocytes. We have shown that antigen presenting cells produce virus without being activated. A defect in maturation of these cells during infection may be the cause of the ineffectual inflammatory and cellular response observed in severe cases of Lassa fever.

Lassa virus induces a disease similar to that seen in man in a monkey (Cynomolgus) model. Cynomolgus monkeys were infected with lassa virus and the kinetics and immune response studied. The virus replication in different tissues and the humoral and cellular responses were compared in animals which died or survived the infection. The results confirm the correlation between the viral load and the activation of the cellular immune response in the development of the disease.

These studies enabled us to test a number of candidate vaccines amongst which were recombinants with yellow fever.

(Collaborations : IMTSSA Pharo Marseille, Michèle Chevallier).

Nipah virus studies (P. Marianneau, M-C. Georges-Courbot, P. Loth, H. Contamin)

Nipah virus belongs to the genre hénipavirus in the Paramyxoviridae family. It was first discovered in Malaysia in 1998 where it was responsible for an epidemic in pigs which was then transmitted to humans in contact with these animals. 40% of the infected humans died from acute encephalitis. The reservoir of the virus is probably the fruit bat, Pteropus and the virus was transmitted to pigs which amplified the virus. In man the virus is pleiotropic, induces necrosis in blood vessel endothelial cells and a neuronal tropism. Nipah virus can only be manipulated at the P4 laboratory level.

To study the pathogenesis of Nipah virus infections we developed a model using the golden hamster. The tropism and lesions produced in these infected animals were similar to those found in human cases. Hamsters vaccinated with a recombinant vaccine expressing the envelope proteins were protected against a lethal infection. In parallel, we studied the possibility of an immunotherapy treatment using antibodies specific for the envelope proteins. Passive transfer of these antibodies also protected the animals.

To continue our studies, we have tested the possibility of infecting non human primates (squirrel monkeys, Saimiri sciureus).

(Collaborations : U404 Inserm, Michèle Chevallier Laboratoire Marcel Mérieux, Christine Brisson, Kum Thong Wong)

I. 3. Study of the hepatic tropism of yellow fever virus (A. Lefeuvre, H. Contamin, P. Loth, P. Marianneau)

Yellow fever remains a public health problem due to it being endemic and a number of deaths which have been recently reported after vaccination. Yellow fever virus is hepatatropic. To study this at the in vitro level, we have studied the response of the human hepatic cell line, HepG2 after infection with either the vaccine strain 17D or the wild type parental strain, Asibi inorder to identify attenuation markers. These were identified with the aid of DNA micro-arrays. We were able to identify different phenotypes between the two viral strains. Infection of monkeys (macaque) by the different viruses allowed us to confirm in vivo the different parameters and will in the future serve as a basis to study the response of hepatic cells to infection by chimeric viruses based on the 17D virus and expressing proteins to other viruses.

I.4. Contribution to the development of tools to study SARS (H. Contamin, MC. Georges-Courbot, P. Loth, I. Marendat, P. Marianneau)

The human coronavirus responsible for the SARS epidemic is highly contagious. Our contribution to the Pasteur project included the preparation of large quantities of inactivated virus and establishing a sensitive animal model. These activities were undertaken in the P4 laboratory.

We compared the sensitivity of several lines of mice and also golden hamsters to infection with the SARS virus. Our results show that the golden hamster is a good model to test vaccines.

(Collaborations : W. Praiser, F. Tangy, Unité GMVR)

CNR/CCOMS activities

II.1. Prediction and prevention of haemorrhagic fever with renal syndrome (HFRS) caused by Puumala virus. . (I. Marendat, S. Michel, S. Murri, I. Schuffenecker, H. Zeller)

Puumala virus is a hantavirus belonging to the family Bunyaviridae and is transmitted to man by the bank vole (Clethrionomys glareolus). The project consists of studying the reservoir (ecology, dynamics of the infection incidence, distrubution), identification of circulating viruses, improvement of diagnostic techniques, modelisation of virus-host interaction and the study of factors of risk for transmission to man. The National Reference Centre for haemorrhagic viral fevers showed that after a peak in 2003 (128 cases), it fell to approximately 50 cases in 2004.

(Collaborations : AFSSA Nancy, Comité Interdépartemental de Lutte contre la Rage, Université Lyon I, Ecole Nationale Vétérinaire de Lyon, et l'unité postulante de Génétique des Bunyaviridés

II.2. West Nile Virus surveillance (I. Marendat, S. Michel, S. Murri, I. Schuffenecker, H. Zeller</p>

The National Reference Centre for Arboviruses, involved in the surveillance of West Nile Virus (WNV), showed that WNV circulated in birds in the Camargue at the begining of August 2004, one month before infections in horses (33 cases) and without any notified human cases. The infected zone was the same as that observed in the equine outbreak in 2000. This reinforces the interest of an active surveillance by the bird sentinel. The complete viral genome of WNV isolated from horses in Morocco in 1996 and 2003 was sequenced and shown to be related to the West European cluster.

II.3. Development of poxvirus diagnostic tests (S. Lacote, P. Marianneau, M-C. Georges-Courbot)

In the framework of the fight against bioterrorism and at the request of the InVS, we have developed molecular and virological diagnostic techniques for orthopoxvirus infections.

II.4. Activités de diagnostic (M-C. Georges-Courbot, S. Lacote, I. Marendat, P. Marianneau, S. Murri, H. Zeller)

The national Reference - WHO Collaborative Centres have a diagnostic function for viral haemorrhagic fevers and viral encephalitis samples from patients in endo-epidemic regions or in imported cases. The UBIVE has developed classical and molecular tools for rapid diagnosis, virological and serological for class 3 level viruses (yellow fever, dengue ; tick -borne,Japanese, and West Nile encephalitis, Rift Valley fever) and class 4 viruses (Ebola, Marburg, Lassa, Crimean Congo, Nipah).

(Collaborations : C. Akoua-Koffi, L. Koivogui, E. Leroy, A. Sall, S. Günther)

Keywords: Viral haemorrhagic fevers, viral encephalitis, Lassa, Nipah, yellow fever, SARS, West Nile, hepatocytes, dendritic cells, macrophages, animal model

Activity Reports 2004 - Institut Pasteur

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