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.

摘要 该提案的目的是确定肺炎球菌疫苗的有效性， 常见的人STING（干扰素基因刺激因子）变体R71 H-G230 A-R293 Q（HAQ）。肺炎球菌 这些疾病造成的死亡人数超过了所有其他疫苗可预防疾病的总和。Pneumovax® 23和Prevnar 13®是多糖疫苗，可提供针对特定类型的保护。自1983年批准以来， Pneumovax 23®仅能减少约57%的总体疾病。最近，布鲁斯·伯特勒博士的研究小组发现， 该多糖Ag产生称为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途径的激活。STING是CDN的受体。STING-/-小鼠 减少了Pneumovax® 23的抗体产生。我们自己的数据显示，STING-/-小鼠也有 将Ab产量降低至Prevnar® 13。我们先前鉴定了一种人类STING变体HAQ， 在非洲以外的地方很常见。约3%的白人和约16%的东亚人是HAQ/HAQ。事实上，R232（wt）/HAQ， 而不是R232（wt）/R232（wt），是东亚人中最常见的STING基因型。检查B细胞来源 从人类HAQ/HAQ个体中，我们发现HAQ B细胞具有显著降低的STING， 表情我们假设Pneumovax ® 23和Prevnar 13®疫苗的有效性受到以下因素的影响： HAQ STING变体。为了测试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Prevnar 13 ®疫苗的体内作用（目的1.1）;（B）HAQ STING影响Pneumovax® 23和Prevnar 13 ®的有效性（目标1.2）。Pneumovax® 23和Prevnar 13®不引起强粘膜免疫。粘膜肺炎球菌疫苗由一种常见的蛋白质Ag 并且有效的粘膜佐剂可以提供非依赖于粘膜类型的粘膜保护。最近，一种合成的 据报道，CDN RpRp-c-di-AMPss激活HEK 293 T细胞中的所有人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，引起强Ab产生 以及依赖于STING的平衡的Th 1/Th 2/Th 17应答。在目标2中，我们将确定（a） HAQ STING对RpRp-c-di-AMPss的体内粘膜佐剂活性的影响（目的2.1）;（B）体内机制 HAQSTING通过其影响RpRp-c-di-AMPss粘膜佐剂活性（目的2.2）。我们将评估 RpRp-c-di-AMPss佐剂肺炎球菌表面蛋白A（PspA）疫苗诱导的体液、细胞免疫应答 免疫应答，以及对S. pneumoniae肺炎infection感染in our knockin敲入mice小鼠. 实现这些目标将为人类靶向STING精准医学的发展铺平道路。