Mechanisms of STING-Mediated Mucosal Vaccine Adjuvant Activity of Cyclic di-GMP

STING 介导的环二 GMP 粘膜疫苗佐剂活性机制

• 批准号: 9185213
• 负责人: LEI JIN
• 金额: $ 29.86万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9185213
• 关键词: Adjuvant; Adopted; Advanced Development; Antibody Formation; Antigens; Attenuated; CD8B1 gene; Cells; Data; Dendritic Cells; Development; Effector Cell; Exhibits; Future; Gene Expression; Genes; Goals; Human; ITGAM gene; IgG1; Immune response; Immunity; Immunization; Immunoglobulin A; Infection; Infectious Agent; Inflammatory; Influenza A Virus, H5N1 Subtype; Interferons; Knowledge; Lead; Lung; Lymphoid Tissue; Mediating; Modeling; Mucosal Immune Responses; Mucosal Immunity; Mus; Nose; Periodicity; Play; Production; Proteins; Publishing; Research; Role; Route; Safety; Signal Transduction; Streptococcus pneumoniae; Surface; T cell response; TNF gene; TNFRSF1A gene; TNFRSF1B gene; Vaccine Adjuvant; Vaccines; base; cytokine; immunogenic; immunogenicity; improved; in vivo; macrophage; migration; mucosal vaccination; mucosal vaccine; pathogen; pneumococcal surface protein A; public health relevance; receptor; response; vaccine development

DESCRIPTION (provided by applicant): The goal of this proposal is to uncover the in vivo mechanisms by which STING (Stimulator of interferon genes) mediates the mucosal vaccine adjuvant activity of cyclic di-GMP (CDG). Protective mucosal immune responses are most effectively induced by mucosal immunization. However, most of the currently approved human vaccines are administered systemically and generally fail to elicit effective mucosal immunity. Live attenuated mucosal vaccines present safety and acceptability issues while purified antigens are generally poor immunogenic when administered by the mucosal route. CDG exhibits potent mucosal immunogenicity thus, has been explored as a promising mucosal vaccine adjuvant. The mechanism by which CDG executes its mucosal adjuvant activity is unknown, which hinders the further development of CDG as an efficacious mucosal adjuvant. STING, also known as MPYS/MITA, is a receptor for CDG. We recently showed that STING-/- mice fail to generate Ag-specific antibody production or TH1-TH2-TH17 T cell response after intranasal CDG/Ag immunization. We further discovered that STING-dependent TNF-a is essential for CDG adjuvant activity in vivo. Intranasal co-administration of CDG/Ag induces immune response in lung and nasal-associated lymphoid tissue (NALT). Here, we will use TNFR1-/-TNFR2-/- and conditional STING-/- mice to dissect the in vivo mechanism of CDG/STING-induced adjuvant activity in lung and NALT. We will adopt both the model Ag OVA and pneumococcal surface protein A (PspA) Ag for our study. Dendritic cells (DC) play a central role in adjuvant activity. We hypothesize that CDG induces STING-dependent inflammatory signals that activate DC directly or indirectly to execute the adjuvant activity of CDG. Two specific Aims are proposed to carry out this objective. Aim 1. Determine how STING regulates CDG-induced adjuvant activity in DC. Aim 2. Determine how TNF-a regulates CDG-induced adjuvant activity. Currently, there is no vaccine formulation containing a mucosal adjuvant approved for human use. The knowledge generated by our studies can help advance the development of CDG as an efficacious mucosal vaccine adjuvant for human use.

描述（由申请人提供）：本提案的目的是揭示STING（干扰素基因刺激剂）介导环二-GMP（CDG）粘膜疫苗佐剂活性的体内机制。粘膜免疫最有效地诱导保护性粘膜免疫反应。然而，目前批准的大多数人类疫苗都是全身给药，通常无法引发有效的粘膜免疫。减毒活粘膜疫苗存在安全性和可接受性问题，而纯化的抗原在通过粘膜途径施用时通常免疫原性较差。 CDG 表现出强大的粘膜免疫原性，因此已被探索作为一种有前途的粘膜疫苗佐剂。 CDG执行其粘膜佐剂活性的机制尚不清楚，这阻碍了CDG作为有效粘膜佐剂的进一步发展。 STING，也称为 MPYS/MITA，是 CDG 的受体。我们最近表明，STING-/- 小鼠在鼻内 CDG/Ag 免疫后无法产生 Ag 特异性抗体或 TH1-TH2-TH17 T 细胞反应。我们进一步发现 STING 依赖性 TNF-a 对于体内 CDG 佐剂活性至关重要。 CDG/Ag 鼻内联合给药可诱导肺和鼻相关淋巴组织 (NALT) 的免疫反应。在这里，我们将使用 TNFR1-/-TNFR2-/- 和条件 STING-/- 小鼠来剖析 CDG/STING 诱导肺和 NALT 佐剂活性的体内机制。我们将采用 Ag OVA 模型和肺炎球菌表面蛋白 A (PspA) Ag 进行研究。树突状细胞（DC）在佐剂活性中发挥核心作用。我们假设 CDG 诱导 STING 依赖性炎症信号，直接或间接激活 DC 以执行 CDG 的佐剂活性。为了实现这一目标，提出了两个具体目标。目标 1. 确定 STING 如何调节 DC 中 CDG 诱导的佐剂活性。目标 2. 确定 TNF-a 如何调节 CDG 诱导的佐剂活性。目前，还没有批准用于人类使用的含有粘膜佐剂的疫苗制剂。我们的研究产生的知识可以帮助推动 CDG 作为人类使用的有效粘膜疫苗佐剂的发展。