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Ambivalent role of the innate immune response in rabies virus pathogenesis.

Abstract : The neurotropic rabies virus (RABV) has developed several evasive strategies including immunoevasion to successfully infect the nervous system (NS) and trigger a fatal encephalomyelitis. Here, we show that LGP2 expression, a protein known either as a positive or negative regulator of the RIG-I mediated-innate immune response, is restricted in the NS. We use a new transgenic mouse model (LGP2 TG) over-expressing LGP2 to impair RABV innate immune response and thus reveals the role of the RIG-I-mediated innate immune response in RABV pathogenesis. After infection, LGP2 TG exhibit reduced expression of inflammatory/chemoattractive molecules, IFN-β, and IFN-stimulated genes in their NS compared to WT, demonstrating the inhibitory function of LGP2 on RABV innate immune response. Surprisingly, LGP2 TG showed a better viral clearance in the brain and lower morbidity compared to WT, indicating that paradoxically the host innate immune response favors RABV neuroinvasiveness and morbidity. LGP2 TG mice exhibited similar neutralizing antibodies and microglia activation as WT, but a reduction of infiltrating CD4(+) T cell and a lower disappearance of infiltrating CD8(+) T cells. This occurs concomitantly to a reduced neural expression of the IFN-inducible B7-H1, an immunoevasive protein involved in the elimination of infiltrated CD8(+) T cells. Our study shows that host innate immune response favors the infiltration of T cells and, at the same time promotes the CD8(+)T cells elimination. Thus, RABV exploits, in a certain extent, the innate immune response to develop its immune-evasive strategy.
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Submitted on : Wednesday, November 9, 2011 - 7:00:05 AM
Last modification on : Tuesday, October 20, 2020 - 11:24:38 AM
Long-term archiving on: : Friday, February 10, 2012 - 2:20:40 AM

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Damien Chopy, Julien Pothlichet, Mireille Lafage, Françoise Mégret, Laurence Fiette, et al.. Ambivalent role of the innate immune response in rabies virus pathogenesis.. Journal of Virology, American Society for Microbiology, 2011, epub ahead of print. ⟨10.1128/JVI.00302-11⟩. ⟨pasteur-00591084⟩

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