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.
Highlights
The recent epidemic caused by Zika virus (ZIKV), a mosquito-borne flavivirus, revealed the potential of the virus to inflict severe harm on infected individuals
A549 and HEK293 cells were single-cell FACS sorted according to the co-expressed fluorescent protein (Ruby+ for cells transfected with the sgRNAs targeting RIG-I or melanoma differentiation-associated gene 5 (MDA5), GFP+ for IFNAR1) 48 h post transfection
We showed that total RNA extracted from cells infected with ZIKV contains immunostimulatory RNAs that activate the mitochondrial antiviral-signaling protein (MAVS) pathway when transfected into reporter cells [13]
Summary
The recent epidemic caused by Zika virus (ZIKV), a mosquito-borne flavivirus, revealed the potential of the virus to inflict severe harm on infected individuals. Viral RNAs are detected by RIG-I-like receptors (RLRs) including retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). Binding of the secreted type I IFNs to their receptor in turn induces a signaling cascade involving signal transducer and activator of transcription (STAT) 1 and 2 hetero-dimerization that leads to the expression of interferon stimulated genes (ISGs). Deficiency of PRRs increases ZIKV replication in human skin fibroblasts and mice lacking the type I IFN receptor (IFNAR), STAT2, MAVS or a combination of IRF transcription factors show higher viral replication and pathology [5,7,8,10,11,12]. We show that ZIKV NS5 interferes with IFNAR signaling, but inhibited type I IFN induction upstream of type I IFN gene transcription
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