Impact of Human STING Variants on Pneumococcal Vaccine Effectiveness

人类 STING 变体对肺炎球菌疫苗有效性的影响

• 批准号: 9165880
• 负责人: LEI JIN
• 金额: $ 22.5万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-10 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9165880
• 关键词: Adjuvant; Asians; B-Lymphocytes; Caucasians; Cells; Cyclic GMP; Data; Development; Dinucleoside Phosphates; Disease; Effectiveness; Equilibrium; Exhibits; FDA approved; Figs - dietary; Gene Expression; Gene Targeting; Genes; Genotype; Goals; Heterogeneity; Human; Immune response; Immunity; Individual; Infection; Interferons; Knock-in Mouse; Knowledge; Mediating; Mucosal Immunity; Mus; Pathway interactions; Pneumococcal Infections; Pneumococcal vaccine; Polysaccharides; Polyvalent pneumococcal vaccine; Prevnar; Production; Proteins; Reporting; Serotyping; Streptococcus pneumoniae; T-Lymphocyte; Testing; Vaccine Adjuvant; Vaccines; abstracting; aluminum sulfate; genetic variant; in vivo; interest; killings; mucosal vaccine; novel vaccines; pneumococcal surface protein A; pre-clinical; precision medicine; receptor; response; vaccination strategy; vaccine effectiveness

Abstract The goal of this proposal is to determine the effectiveness of pneumococcal vaccines influenced by the common human STING (stimulator of interferon genes) variant R71H-G230A-R293Q (HAQ). Pneumococcal diseases kill more people than all other vaccine-preventable diseases combined. Pneumovax® 23 and Prevnar 13® are polysaccharide vaccines providing serotype-specific protection. Since its approval in 1983, Pneumovax 23® results in only ~57% of overall disease reduction. Recently, Dr. Bruce Beutler’s group showed that polysaccharide Ag generates a cyclic dinucleotide (CDN) called 2’5’-3’5’-cyclic GMP-AMP (2’3’-cGAMP) in B cells leading to the activation of STING-Type I IFN pathway. STING is a receptor for CDN. STING-/- mice have decreased Ab production to Pneumovax® 23. Our own data showed that STING-/- mice also have decreased Ab production to Prevnar® 13. We previously identified a human STING variant HAQ that is common in non-Africans. ~3% of Caucasians and ~16% of East Asians are HAQ/HAQ. In fact, R232(wt)/HAQ, not the R232(wt)/R232(wt), is the most common STING genotype in East Asians. Examining B cells derived from human HAQ/HAQ individuals, we found that HAQ B cells have dramatically decreased STING expression. We hypothesize that Pneumovax ® 23 and Prevnar 13® vaccine effectiveness is influenced by HAQ STING variant. To test this hypothesis and uncover the in vivo mechanism, we generated the HAQ, AQ and Q293 STING knock-in mice. In Aim 1, we will determine (a) the impact of HAQ STING on the effectiveness of Pneumovax® 23 and Prevnar13® vaccines in vivo (Aim 1.1); (b) the in vivo mechanism by which HAQ STING influences Pneumovax® 23 and Prevnar13® effectiveness (Aim 1.2). Pneumovax® 23 and Prevnar 13® do not elicit strong mucosal immunity. A mucosal pneumococcal vaccine consists of a common protein Ag and a potent mucosal adjuvant can provide serotype-independent mucosal protection. Recently, a synthetic CDN, RpRp-c-di-AMPss, was reported to activate all human STING variants in HEK293T cells. Our preliminary data demonstrated that RpRp-c-di-AMPss has mucosal vaccine adjuvant activity eliciting strong Ab production and balanced Th1/Th2/Th17 response that depends on STING. In Aim 2, we will determine (a) the impact of HAQ STING on the mucosal adjuvant activity of RpRp-c-di-AMPss in vivo (Aim 2.1); (b) the in vivo mechanism by which HAQ STING influences RpRp-c-di-AMPss mucosal adjuvant activity (Aim 2.2). We will evaluate RpRp-c-di-AMPss adjuvanted pneumococcal surface protein A (PspA) vaccine induced humoral, cellular immune responses, and the protective immunity against S. pneumoniae infection in our knock-in mice. Achieving these Aims will pave the way for the development of STING-targeting precision medicine in humans.

抽象的 该提案的目标是确定受以下因素影响的肺炎球菌疫苗的有效性： 常见的人类 STING（干扰素基因刺激剂）变体 R71H-G230A-R293Q (HAQ)。肺炎球菌 疾病导致的死亡人数比所有其他疫苗可预防疾病的死亡人数总和还多。 Pneumovax® 23 和 Prevnar 13® 是多糖疫苗，提供血清型特异性保护。自1983年批准以来， Pneumovax 23® 只能使总体疾病减少约 57%。最近，Bruce Beutler 博士的团队展示了 多糖 Ag 会生成一种称为 2’5’-3’5’-环状 GMP-AMP (2’3’-cGAMP) 的环状二核苷酸 (CDN) B 细胞导致 STING-I 型 IFN 通路激活。 STING 是 CDN 的受体。 STING-/- 小鼠 Pneumovax® 23 的抗体产量减少。我们自己的数据表明，STING-/- 小鼠也有 Prevnar® 13 的抗体产量减少。我们之前发现了一种人类 STING 变体 HAQ，它是 在非非洲人中很常见。约 3% 的白种人和约 16% 的东亚人属于 HAQ/HAQ。事实上，R232(wt)/HAQ， 东亚人中最常见的 STING 基因型不是 R232(wt)/R232(wt)。检查 B 细胞来源 从人类 HAQ/HAQ 个体中，我们发现 HAQ B 细胞显着减少了 STING 表达。我们假设 Pneumovax ® 23 和 Prevnar 13® 疫苗的有效性受到以下因素的影响 HAQ STING 变种。为了检验这一假设并揭示体内机制，我们生成了 HAQ、AQ 和 Q293 STING 敲入小鼠。在目标 1 中，我们将确定 (a) HAQ STING 对有效性的影响 Pneumovax® 23 和 Prevnar13® 疫苗的体内效果（目标 1.1）； (b) HAQ 的体内机制 STING 影响 Pneumovax® 23 和 Prevnar13® 的有效性（目标 1.2）。 Pneumovax® 23 和 Prevnar 13® 不会引起强烈的粘膜免疫。粘膜肺炎球菌疫苗由常见的蛋白质 Ag 组成 有效的粘膜佐剂可以提供与血清型无关的粘膜保护。最近，合成了 据报道，CDN（RpRp-c-di-AMPss）可激活 HEK293T 细胞中的所有人类 STING 变体。我们的初步 数据表明 RpRp-c-di-AMPss 具有粘膜疫苗佐剂活性，可引发强烈的抗体产生 以及取决于 STING 的平衡 Th1/Th2/Th17 反应。在目标 2 中，我们将确定 (a) 的影响 HAQ STING 对 RpRp-c-di-AMPss 体内粘膜佐剂活性的影响（目标 2.1）； (b) 体内机制 HAQ STING 通过其影响 RpRp-c-di-AMPss 粘膜佐剂活性（目标 2.2）。我们将评估 RpRp-c-di-AMPss 佐剂肺炎球菌表面蛋白 A (PspA) 疫苗诱导体液、细胞 免疫反应，以及我们的敲入小鼠对肺炎链球菌感染的保护性免疫力。 实现这些目标将为人类 STING 靶向精准医学的发展铺平道路。