title: 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 expression of LGP2, a protein known as either a positive or negative regulator of the RIG-I-mediated innate immune response, is restricted in the NS. We used a new transgenic mouse model (LGP2 TG) overexpressing LGP2 to impair the innate immune response to RABV and thus revealed the role of the RIG-I-mediated innate immune response in RABV pathogenesis. After infection, LGP2 TG mice exhibited reduced expression of inflammatory/chemoattractive molecules, beta interferon (IFN-β), and IFN-stimulated genes in their NS compared to wild-type (WT) mice, demonstrating the inhibitory function of LGP2 in the innate immune response to RABV. Surprisingly, LGP2 TG mice showed more viral clearance in the brain and lower morbidity than WT mice, indicating that the host innate immune response, paradoxically, favors RABV neuroinvasiveness and morbidity. LGP2 TG mice exhibited similar neutralizing antibodies and microglia activation to those of WT mice but showed a reduction of infiltrating CD4(+) T cells and less disappearance of infiltrating CD8(+) T cells. This occurred concomitantly with reduced neural expression of the IFN-inducible protein B7-H1, an immunoevasive protein involved in the elimination of infiltrated CD8(+) T cells. Our study shows that the host innate immune response favors the infiltration of T cells and, at the same time, promotes CD8(+) T cell elimination. Thus, to a certain extent, RABV exploits the innate immune response to develop its immunoevasive strategy.
authors.affiliation: Institut Pasteur, Unité de Neuroimmunologie Virale, Département de Virologie, F-75015 Paris, France. monique.lafon@pasteur.fr
authors.forename: Damien
authors.initials: D
authors.lastname: Chopy
authors.forename: Julien
authors.initials: J
authors.lastname: Pothlichet
authors.forename: Mireille
authors.initials: M
authors.lastname: Lafage
authors.forename: Françoise
authors.initials: F
authors.lastname: Mégret
authors.forename: Laurence
authors.initials: L
authors.lastname: Fiette
authors.forename: Mustapha
authors.initials: M
authors.lastname: Si-Tahar
authors.forename: Monique
authors.initials: M
authors.lastname: Lafon
mesh_terms: D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics / Q000378:metabolism*; D060890:B7-H1 Antigen; D001921:Brain / Q000276:immunology / Q000821:virology; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D007113:Immunity, Innate; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D009474:Neurons / Q000276:immunology / Q000821:virology; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D020365:RNA Helicases / Q000235:genetics / Q000378:metabolism*; D011818:Rabies / Q000276:immunology* / Q000821:virology; D011820:Rabies virus / Q000276:immunology* / Q000472:pathogenicity*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D008562:Membrane Glycoproteins; D010455:Peptides; C520569:DHX58 protein, human; D020365:RNA Helicases