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.

项目总结/摘要 SARS-CoV-2感染在全世界造成了可怕的发病率和死亡率负担。 虽然我们有很多关于病毒和COVID-19的知识，但它引起的疾病，最有可能是 控制和可能消除COVID-19的方法是SARS-CoV-2疫苗。通常 成功的疫苗需要佐剂来增加其应答的免疫原性。一个强大 对于COVID-19而言，反应将特别重要，因为病毒颗粒具有多个尖峰（S- 蛋白质），这是大多数正在开发的疫苗的目标。这个项目将 利用正在进行的努力，发现新的小分子免疫调节剂， 人类肠道微生物群成员发现和开发佐剂。所述小分子 在该项目中发现的免疫调节剂似乎具有作为佐剂的极好前景， 它们都能增强和消除免疫反应。可以起诉的两个具体目的 同时，对一组有希望脂质进行进一步的分子和机理分析 由嗜粘蛋白阿克曼氏菌（Akkermansia muciniphila）产生， 微生物群，其丰度与2型糖尿病（T2 D）的结果高度相关， 和PD-1癌症免疫疗法。具体目标1中的工作将确定结构-活性 与脂质的关系，其中活性是释放炎性细胞因子如TNFα和IL-6。的 脂质信号通过TLR 2，我们将建立是否与TLR-1或 TLR-6是活性所必需的，并且需要衔接蛋白如MAL/TIRAP和MyD 88。我们 还将评估mBMDC活化后的下游T细胞极化。具体目标 我们将重复导致A.嗜粘蛋白脂质体 人类肠道微生物群的其他成员，特别是那些与人类肠道微生物群相关或反相关的成员， 与炎症性疾病密切相关。总之，该项目将表征免疫信号传导 细菌TLR 2激动剂触发的途径，以识别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

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

重新审视COLEY的毒素：化脓性链球菌的免疫原生脂蛋白。

• DOI: 10.1021/jacs.3c07727
• 发表时间: 2023-10-04
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 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

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

• DOI: 10.1021/jacs.3c09734
• 发表时间: 2023-11-01
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Bang, Sunghee;Shin, Yern-Hyerk;Ma, Xiao;Park, Sung-Moo;Graham, Daniel B.;Xavier, Ramnik J.;Clardy, Jon
• 通讯作者: Clardy, Jon

Plasmalogen Biosynthesis by Anaerobic Bacteria: Identification of a Two-Gene Operon Responsible for Plasmalogen Production in Clostridium perfringens.

• DOI: 10.1021/acschembio.0c00673
• 发表时间: 2021-01-15
• 期刊: ACS chemical biology
• 影响因子: 4
• 作者: Jackson DR;Cassilly CD;Plichta DR;Vlamakis H;Liu H;Melville SB;Xavier RJ;Clardy J
• 通讯作者: Clardy J

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

• 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

Collinsella aerofaciens Produces a pH-Responsive Lipid Immunogen.

• DOI: 10.1021/jacs.3c00250
• 发表时间: 2023-04-05
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Kwon, Jaeyoung;Bae, Munhyung;Szamosvari, David;Cassilly, Chelsi D.;Bolze, Andrew S.;Jackson, David R.;Xavier, Ramnik J.;Clardy, Jon
• 通讯作者: Clardy, Jon