Abstract
BackgroundFlaviviruses are a group of diverse and emerging arboviruses and an immense global health problem. A number of flaviviruses are neurotropic, causing severe encephalitis and even death. Type I interferons (IFNs) are the first line of defense of the innate immune system against flavivirus infection. IFNs elicit the concerted action of numerous interferon-stimulated genes (ISGs) to restrict both virus infection and replication. Viperin (virus-inhibitory protein, endoplasmic reticulum-associated, IFN-inducible) is an ISG with broad-spectrum antiviral activity against multiple flaviviruses in vitro. Its activity in vivo restricts neurotropic infections to specific regions of the central nervous system (CNS). However, the cell types in which viperin activity is required are unknown. Here we have examined both the regional and cell-type specificity of viperin in the defense against infection by several model neurotropic flaviviruses.MethodsViral burden and IFN induction were analyzed in vivo in wild-type and viperin−/− mice infected with Langat virus (LGTV). The effects of IFN pretreatment were tested in vitro in primary neural cultures from different brain regions in response to infection with tick-borne encephalitis virus (TBEV), West Nile virus (WNV), and Zika virus (ZIKV).ResultsViperin activity restricted nonlethal LGTV infection in the spleen and the olfactory bulb following infection via a peripheral route. Viperin activity was also necessary to restrict LGTV replication in the olfactory bulb and the cerebrum following CNS infection, but not in the cerebellum. In vitro, viperin could restrict TBEV replication in primary cortical neurons, but not in the cerebellar granule cell neurons. Interferon-induced viperin was also very important in primary cortical neurons to control TBEV, WNV, and ZIKV.ConclusionsOur findings show that viperin restricts replication of neurotropic flaviviruses in the CNS in a region- and cell-type-specific manner. The most important sites of activity are the olfactory bulb and cerebrum. Activity within the cerebrum is required in the cortical neurons in order to restrict spread. This study exemplifies cell type and regional diversity of the IFN response within the CNS and shows the importance of a potent broad-spectrum antiviral ISG.
Highlights
Flaviviruses are a group of diverse and emerging arboviruses and an immense global health problem
A high viral burden was detected in the olfactory bulb at 6–10 dpi, and in the absence of viperin, Langat virus (LGTV) disseminated into the cerebrum
Robust induction of viperin after infection restricts viral growth in the cerebral neurons and astrocytes Since we found that viperin was able to restrict LGTV in vivo, we wanted to determine the role of viperin in response to highly pathogenic tick-borne encephalitis virus (TBEV) infection (Biosafety level 3)
Summary
Flaviviruses are a group of diverse and emerging arboviruses and an immense global health problem. Viperin (virus-inhibitory protein, endoplasmic reticulum-associated, IFN-inducible) is an ISG with broad-spectrum antiviral activity against multiple flaviviruses in vitro. Upon viral recognition, it is highly induced in an IFN-dependent as well as in an IFNindependent manner [7,8,9] It has broad-range antiviral activity against influenza A virus [10, 11], human immunodeficiency virus [12], chikungunya virus [13], Sindbis virus [14], and respiratory syncytial virus [15]. Low basal levels of viperin are found in most cell types, we have found high levels of viperin in the brain, in primary astrocyte cultures in vitro [4] They show a rapid response to viral infection by upregulation of viperin expression. Since these are neurotropic viruses, they represent useful models to investigate the antiviral capacity of viperin in the brain
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