Identification and characterization of gut microbial bioactive molecules that determine predisposition to autoimmune disease and atopy

确定自身免疫性疾病和特应性倾向的肠道微生物生物活性分子的鉴定和表征

• 批准号: 10239455
• 负责人: Jon Clardy
• 金额: $ 25.35万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10239455
• 关键词: 2019-nCoV; Adaptor Signaling Protein; Address; Adjuvant; Agonist; Antibodies; Antigens; Attention; Autoimmune Diseases; Award; Bacteria; Bone Marrow; COVID-19; COVID-19 pandemic; COVID-19 vaccine; Cells; Characteristics; Chemicals; Coculture Techniques; Column Chromatography; Consensus; Coupled; Dendritic Cells; Dendritic cell activation; Dependence; Development; Disease; Dose; Effectiveness; Ensure; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Generations; Heterodimerization; High Pressure Liquid Chromatography; Human; Immune; Immune response; Immune signaling; Immunization; Immunologist; Immunology; Immunology procedure; Immunomodulators; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Interleukin-6; Learning; Libraries; Lipids; Methods; Molecular; Morbidity - disease rate; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Magnetic Resonance; Outcome; Parents; Pathway interactions; Performance; Peripheral Blood Mononuclear Cell; Physiological; Predisposition; Property; Proteins; Protocols documentation; Public Health; SARS-CoV-2 infection; Safety; Signal Pathway; Signal Transduction; Structure; Sum; Surface; T-Lymphocyte; TIRAP gene; TLR1 gene; TLR2 gene; TLR6 gene; TNF gene; Testing; Therapeutic; Time; Treatment Efficacy; Vaccines; Virion; Virus; Work; atopy; base; cancer immunotherapy; cytokine; expectation; experience; experimental study; gut microbiome; gut microbiota; immunogenicity; liquid chromatography mass spectrometry; member; microbial; mortality; novel; polarized cell; programmed cell death protein 1; programs; response; small molecule; success; therapeutically effective; vaccine candidate

Project Summary/Abstract SARS-CoV-2 infections are exacting a horrific burden of morbidity and mortality around the world. While we have much to learn about the virus and COVID-19, the disease it causes, the most likely way to control and possibly eliminate COVID-19 is a vaccine for SARS-CoV-2. Typically successful vaccines need adjuvants to increase the immunogenicity of their response. A strong response will be especially important for COVID-19 as the virus particle has multiple spikes (S- proteins) that are the target of the majority of vaccines under development. This project would leverage ongoing efforts to discover novel small molecule immunomodulators produced by members of the human gut microbiota to discover and develop adjuvants. The small molecule immunomodulators discovered in this project appear to have excellent prospects as adjuvants as they both boost and resolve immune responses. The two Specific Aims, which can be prosecuted simultaneously, deal with further molecular and mechanistic analysis of a promising set of lipids produced by Akkermansia muciniphila, a recently recognized member of the human gut microbiota whose abundance is highly correlated with outcomes in both type 2 diabetes (T2D), and PD-1 cancer immunotherapy. Work in Specific Aim 1 will identify the structure-activity relations for the lipids where activity is release of inflammatory cytokines like TNFα and IL-6. The lipids signal through TLR2, and we would establish whether heterodimerization with TLR-1 or TLR-6 is required for activity and the need for adaptor proteins like MAL/TIRAP and MyD88. We will also assess the downstream T cell polarization following mBMDC activation. In Specific Aim 2 we will replicate the studies that led to the initial identification of the A. mucinophila lipids on other members of the human gut microbiota, especially those that correlate or anti-correlate strongly with inflammatory diseases. In sum, the project will characterize the immune signaling pathways triggered by bacterial TLR2 agonists to identify adjuvant candidates that may increase the therapeutic efficacy of soon to be developed COVID-19 vaccines.

