Abstract
Flaviviruses have evolved complex mechanisms to evade the mammalian host immune systems including the RIG-I (retinoic acid-inducible gene I) like receptor (RLR) signaling. Zika virus (ZIKV) is a re-emerging flavivirus that is associated with severe neonatal microcephaly and adult Guillain-Barre syndrome. However, the molecular mechanisms underlying ZIKV pathogenesis remain poorly defined. Here we report that ZIKV non-structural protein 4A (NS4A) impairs the RLR-mitochondrial antiviral-signaling protein (MAVS) interaction and subsequent induction of antiviral immune responses. In human trophoblasts, both RIG-I and melanoma differentiation-associated protein 5 (MDA5) contribute to type I interferon (IFN) induction and control ZIKV replication. Type I IFN induction by ZIKV is almost completely abolished in MAVS-/- cells. NS4A represses RLR-, but not Toll-like receptor-mediated immune responses. NS4A specifically binds the N-terminal caspase activation and recruitment domain (CARD) of MAVS and thus blocks its accessibility by RLRs. Our study provides in-depth understanding of the molecular mechanisms of immune evasion by ZIKV and its pathogenesis.
Highlights
Zika virus (ZIKV) is a re-emerging Flaviviridae member that was first identified in a sentinel rhesus monkey in the Zika Forest of Uganda in 1947 (Dick et al, 1952)
We first asked if this signaling pathway was important for anti-ZIKV responses in human trophoblast, a cell type of the placental barrier that is physiologically relevant to ZIKV congenital transmission (Miner et al, 2016)
A previous study revealed that the cytoplasmic pattern recognition receptors (PRRs), melanoma differentiation-associated protein 5 (MDA5), and retinoic acid-inducible gene I (RIG-I), recognized a specific subset of RNA viruses (Kato et al, 2006)
Summary
Zika virus (ZIKV) is a re-emerging Flaviviridae member that was first identified in a sentinel rhesus monkey in the Zika Forest of Uganda in 1947 (Dick et al, 1952). ZIKV spread to Asia and more recently the Central and South America (Cao-Lormeau and Musso, 2014; Colon-Gonzalez et al, 2017; Fu et al, 2017; Perry et al, 2017). Increasing evidence suggests that ZIKV infection is responsible for severe neurological complications such as neonatal microcephaly, adult GuillainBarre syndrome, and maculopathy (Oehler et al, 2014; Cao-Lormeau et al, 2016; Miranda-Filho Dde et al, 2016; Petersen et al, 2016). The RLR family has 3 members, RIG-I, melanoma differentiation-associated gene 5 (MDA5), and Laboratory of Genetics and Physiology 2 (LGP2). Once bound by viral RNA, RIG-I/MDA5 will undergo conformational change and expose its N-terminal caspase-recruitment domains (CARD) which bind the CARD of mitochondrial antiviral-signaling
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