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An evolutionary NS1 mutation enhances Zika virus evasion of host interferon induction.

ABSTRACT: Virus-host interactions determine an infection outcome. The Asian lineage of Zika virus (ZIKV), responsible for the recent epidemics, has fixed a mutation in the NS1 gene after 2012 that enhances mosquito infection. Here we report that the same mutation confers NS1 to inhibit interferon-? induction. This mutation enables NS1 binding to TBK1 and reduces TBK1 phosphorylation. Engineering the mutation into a pre-epidemic ZIKV strain debilitates the virus for interferon-? induction; reversing the mutation in an epidemic ZIKV strain invigorates the virus for interferon-? induction; these mutational effects are lost in IRF3-knockout cells. Additionally, ZIKV NS2A, NS2B, NS4A, NS4B, and NS5 can also suppress interferon-? production through targeting distinct components of the RIG-I pathway; however, for these proteins, no antagonistic difference is observed among various ZIKV strains. Our results support the mechanism that ZIKV has accumulated mutation(s) that increases the ability to evade immune response and potentiates infection and epidemics.

SUBMITTER: Xia H

PROVIDER: S-EPMC5788864 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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An evolutionary NS1 mutation enhances Zika virus evasion of host interferon induction.

Xia Hongjie H Luo Huanle H Shan Chao C Muruato Antonio E AE Nunes Bruno T D BTD Medeiros Daniele B A DBA Zou Jing J Xie Xuping X Giraldo Maria Isabel MI Vasconcelos Pedro F C PFC Weaver Scott C SC Wang Tian T Rajsbaum Ricardo R Shi Pei-Yong PY

Nature communications 20180129 1

Virus-host interactions determine an infection outcome. The Asian lineage of Zika virus (ZIKV), responsible for the recent epidemics, has fixed a mutation in the NS1 gene after 2012 that enhances mosquito infection. Here we report that the same mutation confers NS1 to inhibit interferon-β induction. This mutation enables NS1 binding to TBK1 and reduces TBK1 phosphorylation. Engineering the mutation into a pre-epidemic ZIKV strain debilitates the virus for interferon-β induction; reversing the mu ...[more]

PMID: 29379028

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Project description:Zika virus (ZIKV) infection continues to pose a significant public health concern due to limited available preventive measures and treatments. ZIKV is unique among flaviviruses in its vertical transmission capacity (i.e., transmission from mother to fetus) yet the underlying mechanisms remain incompletely understood. Here, we show that both African and Asian lineages of ZIKV induce tunneling nanotubes (TNTs) in placental trophoblasts and multiple other mammalian cell types. Amongst investigated flaviviruses, only ZIKV strains trigger TNTs. We show that ZIKV-induced TNTs facilitate transfer of viral particles, proteins, and RNA to neighboring uninfected cells. ZIKV TNT formation is driven exclusively via its non-structural protein 1 (NS1); specifically, the N-terminal region (50 aa) of membrane-bound NS1 is necessary and sufficient for triggering TNT formation in host cells. Using affinity purification-mass spectrometry of cells infected with wild-type NS1 or non-TNT forming NS1 (pNS1ΔTNT) proteins, we found mitochondrial proteins are dominant NS1-interacting partners, consistent with the elevated mitochondrial mass we observed in infected trophoblasts. We demonstrate that mitochondria are siphoned via TNTs from healthy to ZIKV-infected cells, both homotypically and heterotypically, and inhibition of mitochondrial respiration reduced viral replication in trophoblast cells. Finally, ZIKV strains lacking TNT capabilities due to mutant NS1 elicited a robust antiviral IFN-λ 1/2/3 response, indicating ZIKV's TNT-mediated trafficking also allows ZIKV cell-cell transmission that is camouflaged from host defenses. Together, our findings identify a new stealth mechanism that ZIKV employs for intercellular spread among placental trophoblasts, evasion of antiviral interferon response, and the hijacking of mitochondria to augment its propagation and survival. Discerning the mechanisms of ZIKV intercellular strategies offers a basis for novel therapeutic developments targeting these interactions to limit its dissemination.

Dataset Information

An evolutionary NS1 mutation enhances Zika virus evasion of host interferon induction.

Publications

An evolutionary NS1 mutation enhances Zika virus evasion of host interferon induction.

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