Enhancing protective immunity against RSV by inhibitors of sphingolipid synthesis

项目摘要 呼吸道合胞病毒（RSV）感染是一个相当大的全球健康威胁， 高危人群，特别是幼儿的发病率和死亡率。尽管经过数十年的 尽管付出了巨大的努力，但仍然没有一种安全有效的抗RSV疫苗。的发展 积极的免疫战略受到严重肺病风险的阻碍。严重 RSV肺病首先发生在接种过福尔马林疫苗的儿童身上， 在感染RSV后灭活疫苗。研究严重RSV的经验教训 疾病，以及对RSV抗原的应答表明需要成功的疫苗来诱导 强大的Th 1偏向免疫反应和有效的中和抗体。我们发现 同时抑制鞘脂从头合成和粘膜给药RSV 诱导稳健的、偏向Th 1的和保护性的免疫应答。我们假设抑制剂 丝氨酸-棕榈酰CoA转移酶（SPT）是鞘脂合成的限速步骤， 作为有效的佐剂以增强和有利地塑造RSV的免疫原性 疫苗此外，这种新的佐剂策略的机制可能与传统的佐剂策略有很大不同。 其他佐剂的促炎和TLR激活特性。其目的是 探索性的建议是两方面的：首先，确认SPT抑制剂的辅助作用， RSV疫苗的种类或生物学相关变量和靶标，最重要的是 增强Th 1免疫力和降低疫苗增强疾病风险的能力。第二、 阐明先天免疫机制，触发增加适应性免疫， 应答鉴于该项目的早期阶段，我们将主要关注肺树突状细胞， 肺粘膜变化诱导的免疫细胞运输的潜在变化 鞘脂合成这些结果可以为进一步详细的免疫表征提供信息 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抑制剂作为抗其他呼吸道疾病疫苗的潜在佐剂的开发 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.