The interplay between viperin antiviral activity, lipid droplets and Junín mammarenavirus multiplication

Abstract

Junín arenavirus infections are associated with high levels of interferons in both severe and fatal cases. Upon Junín virus (JUNV) infection a cell signaling cascade initiates, that ultimately attempts to limit viral replication and prevent infection progression through the expression of host antiviral proteins. The interferon stimulated gene (ISG) viperin has drawn our attention as it has been highlighted as an important antiviral protein against several viral infections. The studies of the mechanistic actions of viperin have described important functional domains relating its antiviral and immune-modulating actions through cellular lipid structures. In line with this, through silencing and overexpression approaches, we have identified viperin as an antiviral ISG against JUNV. In addition, we found that lipid droplet structures are modulated during JUNV infection, suggesting its relevance for proper virus multiplication. Furthermore, our confocal microscopy images, bioinformatics and functional results also revealed viperin-JUNV protein interactions that might be participating in this antiviral pathway at lipid droplet level. Altogether, these results will help to better understand the factors mediating innate immunity in arenavirus infection and may lead to the development of pharmacological agents that can boost their effectiveness thereby leading to new treatments for this viral disease.

Fat, fight, and beyond: The multiple roles of lipid droplets in infections and inflammation

“…175,176 The mechanism for subcellular targeting of viperin via its -helix to the LDs is similar to that described for the HCV NS5A viral protein, indicating that part of viperin's antiviral activity may be mediated by the subcellular localization of the protein, 31 probably acting as part of localized antiviral tactics to limit viral propagation. The viperin antiviral pathway at the LD level was also proposed for JUNG virus 143 and probably for other flaviviruses. 31 However, viperin anchorage onto LDs is dispensable for DENV inhibition.…”

“…Several (+)RNA viruses use host LDs at different steps of their life cycle, such as reovirus, rotavirus, norovirus, Junín virus, and poliovirus, as well as various members of the Flaviviridae . These viruses manipulate lipid metabolism for efficient viral morphogenesis, and inhibition of lipid metabolism and/or interference with LD homeostasis decreases viral replication and/or assembly …”

“…Viperin has a broad and potent antiviral activity, however the exact mechanism of viperin antiviral action remains unknown, but several indications suggest that viperin can inhibit different viruses by different pathways . Structurally, viperin's amino‐terminal amphipathic α‐helix seems to be important for full antiviral activity because it is involved in protein subcellular localization and physical interaction with proteins essential to viral replication . Tagged proteins inhibited by viperin have been reported, including HCV NS5A, DENV NS3, Junín mammarenavirus N protein, and probably chikungunya nsP2, which are important proteins in viral RNA transcription and replication .…”

“…24,25,144 These viruses manipulate lipid metabolism for efficient viral morphogenesis, and inhibition of lipid metabolism and/or interference with LD homeostasis decreases viral replication and/or assembly. 25,52,143 Although the replication of flaviviruses is associated with the endoplasmic reticulum, LDs are also an important component of viral morphogenesis. 24,25,52,145 In this context, several viral proteins have been reported on LDs, including nonstructural proteins (NS) linked to replication, such NS4B, 146 NS5A, and NS3 protein 144,145 of HCV, as well as the capsid core proteins of HCV, 147,148 GB virus-B, 149 and dengue virus (DENV).…”

“…109,166 Structurally, viperin's amino-terminal amphipathic -helix seems to be important for full antiviral activity because it is involved in protein subcellular localization 31 and physical interaction with proteins essential to viral replication. 31,143,170 Tagged proteins inhibited by viperin have been reported, including HCV NS5A, 31 DENV NS3, 170 Junín mammarenavirus N protein, 143 and probably chikungunya nsP2, 171 which are important proteins in viral RNA transcription and replication. [172][173][174] Furthermore, viperin seems to induce lipid raft disturbance and, as a consequence, impairment of membrane localization of viral proteins and inhibition of virus release.…”