Lyssavirus dynamics and host adaptation  


  Annual Report

Rabies is an acute, progressive, incurable viral encephalitis. The causative agents are neurotropic RNA viruses in the family Rhabdoviridae, genus Lyssavirus. Rabies is an anthropozoonosis that affects many different animal species and which has an epidemiology that changes with time. The main objective of the Unit is to study the relationships between genomic evolution in lyssaviruses and host response to infection, and the consequences in terms of dynamic of lyssavirus infection in the different human and animal populations.

Part of our work deals with the determination of the ecological and virological factors involved in the dynamics of lyssavirus infection in animal populations (dogs and bats). It is based on ecological, epidemiological and viral genetic studies which together help to explain how a lyssavirus spreads or maintains itself in a target animal species. In 2010, we have analysed the spatio-temporal spreading of dog rabies virus in North Africa. Our results are strongly supportive of human-mediated dispersal, and demonstrate how an integrated phylogeographic approach will turn viral genetic data into a powerful asset for characterizing, predicting, and potentially controlling the spatial spread of pathogens.

The other part presents an analysis of the host cell and virus interplay at the molecular level and its relations with the crossing of the species barrier. The role of the viral proteins and in particular the matrix protein and the phosphoprotein are studied in details. In 2010, the three dimensional structure of the phosphoprotein was obtained allowing us to describe important domains in the regulation of the virus biological life cycle. Further, we identified a 20-amino-acid fragment of the matrix protein responsible of the cell death activities via both the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and inhibition of cytochrome c oxidase (CcO) activity. We found that the amino acids at positions 77 and 81 have an essential role in triggering these two cell death pathways. The elucidation of the critical points of the early phase of lyssavirus infection together with the identification and the localization of the potential viral and cellular determinants of virulence on these proteins should result in a better understanding of the basic molecular mechanisms involved in lyssavirus adaptation and pathogenesis for humans.

To reach these goals, the unit gathers researchers and collaborations with complementary expertise. Briefly, these are with our colleagues from the Departments of "Infection and Epidemiology" and "Virology", from the technological platforms in Pasteur Institute, from other institutes of the International Network of Pasteur Institutes, particularly those located in Africa and in Asia where the burden of rabies is the highest and with all those participating to FP7 funded project SILVER in which we are involved. The research project is also intimately connected with public health problems of interest for the National Reference Centre for Rabies and for the World Health Organization Collaborative Centre for Research and Reference for Rabies that are housed in the unit. In 2010, the Unit developed and validated a broad spectrum resequencing microarray for the detection and genotyping of rhabdoviruses.

Keywords: Rabies virus, phylogeny, evolution, pathogenesis, epidemiology


Talbi C, Lemey P, Suchard MA, Abdelatif E, Elharrak M, Jalal N, Faouzi A, Echevarría JE, Vazquez Morón S, Rambaut A, Campiz N, Tatem AJ, Holmes EC, Bourhy H. 2010. Phylodynamics and human-mediated dispersal of a zoonotic virus. PLoS Pathog. 6(10):e1001166. PMID: 21060816

Larrous F, Gholami A, Mouhamad S, Estaquier J, Bourhy H. 2010. Two overlapping domains of a lyssavirus matrix protein that acts on different cell death pathways. J Virol. 84(19):9897-906. PMID: 20631119

Dacheux L, Berthet N, Dissard G, Holmes EC, Delmas O, Larrous F, Guigon G, Dickinson P, Faye O, Sall AA, Old IG, Kong K, Kennedy GC, Manuguerra JC, Cole ST, Caro V, Gessain A, Bourhy H. 2010. Application of broad-spectrum resequencing microarray for genotyping rhabdoviruses. J Virol. 84(18):9557-74.

PMID: 20610710

Assenberg R, Delmas O, Ren J, Vidalain PO, Verma A, Larrous F, Graham SC, Tangy F, Grimes JM, Bourhy H. 2010. Structure of the nucleoprotein binding domain of Mokola virus phosphoprotein. J Virol. 84(2):1089-96. PMID: 19906936

Graham SC, Assenberg R, Delmas O, Verma A, Gholami A, Talbi C, Owens RJ, Stuart DI, Grimes JM, Bourhy H. 2008. Rhabdovirus matrix protein structures reveal a novel mode of self-association. PLoS Pathog. 4(12):e1000251. PMID: 19112510

Activity Reports 2010 - Institut Pasteur
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