Enhancing protective immunity against RSV by inhibitors of sphingolipid synthesis

项目概要 呼吸道合胞病毒（RSV）感染是一个相当大的全球健康威胁，其发病率很高。 高危人群，尤其是幼儿的发病率和死亡率。尽管几十年来 经过不懈的努力，仍然没有安全有效的 RSV 疫苗。的发展 严重肺部疾病的风险阻碍了积极的免疫策略。严重 RSV 肺部疾病首先发生在接种福尔马林疫苗的幼儿身上。 感染 RSV 后接种灭活疫苗。研究严重 RSV 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 诱导强大的、偏向 Th1 的保护性免疫反应。我们假设抑制剂 丝氨酸棕榈酰辅酶 A 转移酶 (SPT) 是鞘脂合成的限速步骤， 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，这种新颖的佐剂策略的机制可能与 其他佐剂的促炎和 TLR 激活特性。本次活动的目的 探索性建议有两个方面：首先，确认 SPT 抑制剂的辅助作用 RSV 疫苗的品种或生物相关变量和目标，最重要的是 增强 Th1 免疫力并降低疫苗增强疾病风险的能力。第二， 阐明触发增强的适应性免疫的先天免疫机制 回应。鉴于该项目的早期阶段，我们将主要关注肺树突状细胞和 肺粘膜变化引起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特征提供信息 其他可能受影响的细胞，例如滤泡辅助 T 细胞和调节细胞，以及进一步 开发 SPT 抑制剂作为其他呼吸道疾病疫苗的潜在佐剂 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.