Enhancing protective immunity against RSV by inhibitors of sphingolipid synthesis

项目总结 呼吸道合胞病毒(RSV)感染是一个相当大的全球健康威胁，具有很高的 高危人群，特别是幼儿的发病率和死亡率。尽管几十年来 尽管进行了激烈的努力，但目前还没有安全有效的RSV疫苗。的发展。 由于存在严重肺部疾病的风险，积极的免疫战略受到了阻碍。严重者 呼吸道合胞病毒肺病最早发生在接种了福尔马林疫苗的小孩子身上。 感染RSV后的灭活疫苗。研究严重呼吸道合胞病毒的经验教训 疾病和对RSV抗原的反应表明，需要一种成功的疫苗来诱导 强大的Th1偏向免疫反应和强大的中和抗体。我们发现 RSV同时抑制鞘磷脂从头合成和粘膜给药 诱导强大的、偏向Th1的和保护性的免疫反应。我们假设抑制物 丝氨酸棕榈酰辅酶A转移酶(SPT)是鞘磷脂合成的限速步骤，可以 作为有效的佐剂来增强和有利地塑造RSV的免疫原性 疫苗。此外，这种新的佐剂策略的机制可能与 其他佐剂的促炎和激活TLR的特性。这样做的目的是 探索性建议有两个方面：第一，确认SPT-抑制剂对 RSV疫苗的品种或生物相关变量和靶点，最重要的是 增强Th1免疫和降低疫苗增强型疾病风险的能力。第二, 阐明触发获得性免疫增强的先天免疫机制 回应。鉴于这个项目的早期阶段，我们将主要关注肺树突状细胞和 肺粘膜改变可能引起的免疫细胞转运的改变 鞘脂合成。这些结果可以为更详细的免疫特性提供信息 其他可能受影响的细胞，如T滤泡辅助细胞和调节细胞，以及进一步 SPT抑制剂作为其他呼吸道疫苗潜在佐剂的研究进展 病原体。

PROJECT SUMMARY Infections with respiratory syncytial virus (RSV) are a considerable global health threat with high morbidity and mortality in populations at risk, especially young children. Despite decades of intense efforts, a safe and effective vaccine against RSV is not available. The development of an active immunization strategy has been hampered by the risk for severe lung disease. Severe RSV lung disease first occurred in small children who had been vaccinated with a formalin- inactivated vaccine upon infection with RSV. Lessons learned from studying severe RSV disease, and responses to RSV antigens point to the need for a successful vaccine to induce robust Th1-biased immune response and potent neutralizing antibodies. We found that simultaneous inhibition of sphingolipid de novo synthesis and mucosal administration RSV induces a robust, Th1 biased and protective immune responses. We hypothesize that inhibitors of serine-palmitoyl CoA transferase (SPT), the rate-limiting step of sphingolipid synthesis, can function as potent adjuvants to enhance and favorably shape the immunogenicity of an RSV vaccine. Further, the mechanism of this novel adjuvant strategy might differ substantially from the pro-inflammatory and TLR-activating properties of other adjuvants. The aims of this exploratory proposal are two-fold: First, to confirm the adjuvant effect of SPT-inhibitors for a variety or biological relevant variables and targets for a RSV vaccine, most importantly the capacity to enhance Th1 immunity and to lower the risk for vaccine-enhanced disease. Second, to elucidate the innate immune mechanisms that trigger the increased adaptive immune responses. Given the early stage of this project, we will focus mostly on lung dendritic cells and potential alterations in immune cell trafficking induced by changes in pulmonary mucosal sphingolipid synthesis. These results could then inform further detailed immune characterization of other potentially affected cells, such as T follicular helper and regulatory cells and further development of SPT-inhibitors as potential adjuvants for vaccines against other respiratory pathogens.