2’-O Methylation of the Viral mRNA Cap by West Nile Virus Evades Ifit1-Dependent and –Independent Mechanisms of Host Restriction In Vivo

Szretter, K.J. et al. PLoS Pathog 8 (5), e1002698 (2012).

Speaker: Chao-Ho Li (李兆和)                                             Date: 13:00-14:00 Oct. 17, 2012

Commentator: Dr. Yao Chang (張堯老師)                           Place: Room 601

Abstract:

        How to identify self and non-self components is an important issue in the immune system. Therefore, some viruses also evolve to mimic host components for escaping immune system attack^1,2. Previous studies have shown 5’-triphosphate or 2’-O-unmethylated virus mRNA can be recognized by an anti-viral protein, interferon-induced protein with tetratricopeptide repeat 1 (IFIT1)³, which can induce higher TNF-α/β secretion. Some viruses like coronaviruses and flaviviruses have 2’-O methyltransferase activity to escape sensors of innate immune response. Here, the authors characterized a 2’-O methyltransferase-defective West Nile Virus (WNV) mutant, WNV-E218A. They used this mutant to study ifit restriction mechanism in vivo. WNV-E218A infected mice still survived after 21 days post infection, but WNV-WT infected ifit^-/- mice showed a 50% survival rate. This result indicates that ifit plays an important role in 2’-O methylated viral mRNA recognition. Higher WNV replication was observed in CNS and spleen in ifit^-/- mice, especially regions normally infected by WNV such as the cortex, brain stem, cerebellum. By analyzing leukocytes and confocal microscopic observation, neuronal death was found to be mediated by CD8⁺ T cell. In sum, WNV infection triggers higher ifit-induced immune responses in WT mice to accelerate virus clearance. In contrast, ifit^-/- mice showed more neuronal death as a result of poor clearance ability of WNV infection.

References:

¹      Zust, R. et al., Ribose 2[prime]-O-methylation provides a molecular signature for the distinction of self and non-self mRNA dependent on the RNA sensor Mda5. Nat Immunol 12 (2), 137-143 (2011).

²      Daffis, S. et al., 2[prime]-O methylation of the viral mRNA cap evades host restriction by IFIT family members. Nature 468 (7322), 452-456 (2010).

³      Pichlmair, A. et al., IFIT1 is an antiviral protein that recognizes 5[prime]-triphosphate RNA. Nat Immunol 12 (7), 624-630 (2011).