Neuro-Immuno Virology


  HEADDr LAFON Monique / mlafon@pasteur.fr
  MEMBERSMEGID Jane / MEGRET Françoise / MENAGER Pauline / Dr PREHAUD Christophe / WAUQIER Nadia


  Annual Report

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.

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 favor 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 (Vidy et al, 2005, Brzozka et al, 2006,2004). 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 which were thought to rely on companion glial cells to detect infection, 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. Rabies virus-induced apoptosis is inversely correlated with pathogenicity (. Induction of apoptosis is largely determined by the level of expression of rabies virus glycoprotein (G-protein) and by the nature of the G-protein . We are currently investigating in a structure/function analysis the molecular basis of the balance between death or survival control by the virus.

lafon.jpg

Neurons from the cerebellum of a human rabies case express TLR3 (brown staining)



  Publications

Publications 2006 of the unit on Pasteur's references database




Activity Reports 2006 - Institut Pasteur
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