RIG-I Plays a Dominant Role in the Induction of Transcriptional Changes in Zika Virus-Infected Cells, which Protect from Virus-Induced Cell Death

Abstract

The Zika virus (ZIKV) has received much attention due to an alarming increase in cases of neurological disorders including congenital Zika syndrome associated with infection. To date, there is no effective treatment available. An immediate response by the innate immune system is crucial for effective control of the virus. Using CRISPR/Cas9-mediated knockouts in A549 cells, we investigated the individual contributions of the RIG-I-like receptors MDA5 and RIG-I to ZIKV sensing and control of this virus by using a Brazilian ZIKV strain. We show that RIG-I is the main sensor for ZIKV in A549 cells. Surprisingly, we observed that loss of RIG-I and consecutive type I interferon (IFN) production led to virus-induced apoptosis. ZIKV non-structural protein NS5 was reported to interfere with type I IFN receptor signaling. Additionally, we show that ZIKV NS5 inhibits type I IFN induction. Overall, our study highlights the importance of RIG-I-dependent ZIKV sensing for the prevention of virus-induced cell death and shows that NS5 inhibits the production of type I IFN.

The Molecular Interactions of ZIKV and DENV with the Type-I IFN Response

“…This interaction triggers MAVS activation leading to subsequent activation of cytosolic kinases TBK1 and IKKε [ 31 ]. Interestingly, CRISPR/Cas9-mediated knockout of RIG-I but not MDA5 led to significantly increased ZIKV replication in A549 cells compared to control, indicating that RIG-I is the main sensor of ZIKV infection in these cells [ 40 ]. Furthermore, knockout of the RLR signaling intermediate MAVS was shown to enhance ZIKV infection in human placental trophoblast cell lines [ 41 ].…”

Placental Immune Responses to Viruses: Molecular and Histo-Pathologic Perspectives

“…CMV, Zika, and many other viruses employ multiple mechanisms to exploit the vulnerability of the placenta. Zika virus NS5 inhibits type I interferon receptor signaling and blocks induction of type I interferon via the RIG-I pathway [ 39 , 40 , 41 ]. ( Figure 2 ) Like Zika and other flaviviruses, CMV uses multiple strategies to impair the innate host response to infection.…”

Chikungunya and Zika Viruses: Co-Circulation and the Interplay between Viral Proteins and Host Factors

“…Moreover, both MDA5 and RIG-I expression levels can be inhibited by NS2A and NS4A of ZIKV in HEK293T cells [ 217 ]. Interestingly, Schilling and team announced that only RIG-I functions as a ZIKV detector because the knockout of RIG-I, but not of MDA5, significantly increases virus replication [ 243 ]. As 14–3-3ϵ and 14–3-3η proteins promote MDA5 and RIG-I cytosolic-to-mitochondrial translocation, the inhibition of these proteins inhibits downstream RIG-I-like receptor (RLR) signaling.…”