DDX3 suppresses type I interferons and favors viral replication during Arenavirus infection

Abstract

Several arenaviruses cause hemorrhagic fever (HF) diseases that are associated with high morbidity and mortality in humans. Accordingly, HF arenaviruses have been listed as top-priority emerging diseases for which countermeasures are urgently needed. Because arenavirus nucleoprotein (NP) plays critical roles in both virus multiplication and immune-evasion, we used an unbiased proteomic approach to identify NP-interacting proteins in human cells. DDX3, a DEAD-box ATP-dependent-RNA-helicase, interacted with NP in both NP-transfected and virus-infected cells. Importantly, DDX3 deficiency compromised the propagation of both Old and New World arenaviruses, including the HF arenaviruses Lassa and Junin viruses. The DDX3 role in promoting arenavirus multiplication associated with both a previously un-recognized DDX3 inhibitory role in type I interferon production in arenavirus infected cells and a positive DDX3 effect on arenavirus RNA synthesis that was dependent on its ATPase and Helicase activities. Our results uncover novel mechanisms used by arenaviruses to exploit the host machinery and subvert immunity, singling out DDX3 as a potential host target for developing new therapies against highly pathogenic arenaviruses.

E3 Ligase ITCH Interacts with the Z Matrix Protein of Lassa and Mopeia Viruses and Is Required for the Release of Infectious Particles

“…To date, lists of host-cell proteins associated with various arenavirus infections have been established, providing new bases to investigate the potential roles of such interactions during the course of infection. With the exception of one study, which focused on the proteins of cellular origin associated with the Z protein of JUNV, most reports have focused on the NP and L interactomes during JUNV and LCMV infection [44][45][46][47][48]. However, these reports were based on the expression of tagged viral proteins through transfection or infection with genetically modified viruses and the identification of associated host-cell partners after purification and mass spectrometry analysis.…”

Differential Immune Responses to Hemorrhagic Fever-Causing Arenaviruses

“…A recent large-scale protein interaction screen revealed that both OW and NW arenavirus NPs interact with the host DEAD-box ATP-dependent RNA helicase, DDX3 [81]. DDX3 exhibits a proviral role for arenaviruses, as replication of LCMV, LASV, and JUNV was substantially impaired in DDX3 knockout cells [81]. Two different mechanisms have been proposed for the proviral effect of DDX3.…”

“…Two different mechanisms have been proposed for the proviral effect of DDX3. Early in infection, DDX3 assists in viral RNA replication, as supported by the reduced arenavirus minigenome replication in DDX3 knockout cells [81]. Mutation in the DDX3 ATPase and helicase domains also leads to reduced minigenome replication, indicating that these domains are essential for the proviral function of DDX3 [81].…”

“…Early in infection, DDX3 assists in viral RNA replication, as supported by the reduced arenavirus minigenome replication in DDX3 knockout cells [81]. Mutation in the DDX3 ATPase and helicase domains also leads to reduced minigenome replication, indicating that these domains are essential for the proviral function of DDX3 [81]. Late in infection, DDX3 may act to suppress IFN production and facilitate LCMV infection [81].…”

“…Mutation in the DDX3 ATPase and helicase domains also leads to reduced minigenome replication, indicating that these domains are essential for the proviral function of DDX3 [81]. Late in infection, DDX3 may act to suppress IFN production and facilitate LCMV infection [81]. By contrast, DDX3 does not affect IFN-β transcription in JUNV infection [81].…”