Live-attenuated virus vaccine defective in RNAi suppression induces rapid protection in neonatal and adult mice lacking mature B and T cells.
Live-attenuated virus vaccine defective in RNAi suppression induces rapid protection in neonatal and adult mice lacking mature B and T cells.
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DOI：
10.1073/pnas.2321170121
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发表时间：
2024-04
影响因子：
11.1
通讯作者：
Gang Chen;Qingxia Han;Wan-Xiang Li;Rong Hai;Shou-Wei Ding
中科院分区：
文献类型：
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作者：
Gang Chen;Qingxia Han;Wan-Xiang Li;Rong Hai;Shou-Wei Ding
传染病的全球控制取决于不断制定和部署各种疫苗接种战略。目前可用的减毒活疫苗和灭活病毒疫苗通常需要一周或更长时间才能激活适应性免疫的特异性保护。蚊子传播的野村病毒（NoV）在小鼠体内通过阻止B2病毒RNA干扰抑制因子（VSR）表达的突变而减弱，从而大大增强了病毒靶向小干扰RNA的体内生产。我们最近报道，用减毒的vsr失活的NoV （NoVΔB2）免疫2天后，新生小鼠完全免受致命的NoV攻击，并且没有发生可检测到的感染。我们以不产生成熟B淋巴细胞和T淋巴细胞的Rag1-/-小鼠为模型，检验了NoVΔB2免疫激活的基于rnai的保护性免疫是否需要适应性免疫的假设。研究表明，新生和成年Rag1-/-小鼠（活的但未死的NoVΔB2）免疫在刺激后2或14 d对NoV攻击具有充分的保护作用。此外，NoVΔB2-induced保护性抗病毒免疫是病毒特异性的，在Rag1-/-成年小鼠单次免疫42和90 d后仍然有效。我们得出的结论是，用减毒的vsr失活RNA病毒疫苗免疫，通过一种独立于B细胞和T细胞介导的适应性免疫的独特机制，激活针对致命挑战的快速和持久的保护性免疫。未来的研究需要确定VSR灭活后的其他动物和人类病毒是否会在健康和适应性免疫受损的个体中诱导类似的保护性免疫。
Global control of infectious diseases depends on the continuous development and deployment of diverse vaccination strategies. Currently available live-attenuated and killed virus vaccines typically take a week or longer to activate specific protection by the adaptive immunity. The mosquito-transmitted Nodamura virus (NoV) is attenuated in mice by mutations that prevent expression of the B2 viral suppressor of RNA interference (VSR) and consequently, drastically enhance in vivo production of the virus-targeting small-interfering RNAs. We reported recently that 2 d after immunization with live-attenuated VSR-disabled NoV (NoVΔB2), neonatal mice become fully protected against lethal NoV challenge and develop no detectable infection. Using Rag1-/- mice that produce no mature B and T lymphocytes as a model, here we examined the hypothesis that adaptive immunity is dispensable for the RNAi-based protective immunity activated by NoVΔB2 immunization. We show that immunization of both neonatal and adult Rag1-/- mice with live but not killed NoVΔB2 induces full protection against NoV challenge at 2 or 14 d postimmunization. Moreover, NoVΔB2-induced protective antiviral immunity is virus-specific and remains effective in adult Rag1-/- mice 42 and 90 d after a single-shot immunization. We conclude that immunization with the live-attenuated VSR-disabled RNA virus vaccine activates rapid and long-lasting protective immunity against lethal challenges by a distinct mechanism independent of the adaptive immunity mediated by B and T cells. Future studies are warranted to determine whether additional animal and human viruses attenuated by VSR inactivation induce similar protective immunity in healthy and adaptive immunity-compromised individuals.