Phytobacterial lipopolysaccharides in Juzen-taiho-to

十善太凤堂中的植物细菌脂多糖

• 批准号: 10263143
• 负责人: AKIRA KAWAMURA
• 金额: $ 11.7万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10263143
• 关键词: Acids; Acquired Immunodeficiency Syndrome; Affect; Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Attenuated; Bacteria; Benign; Biological Assay; Cell Line; Cells; Chemical Agents; Clinical; Communicable Diseases; Country; Development; Diamond; Disease; Drug resistance; Endotoxins; Environment; Extramural Activities; Formulation; Funding; Future; Goals; Herbal Medicine; Hydrolysis; Immune; Immunity; Immunocompromised Host; Immunologics; Immunomodulators; Immunotherapeutic agent; Immunotherapy; In Vitro; Infection prevention; Inflammation; Inflammatory; Invaded; Japan; Learning; Lipid A; Lipopolysaccharides; Mass Spectrum Analysis; Microbial Drug Resistance; Molecular; Mus; National Institute of Allergy and Infectious Disease; Natural Immunity; Oral; Outcome; Pathway interactions; Phytochemical; Plants; Research; Research Personnel; Resistance; Role; Safety; Signal Pathway; Signal Transduction; Stomach; Structure; Testing; Time; Toxic effect; Toxin; Universities; Vaccine Adjuvant; Work; analog; base; clinical efficacy; cytokine; drug resistant microorganism; expectation; experience; global health; immunoregulation; in vivo; in vivo Model; macrophage; microbial; novel; novel strategies; novel therapeutics; pathogen; pre-clinical; prevent; programs

Microbial drug resistance is a serious threat to the global health. It is essential to explore new anti-infective strategies that avoid the emergence of new drug resistance. One promising approach is the host-directed immunotherapy, which aims at boosting the innate immunity to prevent/treat infectious diseases. The approach avoids the emergence of resistance by targeting the host instead of the pathogen. Several host-directed immunotherapeutics are currently in clinical use, including monophosphoryl lipid A (MPL), which is used as a vaccine adjuvant. While the concept is promising, there is one major challenge in the development of new immunotherapeutics. Stimulation of the innate immunity activates the signaling pathways for inflammation as well as for protective immunity. Although inflammation is important for rapid eradication of invading pathogens, its hyperactivation can be very harmful to the host. Thus, the challenge is how to control inflammation without compromising protective immunity. To find a new approach to safely promote protective immunity, the proposed SC3 project will examine Juzen-taiho-to (JTT), an immune-boosting herbal formulation with long- tested clinical efficacy and safety. Recently, our group found that the immunostimulatory activity of JTT arises from lipopolysaccharides (LPSs) of plant-associated bacteria. Since LPSs are pro-inflammatory toxins, JTT must have a mechanism to effectively control the pro-inflammatory pathway. The objective of the proposed SC3 project is to clarify the mechanism by which pro-inflammatory effect of LPSs is controlled in JTT. The central hypothesis is that the pro-inflammatory effect is controlled by dual mechanisms, namely, (1) the LPSs in JTT, which is administered orally, are hydrolyzed by the stomach acid to benign forms that can still promote protective immunity, and (2) anti-inflammatory phytochemicals in JTT selectively attenuate the pro- inflammatory effect without compromising protective immunity. Both of these mechanisms are based on our strong preliminary results. To accomplish the objective, the following aims will be pursued. Aim 1: Characterize the structures and immunological effects of acid-treated LPSs in JTT. A combination of mass spectrometry cell-based assays, and in vivo cytokine profiling will be employed to characterize the impact of acid-treatment on the structures and immunological effects of phytobacterial LPSs. Aim 2: Determine the roles of anti- inflammatory phytochemicals in JTT. Here, anti-inflammatory phytochemicals will be subjected to cell-based assays and in vivo cytokine profiling to determine their effects on inflammation and other immunological pathways. It is our expectation that the proposed work will reveal a time-tested, but hitherto uncharacterized, approach to generate safe immunotherapeutics, which will expand our ability to develop new anti-infective strategies that avoid microbial resistance. The developmental objective of the PI is to build a strong collaborative research program focused on the discovery of novel immunomodulatory agents. Based on the results obtained from the proposed SC3 project, the collaborative team will aggressively seek extramural funding for future studies.

微生物耐药性是对全球健康的严重威胁。探索新的反感染至关重要 避免出现新药的策略。一种有前途的方法是主机定向 免疫疗法旨在提高先天免疫以预防/治疗传染病。方法 通过靶向宿主而不是病原体来避免抗药性的出现。几个主机定向 免疫疗法目前正在临床中，包括单磷酸脂质A（MPL），该脂质用作用作 疫苗佐剂。虽然这个概念很有希望，但新的发展是一个主要的挑战 免疫治疗药。刺激先天免疫会激活炎症的信号传导途径 以及保护性免疫。尽管炎症对于快速根除入侵病原体很重要，但 它的过度激活可能对宿主非常有害。因此，挑战是如何控制炎症而没有 损害保护性免疫。为了找到一种新的方法来安全促进保护性免疫， 拟议的SC3项目将检查Juzen-Taiho-to（JTT），这是一种促进免疫的草药配方 测试的临床功效和安全性。最近，我们的小组发现JTT的免疫刺激活性是 来自植物相关细菌的脂多糖（LPSS）。由于LPS是促炎性毒素，JTT 必须具有有效控制促炎途径的机制。提议的目标 SC3项目旨在阐明在JTT中控制LPSS的促炎作用的机制。这 中心假设是促炎作用受双重机制控制，即（1）LPSS 在口服的JTT中，胃酸将其水解为良性形式，仍然可以促进 保护性免疫，（2）JTT中的抗炎植物化学物质有选择地减弱 炎症作用而不损害保护性免疫。这两种机制都是基于我们的 强烈的初步结果。为了实现目标，将追求以下目标。目标1：特征 酸处理的LPS在JTT中的结构和免疫学作用。质谱法的组合 基于细胞的测定和体内细胞因子分析将用于表征酸治疗的影响 关于植物细菌LPS的结构和免疫学作用。目标2：确定抗 JTT中的炎性植物化学物质。在这里，抗炎植物化学物质将受到基于细胞的影响 测定和体内细胞因子分析，以确定其对炎症和其他免疫学的影响 途径。我们期望拟议的工作将揭示经过时间测试但迄今未经特色的时间， 产生安全免疫治疗剂的方法，这将扩大我们发展新反感染的能力 避免微生物抗性的策略。 PI的发展目标是建立一个强大的 协作研究计划的重点是发现新型免疫调节剂。基于 从拟议的SC3项目获得的结果，协作团队将积极寻求壁外 为将来的研究提供资金。