Expression et activité antivirale des interférons dans les neurones
(2008)
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- Authors
- Supervisors
- Michiels, Thomas
- Abstract
- Type I interferons (IFN-I) form a multigenic family of cytokines which are expressed upon viral infection. They play a crucial antiviral role. Type III IFN (IFN-III) expression is also induced in response to viral infection. Although IFN-III bind a receptor unrelated to that of IFN-I, they exert, in the target cell, activities that are strikingly similar to those of IFN-I. In the first part of this work, we tested whether the multigenic nature of the IFN-I family and the redundancy between IFN-I and IFN-III systems could mean that IFN subtypes acquired specific expression patterns. We showed that IFN-alpha5, -alpha2, -alpha4, -alpha8/6 and IFN beta were the most abundantly transcribed IFN-I subtypes in the brain of encephalitic mice infected with Theiler s virus and La Crosse virus. These IFN-I subtypes were also the most predominantly expressed in the liver of mice infected with an hepatotropic virus (MHV-A59). These data suggest the absence of tissue-specificity for IFN-alpha/-beta expression. IFN-I and IFN-III were similarly produced in infected livers. In contrast, in the brain, IFN-I expression was readily induced in response to infections by neurotropic viruses while IFN-III production was minimal. These data show that the relative expression of IFN-III over that of IFN-I exhibits some extent of tissue specificity and suggests that cells or molecular pathways leading to IFN-I and IFN-III gene expression could vary. The second part of this study focused on IFN-I expression and IFN-I-mediated antiviral activity in primary mouse neurons infected by Theiler s virus. Neurons were previously reported, in our laboratory, to participate to the antiviral immune response by producing IFN-I and by responding to IFN-I, in vivo. However those data suggested that IFN-I synthesis could be more restricted in neurons than in other cell types. We showed that, in neurons, the very poor basal production of viral infection sensors and of factors governing transcriptional upregulation of IFN genes most probably accounted for the slow activation of IFN-I expression observed in these cells after viral infection. Furthermore, we demonstrated that the MDA5 sensor, reported to be crucial for Theiler s virus detection, is not necessary for initiation of IFN-I expression although it plays a predominant role in the amplification of IFN-I production in IFN-treated cells. Finally, we showed that primary neurons strongly expressed interferon-stimulated genes in response to IFN-beta treatment. However, in spite of the activation of these genes, neurons were not protected against a subsequent viral infection, in contrast to fibroblasts. This work contributes to the understanding of antiviral immune responses mounted in the central nervous system which is often targeted by persistent viral infections.
- Affiliations
Citations
Paul, S. (2008). Expression et activité antivirale des interférons dans les neurones. https://hdl.handle.net/2078.5/112042