Russell Ryan F, McDonald Jacqueline U, Ivanova Maria, Zhong Ziyun, Bukreyev Alexander, Tregoning John S
Mucosal Infection and Immunity Group, Section of Virology, Department of Medicine, St. Mary's Campus, Imperial College London, London, United Kingdom.
Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
J Virol. 2015 Sep;89(17):8974-81. doi: 10.1128/JVI.01070-15. Epub 2015 Jun 17.
The small hydrophobic (SH) gene of respiratory syncytial virus (RSV), a major cause of infant hospitalization, encodes a viroporin of unknown function. SH gene knockout virus (RSV ΔSH) is partially attenuated in vivo, but not in vitro, suggesting that the SH protein may have an immunomodulatory role. RSV ΔSH has been tested as a live attenuated vaccine in humans and cattle, and here we demonstrate that it protected against viral rechallenge in mice. We compared the immune response to infection with RSV wild type and RSV ΔSH in vivo using BALB/c mice and in vitro using epithelial cells, neutrophils, and macrophages. Strikingly, the interleukin-1β (IL-1β) response to RSV ΔSH infection was greater than to wild-type RSV, in spite of a decreased viral load, and when IL-1β was blocked in vivo, the viral load returned to wild-type levels. A significantly greater IL-1β response to RSV ΔSH was also detected in vitro, with higher-magnitude responses in neutrophils and macrophages than in epithelial cells. Depleting macrophages (with clodronate liposome) and neutrophils (with anti-Ly6G/1A8) demonstrated the contribution of these cells to the IL-1β response in vivo, the first demonstration of neutrophilic IL-1β production in response to viral lung infection. In this study, we describe an increased IL-1β response to RSV ΔSH, which may explain the attenuation in vivo and supports targeting the SH gene in live attenuated vaccines.
There is a pressing need for a vaccine for respiratory syncytial virus (RSV). A number of live attenuated RSV vaccine strains have been developed in which the small hydrophobic (SH) gene has been deleted, even though the function of the SH protein is unknown. The structure of the SH protein has recently been solved, showing it is a pore-forming protein (viroporin). Here, we demonstrate that the IL-1β response to RSV ΔSH is greater in spite of a lower viral load, which contributes to the attenuation in vivo. This potentially suggests a novel method by which viruses can evade the host response. As all Pneumovirinae and some Paramyxovirinae carry similar SH genes, this new understanding may also enable the development of live attenuated vaccines for both RSV and other members of the Paramyxoviridae.
呼吸道合胞病毒（RSV）的小疏水（SH）基因是婴儿住院的主要原因，编码一种功能未知的病毒孔蛋白。SH基因敲除病毒（RSV ΔSH）在体内部分减毒，但在体外不减毒，这表明SH蛋白可能具有免疫调节作用。RSV ΔSH已在人类和牛中作为减毒活疫苗进行了测试，在此我们证明它能保护小鼠免受病毒再次攻击。我们比较了BALB/c小鼠体内和上皮细胞、中性粒细胞及巨噬细胞体外对野生型RSV和RSV ΔSH感染的免疫反应。令人惊讶的是，尽管病毒载量降低，但对RSV ΔSH感染的白细胞介素-1β（IL-1β）反应大于对野生型RSV的反应，并且当在体内阻断IL-1β时，病毒载量恢复到野生型水平。在体外也检测到对RSV ΔSH的IL-1β反应明显更强，中性粒细胞和巨噬细胞中的反应幅度高于上皮细胞。用氯膦酸脂质体清除巨噬细胞和用抗Ly6G/1A8清除中性粒细胞证明了这些细胞对体内IL-1β反应的贡献，这是首次证明中性粒细胞在病毒肺部感染时产生IL-1β。在本研究中，我们描述了对RSV ΔSH的IL-1β反应增强，这可能解释了其在体内的减毒作用，并支持在减毒活疫苗中靶向SH基因。
迫切需要一种呼吸道合胞病毒（RSV）疫苗。已经开发了许多删除了小疏水（SH）基因的减毒活RSV疫苗株，尽管SH蛋白的功能尚不清楚。SH蛋白的结构最近已被解析，显示它是一种成孔蛋白（病毒孔蛋白）。在此，我们证明尽管病毒载量较低，但对RSV ΔSH的IL-1β反应更强，这有助于其在体内的减毒。这可能暗示了病毒逃避宿主反应的一种新方法。由于所有肺病毒亚科和一些副粘病毒亚科都携带相似的SH基因，这一新认识也可能有助于开发针对RSV和副粘病毒科其他成员的减毒活疫苗。
