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PMID:21525357

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Citation

Chopy, D, Pothlichet, J, Lafage, M, Mégret, F, Fiette, L, Si-Tahar, M and Lafon, M (2011) Ambivalent role of the innate immune response in rabies virus pathogenesis. J. Virol. 85:6657-68

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.

Links

PubMed PMC3126514 Online version:10.1128/JVI.00302-11

Keywords

Animals; Antigens, CD274; Antigens, CD80/genetics; Antigens, CD80/metabolism; Brain/immunology; Brain/virology; Cell Line; Cell Line, Tumor; Humans; Immunity, Innate; Membrane Glycoproteins/genetics; Membrane Glycoproteins/metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; NIH 3T3 Cells; Neurons/immunology; Neurons/virology; Peptides/genetics; Peptides/metabolism; RNA Helicases/genetics; RNA Helicases/metabolism; Rabies/immunology; Rabies/virology; Rabies virus/immunology; Rabies virus/pathogenicity; T-Lymphocytes/immunology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:DHX58

involved_in

GO:0032480: negative regulation of type I interferon production

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:DHX58

involved_in

GO:0045824: negative regulation of innate immune response

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:DHX58

involved_in

GO:0032480: negative regulation of type I interferon production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:DHX58

involved_in

GO:0045824: negative regulation of innate immune response

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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