|HEAD||Monique LAFON, Dr PhD / email@example.com|
|MEMBERS||Monique LAFON, Chef de Laboratoire (Associate Professor) Institut Pasteur Christophe PREHAUD, Chargé de Recherche (Assistant professor) Institut Pasteur / Françoise MEGRET Research Officer, Institut Pasteur
Corinne BARAN, Secretary, Institut Pasteur / Edmond BELLANCE, Glass washer/media maker / Mireille LAFAGE, High-grade technician, Institut Pasteur
Pauline MENAGER, Master II and PhD Student (2005-) / Gaelle MARTIN, Master I student (2007) / Mickael MARIN, BTS student (2007) / Amandine GALIOOT, L3 student (2007) / Christin LUFT, Internship 2007
Rabies remains an important public health problem in the world due to uncontrolled enzootic rabies, lack of vaccines and poor information. Globally there are over 70 000 cases of rabies reported each year. Rabies is becoming a re-emerging disease in several parts of the world including China where epidemics are currently exploding. Rabies virus, which is transmitted by bites of rabid animals, replicates in nervous tissues- only in neurons-, causing fatal encephalitis in nearly all the cases. In the absence of post-exposure treatment, rabies is one of the very few human infections with nearly a 100 % mortality rate. Intriguingly, once the rabies virus has entered the CNS, its progression is interrupted neither by destruction of the infected neuron nor by the immune response. Therefore the classical strategies developed by the host to battle infection are inefficient.
We aimed to elucidate how rabies virus can avoid functional neuron impairment and host immune mechanisms. By using purified post mitotic human neurons in culture and appropriate animal models, we demonstrated that rabies virus has selected unique strategies to favour neuronal survival and paralyze the host immune response. Particularly, the up-regulation by rabies virus of immunosubversive molecules such as FasL and HLA-G which protect the infected neurons from the control by the host immune response was demonstrated (Baloul et al, 2004, Lafon et al, 2005, Mégret et al, 2007 ).
Rabies virus has also developed strategies to escape the innate immune response which represents the first line of host defence against pathogens. Nevertheless, this escape may not be complete since in the few hours following infection, rabies virus triggers strong interferon, inflammatory, chemoattractive and anti-viral responses in human neurons (Prehaud et al, 2005, Lafon et al, 2006). These analyses allowed us to show, for the first time, that human neurons express several Toll-like receptors including TLR3 which recognizes and responds to double stranded RNA. Moreover, TLR3 expression by neurons was observed in human rabies cases (Jackson et al. 2006).
The rabies virus has also evolved intrinsic neuroprotective molecular mechanisms that contribute to the protection of the infected neurons from virus-mediated burden. Identifying the specific proteins that induce apoptosis as well as the precise roles of these proteins was therefore critical for improving the knowledge of virus pathogenicity and virulence. Rabies virus-induced apoptosis is inversely correlated with pathogenicity (. Induction of apoptosis is largely determined by the nature of the G-protein . Recent evidence revealed that rabies virus containing the G-protein from an attenuated virus strain (“G death”) was able to trigger apoptosis of human cells, whereas expression of the pathogenic rabies virus G-protein (“G survival”) was not . The cytoplasmic portions of viral G death and G survival, possess a PDZ binding site, We observed that their host cell partners exhibit a PDZ domain. By biochemical means and rabies virus reverse genetic analysis we demonstrated the importance of the glycoprotein C domain and the PDZ protein-protein interaction (in collaboration with N. Wolff, H. Buc, Institut Pasteur; and M. Schnell, Thomas Jefferson University, USA). We are currently investigating the molecular basis of the balance between death or survival control by the virus.
Keywords: Rabies virus, neuron survival, neuronal apoptosis, TLR3, FasL, HLA-G
BALOUL, L., CAMELO, S., and LAFON, M. (2004). Up-regulation of FasL in the CNS : a mechanism of immune evasion by rabies virus. Journal of Neurovirology, 10 : 372-382.
PREHAUD C., MEGRET F., LAFAGE, M., and LAFON, M. (2005). Virus infection switches TLR-3 positive human neurons into high producers of interferon-beta. Journal of Virology, 79 :12893-904
LAFON M., PREHAUD C., MEGRET F., LAFAGE M., MOUILLOTG., ROAM., MOREAU P., ROUAS-FREISS, N.and CAROSELLA, E. (2005). Modulation of HLA-G expression in human neural cells after neurotropic viral infections Journal of Virology, 79 :15226-37.
LAFON, M. (2005). Modulation of the immune response in the nervous system by rabies virus. Current topics of Microbiology and Immunology, 289, 239-258. In role of apoptosis in infection. Diane Griffins and Hilary Koprowski, Eds.
JACKSON, AC, ROSSITER JP AND M LAFON(2006).Expression of Toll-like receptor 3 in the human cerebellar cortex in rabies, herpes simplex encephalitis, and other neurological diseases.Journal of Neurovirology, 12: 229-234.
Activity Reports 2007 - Institut Pasteur
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