Director: Bourhy Hervé
Rabies is a disease that is widespread throughout the world. It is propagated by many different animal species.
The Rabies laboratory has research activities in biology and in epidemiology. More specifically, the aim of the work is to study the epidemiology of rabies in its natural hosts and to determine the molecular mechanisms involved in the adaptation of the virus to its hosts. Through these activities, the laboratory is able to identify new public health and therapeutic strategies to control rabies. The Rabies Unit hosts the National Reference Centre for Rabies and the WHO Collaborating Centre for Reference and Research in Rabies.
Genetic evolution and natural history of lyssaviruses (Patricia Davis, Florence Larrous, Hervé Bourhy in collaboration with Edward Holmes, University of Oxford,UK)
Recent events in the news have demonstrated the importance of adaptation to new host species for viruses, yet the basic molecular mechanisms and the selective pressures involved in this process are poorly understood, even though such information is crucial to the greater goal of controlling these new virus infections. From this point of view, lyssaviruses that are specifically adapted to different animal species in nature provide a very interesting model.
We have previously shown that a small number of amino acid changes accompany the transmission of a specific lyssavirus from one carnivore species to another and that the sequence of structural genes is highly constrained. We are presently investigating the genetic evolution of lyssaviruses adapted to different animal species. The aim of this work is to to date and determine the origin of these viruses, compare their rates of molecular evolution and to better characterize the selective forces they undergo.
Pathogenesis and transmission dynamics (Blanca Amengual, Florence Larrous, Laurent Audry, Hervé Bourhy in collaboration with Jordi Serra-Cobo, University de Barcelone, Spain and Chokri Bahloul, Institut Pasteur de Tunisie )
Observations of bats in their natural habitat indicate that some bat lyssaviruses, which can sustain effective and long-term circulation in their host species, have evolved towards low virulence or avirulence. These findings were obtained through long-term longitudinal studies of bat colonies. These multi-disciplinary studies involved ecological, population dynamic, virological and phylogenetic analyses. We are presently attempting to model lyssavirus infection in these natural bat colonies. Using the same approach, we are trying to identify key ecological and epidemiological factors involved in the propagation and maintenance of rabies in non-flying carnivores in selected geographical areas in North Africa.
Epidemiology of lyssaviruses in bats in Cambodia (Laurent Audry, Hervé Bourhy en collaboration avec Jean Marc Reynes, Institut Pasteur du Cambodge)
A survey was conducted in Cambodia to look for lyssavirus infection among bat populations. This study reports the first evidence of lyssavirus circulation in frugivorous and insectivorous bats.
Identification of viral and cellular mechanisms involved in the pathogenesis of lyssaviruses (Dorothée Obach, Raïd Kassis, Florence Larrous, Hervé Bourhy en collaboration avec Jérome Estaquié, URE de Physiopathologie des Infections Lentivirales, Yves Jacob, Unité des papillomavirus et Eléonore Real, Département de Virologie, Institut Pasteur)
Another important question is how viral genetic variations influence or restrict the infection of new hosts. We have shown that lyssaviruses with a low pathogenicity index induce early programmed cell death (apoptosis), which limit viral spread to the central nervous system, thereby reducing the lethality of the virus. During apoptosis, it is known that signals generated from within the cell result in the activation of signal transduction pathways that converge on a cysteine protease cascade (caspase), which plays a central role in the execution of the apoptotic process. Cellular death receptors (DRs) located at the cell surface can transmit apoptosis-inducing signals initiated by specific death ligands such as TNF-related apoptosis inducing ligand (TRAIL). Our data demonstrate that apoptosis in lyssavirus-infected neuroblastoma cells requires active viral replication and involvement of TRAIL. This, in turn, leads to the activation of caspase-8 and the downstream effector caspases (caspase-3 and caspase-6). Furthermore, our data demonstrate that the matrix (M) protein of lyssaviruses is likely to be a major component in the induction of this TRAIL- and caspase-8 dependent apoptosis. The role of M is currently being investigated in the laboratory. The identification of this mechanism is a key step in the determination of new therapeutic tools to fight lyssavirus-induced encephalitis.
National Reference Center for Rabies (NRC-Rabies) (Laurent dacheux, Laurent Audry, Patrick Weber, Florence Larrous, Pascal Cozette, Malika Campanaro and Hervé Bourhy in collaboration with Maryvonne Goudal, Yolande Rotivel and Annie Roux, Department of Clinical Research)
The NRC-Rabies is involved in the control of human rabies in France. It is responsible for the laboratory diagnosis of every suspected human case and of any animal that could possibly have transmitted rabies to humans (1849 analyses in total in 2004). Metropolitan France has been free of rabies in non-flying animals since April 2001. However the number of cases of rabies developing in France that have been acquired outside French territory is increasingly posing new epidemiological problems. In addition, new variants of lyssaviruses adapted to bats have been identified in France, and in Europe as a whole. These new epidemiological developments reinforce the need to maintain the survey and control of rabies. We are currently working, in collaboration with other relevant public health institutions, on the measures of prevention to be proposed to bat handlers. In 2004, the NRC-Rabies participated in both the alert and response following the identification of a rabies case in a dog imported from North Africa. As numerous french nationals and individuals from other countries came into contact with the dog, this lead to a large national and European alert to identify those people and animals exposed.
World Health Collaborating Centre for Reference and Research on Rabies (WHOCC Rabies) (Laurent Dacheux, Laurent Audry, Patrick Weber, Florence Larrous, Pascal Cozette, Malika Campanaro and Hervé Bourhy)
During 2004, the WHOCC Rabies participated in the training of 4 scientists in laboratory diagnosis and rabies control methods, in the molecular characterization of isolates sent by foreign collaborating institutes and in strengthening rabies surveillance and prevention in Asia particularly. Furthermore, a multicentric collaborative study involving the network of Pasteur Institutes (in Senegal, Cambodia and Madagascar) to define protocols of intra-vitam rabies diagnosis is currently taking place.
Keywords: Virology, Epidemiology, Ecosystems, Encephalitis, Rabies, Lyssavirus