Phytobacterial lipopolysaccharides in Juzen-taiho-to

十善太凤堂中的植物细菌脂多糖

• 批准号: 10466915
• 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/10466915
• 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.

微生物耐药性严重威胁全球健康。探索新的抗感染药物势在必行 避免新耐药性出现的策略。一种有前途的方法是主机导向 免疫疗法，旨在增强先天免疫力以预防/治疗传染病。方法 通过针对宿主而不是病原体来避免耐药性的出现。多个主机定向 目前临床上使用的免疫治疗药物包括单磷酰脂质 A (MPL)，它被用作免疫治疗药物。 疫苗佐剂。虽然这一概念很有前景，但开发新产品面临着一项重大挑战 免疫治疗。刺激先天免疫会激活炎症信号通路 以及保护性免疫力。尽管炎症对于快速消灭入侵病原体很重要， 它的过度激活可能对宿主非常有害。因此，挑战在于如何在不影响炎症的情况下控制炎症。 损害保护性免疫力。为了找到一种安全促进保护性免疫力的新方法， 拟议的 SC3 项目将研究 Juzen-taiho-to (JTT)，这是一种增强免疫力的草药配方，具有长效作用。 检验了临床疗效和安全性。最近，我们课题组发现JTT的免疫刺激活性产生 来自植物相关细菌的脂多糖（LPS）。由于 LPS 是促炎毒素，JTT 必须有一种机制来有效控制促炎途径。拟议的目标 SC3项目旨在阐明JTT控制LPS促炎作用的机制。这 中心假设是促炎作用由双重机制控制，即（1）LPS 在口服的 JTT 中，被胃酸水解成良性形式，仍然可以促进 保护性免疫，(2) JTT 中的抗炎植物化学物质选择性减弱促 炎症作用而不损害保护性免疫力。这两种机制都是基于我们的 强有力的初步结果。为实现这一目标，将努力实现以下目标。目标 1：表征 JTT 中酸处理的 LPS 的结构和免疫学作用。质谱联用 基于细胞的测定和体内细胞因子分析将用于表征酸处理的影响 植物细菌脂多糖的结构和免疫学作用。目标 2：确定抗病毒药物的作用 JTT 中的炎症植物化学物质。在这里，抗炎植物化学物质将受到基于细胞的 测定和体内细胞因子分析以确定它们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出经过时间考验但迄今为止尚未表征的、 产生安全免疫疗法的方法，这将扩大我们开发新抗感染药物的能力 避免微生物耐药性的策略。 PI的发展目标是建立一个强大的 合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 项目中获得的结果，协作团队将积极寻求校外 为未来的研究提供资金。