Unit: Rabies

Director: Bourhy Hervé

Rabies is a disease that is widespread throughout the world. It is propagated by many different animal species. The aim of the work of the Rabies laboratory 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 Laboratory (opened in April 2003) is involved in the following activities :

Genetic evolution and natural history of lyssaviruses (Patricia Davis, Florence Larrous, Hervé Bourhy in collaboration with Edward Holmes, University of Oxford,UK)

Despite the importance of adaptation to new host species for lyssaviruses, the basic molecular mechanisms and the selective pressures involved in this process are poorly understood, even though this information is crucial to the greater goal of controlling lyssavirus infection. We have previously shown that a small number of amino acid changes accompany the transmission of the virus from one carnivore species to another and that the sequence of structural genes is highly constrained. We are presently investigating the genetic evolution of European bat lyssaviruses. We are using this information to draw comparisons with lyssaviruses adapted to non-flying animals and to date and determine the origin of these viruses.

Pathogenesis and transmission dynamics (Blanca Amengual, Florence Larrous, Laurent Audry, Hervé Bourhy in collaboration with Jordi Serra-Cobo, University de Barcelone, Spain and the international network of Pasteur Institutes).

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 and Madagascar.

Identification of viral and cellular mechanisms involved in the pathogenesis of lyssaviruses (Raïd Kassis, Florence Larrous, Dorothée Obach, 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)

The next question is how viral genetic variations influence or restrict the infection of a new host. 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). In this model, apoptosis is prevented by both a broad and a specific synthetic caspase-inhibitor of caspase-8. A paracrine sensitization of neuroblastoma cells to TRAIL-ligation-mediated apoptosis was also observed during lyssavirus infection of neuroblastoma cells. 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) (Raïd Kassis, Hervé Bourhy, Laurent Audry, Patrick Weber, Florence Larrous, Pascal Cozette, Malika Campanaro 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 (1289 analyses in total in 2003). Metropolitan France is 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 2003, one human rabies cases was diagnosed in France. This small child was bitten in Gabon as revealed by genetic characterization of the virus. This case underlined the importance of vaccinating young children travelling to enzootic areas.

World Health Collaborating Centre for Reference and Research on Rabies (WHOCC Rabies) (Raïd Kassis, Hervé Bourhy, Laurent Audry, Patrick Weber, Florence Larrous, Pascal Cozette, Malika Campanaro)

During the year 2003, the WHOCC Rabies became particularly involved 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 Laos and Cambodia. A multicentric collaborative study involving the network of Pasteur Institutes was started to define protocols of intra-vitam rabies diagnosis.

Keywords: Virology, Epidemiology, Ecosystems, Encephalitis, Rabies, Lyssavirus

Activity Reports 2003 - Institut Pasteur

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