The central nervous system (CNS) harbors highly differentiated cells, such as neurons that are essential to coordinate the functions of complex organisms. This organ is partly protected by the blood-brain barrier (BBB) from toxic substances and pathogens carried in the bloodstream. Yet, neurotropic viruses can reach the CNS either by crossing the BBB after viremia, or by exploiting motile infected cells as Trojan horses, or by using axonal transport. Type I and type III interferons (IFNs) are cytokines that are critical to control early steps of viral infections. Deficiencies in the IFN pathway have been associated with fatal viral encephalitis both in humans and mice. Therefore, the IFN system provides an essential protection of the CNS against viral infections. Yet, basal activity of the IFN system appears to be low within the CNS, likely owing to the toxicity of IFN to this organ. Moreover, after viral infection, neurons and oligodendrocytes were reported to be relatively poor IFN producers and appear to keep some susceptibility to neurotropic viruses, even in the presence of IFN. This review addresses some trends and recent developments concerning the role of type I and type III IFNs in: i) preventing neuroinvasion and infection of CNS cells; ii) the identity of IFN-producing cells in the CNS; iii) the antiviral activity of ISGs; and iv) the activity of viral proteins of neurotropic viruses that target the IFN pathway.
Apolipoprotein L9b (Apol9b) is an interferon-stimulated gene (ISG) that has antiviral activity and is weakly expressed in primary mouse neurons as compared to other cell types. Here, we show that both Apol9 isoforms (Apol9b and Apol9a) inhibit replication of Theiler’s murine encephalomyelitis virus (TMEV) but not replication of vesicular stomatitis virus (VSV), Murid herpesvirus-4 (MuHV-4), or infection by a lentiviral vector. Apol9 genes are strongly expressed in mouse liver and, to a lesser extent, in pancreas, adipose tissue and intestine. Their expression is increased by type I interferon and viral infection. In contrast to genuine apolipoproteins that are involved in lipid transport, ApoL9 has an intracytoplasmic localization and does not seem to be secreted. The cytoplasmic localization of ApoL9 is in line with the observation that ApoL9 inhibits the replication step of TMEV infection. In contrast to human ApoL6, ApoL9 did not sensitize cells to apoptosis, in spite of the presence of a conserved putative BH3 domain, required for antiviral activity. ApoL9a and b isoforms interact with cellular prohibitin 1 (Phb1) and prohibitin 2 (Phb2) and this interaction might contribute to ApoL9 antiviral activity. Knocking down Phb2 slightly increased TMEV replication, irrespective of ApoL9 overexpression. The antiviral activity of prohibitins against TMEV contrasts with the pro-viral activity of prohibitins observed for VSV and reported previously for Dengue 2 (DENV-2), Chikungunya (CHIKV) and influenza H5N1 viruses. ApoL9 is thus an example of ISG displaying a narrow antiviral range, which likely acts in complex with prohibitins to restrict TMEV replication.
We examined the antiviral response promoted by type I interferons (IFN) in primary mouse neurons. IFN treatment of neuron cultures strongly upregulated the transcription of IFN-stimulated genes but conferred a surprisingly low resistance to infection by neurotropic viruses such as Theiler's murine encephalomyelitis virus (TMEV) or vesicular stomatitis virus (VSV). Response of primary mouse neurons to IFN treatment was heterogeneous, as many neurons failed to express the typical IFN response marker Mx1 after IFN treatment. This heterogeneous response of primary neurons correlated with a low level of basal expression of IFN-stimulated genes, such as Stat1, that are involved in signal transduction of the IFN response. In addition, transcriptomic analysis identified 15 IFN-responsive genes whose expression was low in IFN-treated primary neurons compared to that of primary fibroblasts derived from the same mice (Dhx58, Gvin1, Sp100, Ifi203 isoforms 1 and 2, Irgm2, Lgals3bp, Ifi205, Apol9b, Ifi204, Ifi202b, Tor3a, Slfn2, Ifi35, Lgals9). Among these genes, the gene coding for apolipoprotein L9b (Apol9b) displayed antiviral activity against Theiler's virus when overexpressed in L929 cells or in primary neurons. Accordingly, knocking down Apol9b expression in L929 cells increased viral replication. Therefore, we identified a new antiviral protein induced by interferon, ApoL9b, whose lack of expression in primary neurons likely contributes to the high sensitivity of these cells to viral infection. IMPORTANCE The type I interferon (IFN) response is an innate immune defense mechanism that is critical to contain viral infection in the hostuntil an adaptive immune response can be mounted. Neurons are a paradigm for postmitotic, highly differentiated cells. Our data show that primary mouse neurons that are exposed to type I interferon remain surprisingly susceptible to viral infection. On one hand, the low level of basal expression of some factors in neurons might prevent a rapid response of these cells. On the other hand, some genes that are typically activated by type I interferon in other cell types are expressed at much lower levels in neurons. Among these genes is the gene encoding apolipoprotein L9, a protein that proved to have antiviral activity against the neurotropic Theiler's murine encephalomyelitis virus. Our data suggest important functional differences in the IFN response mounted by specific cell populations.
Ten beet virus Q (BVQ) strains from six different countries were sequenced to characterize the readthrough (RT) domain of the coat protein (CP). The GenBank/EMBL/DDBJ accession numbers for the sequences reported in this paper are FM244643-FM244652. With three nucleotide additions of 5, 285 and 1 nt, the common RT of 76 kDa was found to be longer than the single reference available to date (35 kDa). It is hypothesized that multiple inoculation cycles on Chenopodium quinoa were responsible for these three deletions in the C-terminal part of the BVQ RNA-2 previously described. Two putative transmembrane domains, TM1 and TM2, were predicted in the consensus amino acid sequence of the ten BVQ strains, and the putative BVQ TM2 was aligned with that of potato mop-top virus.
No abstract
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.