|Viral Neuro-Immunology - URA CNRS 3015|
|HEAD||Monique Lafon / firstname.lastname@example.org|
|MEMBERS||Monique LAFON / Christophe PREHAUD
Corinne BARAN / Edmond BELLANCE / Mireille LAFAGE
Nicolas ABRAHAM-TARDIEUX / Damien CHOPY / Alexandra MARIE / Pauline MENAGER
Rabies remains an important public health problem in the world due to uncontrolled enzootic rabies, lack of vaccines and poor information. With over 55 000 cases of rabies reported each year, rabies is one of the tenth most important global infectious diseases. 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, HLA-G and B7-H1 which protect the infected neurons from the control by the host immune response was demonstrated (Baloul et al, 2004, Lafon et al, 2005, Lafon, 2008, Lafon et al, 2008).
Rabies virus has 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, chemo attractive 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 (Jackson et al, 2006). Moreover, TLR3 is a central element of Negri Bodies and appears critical for the rabies virus infection both in vivo and in vitro (Menager et al, 2009).
To continue its infectious cycle in the host’s nervous system, the rabies virus must ensure that the neurons it infects survive. Attenuated viral strains, such as those that were used in a vaccine to eradicate the wild rabies virus in France, are not able to do this, and are therefore made non-virulent. The rabies virus has evolved intrinsic neuroprotective molecular mechanisms that contribute to the protection of the infected neurons from virus-mediated cell death. We have shown that induction of neuroprotection or cell death is largely determined by the nature of the G-protein and identified in the G-protein, the key region that can cause the infected human neurons to survive or to be destroyed (Prehaud et al., 2003, 2010). Using recombinant chimeric viruses which express hybrid G proteins from virulent and attenuated viral strains we have shown that only one mutation in the very end cytoplasm portion of the G-protein is enough to alter the nature of the cellular partners and cause the infected neurons to be destroyed, therefore causing the rabies virus to lose its pathogenicity. The very end of the cytoplasm portion of the G-protein has been shown to control the affinity of the G-protein and the nature of the neuron proteins with which the viral protein interacts. We are now looking to understand the molecular signalling mechanisms involved in neuroprotection or neurodestruction and to identify the synthetic molecules – peptides from the G-protein or molecules mimicking them – for therapeutic purposes making the neuron survive or regenerate, or conversely destroying tumour cells which multiply randomly.
Keywords: Rabies virus, TLR3, B7-H1, neuronal plasticity, Negri bodies, neuron, apoptosis, virulence, attenuation
1- Ménager P, Roux P, Mégret F, Bourgeois JP, Le Sourd AM, Danckaert A, Lafage M, Préhaud C, Lafon M. 2009. Toll-like receptor 3 (TLR3) plays a major role in the formation of rabies virus Negri Bodies.PLoS Pathogen. Feb;5(2):e1000315. Epub 2009 Feb 27.PMID: 19247444
2- Lafon M, Mégret F, Meuth SG, Simon O, Velandia Romero ML, Lafage M, Chen L, Alexopoulou L, Flavell RA, Prehaud C, Wiendl H. 2008.Detrimental contribution of the immuno-inhibitor B7-H1 to rabies virus encephalitis.Journal of Immunology. Jun 1;180(11):7506-15.PMID: 18490751
3- Lafon M. 2008. Immune evasion, a critical strategy for rabies virus.Developments in Biology (Basel).;131:413-9. Review.PMID: 18634503
4- Mégret F, Prehaud C, Lafage M, Moreau P, Rouas-Freiss N, Carosella ED, Lafon M. 2007. Modulation of HLA-G and HLA-E expression in human neuronal cells after rabies virus or herpes virus simplex type 1 infections.Human Immunology. Apr;68(4):294-302. Epub 2006 Dec 28.PMID: 17400066
5- Jackson, AC, Rossiter JP, 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, Jun 12 (3): 229-234. PMID: 16877304
Activity Reports 2009 - Institut Pasteur
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