An attenuated Zika virus NS4B protein mutant is a potent inducer of antiviral immune responses.,npj Vaccines

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An attenuated Zika virus NS4B protein mutant is a potent inducer of antiviral immune responses.
npj Vaccines ( IF 6.9 ) Pub Date : 2019-11-28 , DOI: 10.1038/s41541-019-0143-3
Guangyu Li ₁ , Awadalkareem Adam ₁ , Huanle Luo ₁ , Chao Shan ₂ , Zengguo Cao ₂ , Camila R Fontes-Garfias ₂ , Vanessa V Sarathy _{3,

4} , Cody Teleki ₁ , Evandro R Winkelmann ₁ , Yuejin Liang ₁ , Jiaren Sun ₁ , Nigel Bourne _{1,

4,

5} , Alan D T Barrett _{1,

3,

4} , Pei-Yong Shi _{2,

4,

6} , Tian Wang _{1,

3,

4}

Affiliation

Live attenuated vaccines (LAVs) are one of the most important strategies to control flavivirus diseases. The flavivirus nonstructural (NS) 4B proteins are a critical component of both the virus replication complex and evasion of host innate immunity. Here we have used site-directed mutagenesis of residues in the highly conserved N-terminal and central hydrophobic regions of Zika virus (ZIKV) NS4B protein to identify candidate attenuating mutations. Three single-site mutants were generated, of which the NS4B-C100S mutant was more attenuated than the other two mutants (NS4B-C100A and NS4B-P36A) in two immunocompromised mouse models of fatal ZIKV disease. The ZIKV NS4B-C100S mutant triggered stronger type 1 interferons and interleukin-6 production, and higher ZIKV-specific CD4+ and CD8+ T-cell responses, but induced similar titers of neutralization antibodies compared with the parent wild-type ZIKV strain and a previously reported candidate ZIKV LAV with a 10-nucleotide deletion in 3'-UTR (ZIKV-3'UTR-Δ10). Vaccination with ZIKV NS4B-C100S protected mice from subsequent WT ZIKV challenge. Furthermore, either passive immunization with ZIKV NS4B-C100S immune sera or active immunization with ZIKV NS4B-C100S followed by the depletion of T cells affords full protection from lethal WT ZIKV challenge. In summary, our results suggest that the ZIKV NS4B-C100S mutant may serve as a candidate ZIKV LAV due to its attenuated phenotype and high immunogenicity.

中文翻译：

减毒寨卡病毒 NS4B 蛋白突变体是抗病毒免疫反应的有效诱导剂。

减毒活疫苗（LAV）是控制黄病毒病最重要的策略之一。黄病毒非结构 (NS) 4B 蛋白是病毒复制复合体和逃避宿主先天免疫的关键组成部分。在这里，我们使用寨卡病毒 (ZIKV) NS4B 蛋白高度保守的 N 端和中央疏水区残基的定点诱变来鉴定候选减毒突变。产生了三种单位点突变体，其中 NS4B-C100S 突变体在两种致死性 ZIKV 疾病的免疫功能低下小鼠模型中比其他两种突变体（NS4B-C100A 和 NS4B-P36A）的减毒作用更强。 ZIKV NS4B-C100S 突变体触发了更强的 1 型干扰素和白细胞介素 6 产生，以及更高的 ZIKV 特异性 CD4+ 和 CD8+ T 细胞反应，但与亲本野生型 ZIKV 毒株和之前报道的相比，诱导了相似滴度的中和抗体3'-UTR 中具有 10 个核苷酸缺失的候选 ZIKV LAV (ZIKV-3'UTR-Δ10)。接种 ZIKV NS4B-C100S 疫苗可以保护小鼠免受随后的 WT ZIKV 攻击。此外，无论是使用 ZIKV NS4B-C100S 免疫血清进行被动免疫，还是使用 ZIKV NS4B-C100S 进行主动免疫，然后消耗 T 细胞，都能提供针对致命 WT ZIKV 攻击的全面保护。总之，我们的结果表明，ZIKV NS4B-C100S 突变体由于其减毒表型和高免疫原性，可以作为候选 ZIKV LAV。

更新日期：2019-11-28

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