项目概要/摘要 SARS-CoV-2 感染给世界各地带来了可怕的发病率和死亡率负担。 虽然我们对病毒和 COVID-19 有很多了解，但它引起的疾病最有可能是 控制并可能消除 COVID-19 的方法是 SARS-CoV-2 疫苗。 成功的疫苗需要佐剂来增强其反应的免疫原性。 响应对于 COVID-19 尤为重要，因为病毒颗粒具有多个尖峰（S- 蛋白质）是大多数正在开发的疫苗的目标。 利用持续的努力来发现新型小分子免疫调节剂 人类肠道微生物群的成员发现和开发小分子佐剂。 该项目中发现的免疫调节剂作为佐剂似乎具有良好的前景，例如 它们都可以增强和解决免疫反应，这两个目标都是可以利用的。 同时，对一组有前途的脂质进行进一步的分子和机制分析 由最近公认的人类肠道成员 Akkermansia muciniphila 产生 微生物群的丰度与 2 型糖尿病 (T2D) 的结果高度相关， 特定目标 1 中的工作将确定结构-活性。 脂质的关系，其中活性是炎症细胞因子（如 TNFα 和 IL-6）的释放。 通过 TLR2 发出脂质信号，我们将确定是否与 TLR-1 或 TLR-6 是活性所必需的，并且需要 MAL/TIRAP 和 MyD88 等接头蛋白。 还将评估 mBMDC 激活后的下游 T 细胞极化。 2 我们将复制导致初步鉴定 A. mucinophila 脂质的研究 人类肠道微生物群的其他成员，尤其是那些相关或反相关的成员 总之，该项目将表征免疫信号传导。 由细菌 TLR2 激动剂触发途径，以确定可能增加的候选佐剂 即将开发的 COVID-19 疫苗的治疗效果。

项目成果

A Cardiolipin from Muribaculum intestinale Induces Antigen-Specific Cytokine Responses.

来自肠道粘膜的心磷脂诱导抗原特异性细胞因子反应。

• 发表时间: 2023-11-01
• 影响因子: 15
• 作者: Bang, Sunghee;Shin, Yern;Ma, Xiao;Park, Sung;Graham, Daniel B;Xavier, Ramnik J;Clardy, Jon
• 通讯作者: Clardy, Jon

Revisiting Coley's Toxins: Immunogenic Cardiolipins from Streptococcus pyogenes.

重新审视科利毒素：来自化脓性链球菌的免疫原性心磷脂。

• 发表时间: 2023-10-04
• 影响因子: 15
• 作者: Shin, Yern-Hyerk;Bang, Sunghee;Park, Sung-Moo;Ma, Xiao;Cassilly, Chelsi;Graham, Daniel;Xavier, Ramnik;Clardy, Jon
• 通讯作者: Clardy, Jon

Discovery of (Dihydro)pyrazine N-Oxides via Genome Mining in Pseudomonas.

通过假单胞菌基因组挖掘发现（二氢）吡嗪氮氧化物。

• DOI: 10.1021/acs.orglett.8b01944
• 发表时间: 2018-08-17
• 期刊: Organic letters
• 影响因子: 5.2
• 作者: Kretsch AM;Morgan GL;Tyrrell J;Mevers E;Vallet-Gély I;Li B
• 通讯作者: Li B

Molecular messages in human microbiota.

人类微生物群中的分子信息。

• 发表时间: 2019
• 作者: Henke, Matthew T;Clardy, Jon
• 通讯作者: Clardy, Jon

Collinsella aerofaciens Produces a pH-Responsive Lipid Immunogen.

Collinsella aerofaciens 产生 pH 响应性脂质免疫原。

• 发表时间: 2023-04-05
• 影响因子: 15
• 作者: Kwon, Jaeyoung;Bae, Munhyung;Szamosvári, Dávid;Cassilly, Chelsi D;Bolze, Andrew S;Jackson, David R;Xavier, Ramnik J;Clardy, Jon
• 通讯作者: Clardy, Jon