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Functional analysis of the molecular cross-talk between methanogenic archaea and the human immune system

产甲烷古菌与人体免疫系统之间分子串扰的功能分析

基本信息

批准号：
165418551
负责人：
Professor Dr. Holger Heine
金额：
--
依托单位：
Institut für Allgemeine Mikrobiologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2010
资助国家：
德国
起止时间：
2009-12-31 至 2017-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/165418551?language=en
关键词：
Functional analysis molecular cross talk

项目摘要

Although the functional importance of the microbiota in human s health and disease has been confirmed in numerous studies and reports, methanoarchaea as a stable part of the gut microbiota have frequently been overlooked in reports addressing and elucidating the interdependency between members of the microbiome and components of the immune system. During the previous funding period we performed the first comprehensive study of the inflammatory response of human immune cells to methanoarchaea, which demonstrated that Methanosphaera stadtmanae is capable to induce a markedly higher inflammatory cytokine response than Methanobrevibacter smithii. Based on our results of the first funding period we hypothesize that M. stadtmanae has the potential to promote inflammatory processes in the human gut and may thus represent a so far overlooked contributor to pathological conditions in the human gut. In contrast, M. smithii appears to have evolved mechanism to suppress inflammatory processes in the gut and moreover might have immunmodulatory influence in the human gut ecosystem. Our data obtained further strongly argue for the presence of a specific archaea-associated pattern recognition receptor in humans. Finally, we demonstrated that methanoarchaea are prone to the lytic effects of antimicrobial peptides (AMPs) like bacteria and are capable to regulate their release by human immune cells. Accordingly, archaeal strains may influence the overall human immune homeostasis to comparable extents as has been shown for bacteria. Consequently we now aim to (1) identify the involved methanoarchaeal-associated molecular patterns as well as the respective human pattern-recognition receptors and mediators involved in signaling processes, (2) analyze the immunomodulating processes of methanoarchaea within the human intestine by comparing transcriptome changes upon contact of methanoarchaea with human epithelial and peripheral blood cells, (3) evaluate a potential correlation between the presence of M. stadtmanae and inflammatory gut diseases by monitoring the total cell numbers in intestinal biopsy and stool samples of healthy and diseased individuals, (4) elucidating the cellular stress responses of M. stadtmanae and M. smithii to AMPs and cytokines released by human cells, and (5) analyze the ability of M. smithii and M. stadtmanae to form biofilms on human epithelia under various conditions.Generally, these studies will expand our recent discoveries on the molecular and immunological level and evaluate the hypothesized contribution of M. stadtmanae to pathological conditions in the human gut and thus will emphasize the functional importance of methanoarchaea as a part of the human microbiota.

尽管微生物群在人类健康和疾病中的功能重要性已在众多研究和报告中得到证实，但甲烷古菌作为肠道微生物群稳定的一部分，在解决和阐明微生物组成员与免疫系统组成部分之间相互依赖性的报告中经常被忽视。在之前的资助期间，我们对人类免疫细胞对甲烷古菌的炎症反应进行了首次全面研究，结果表明，Methanosphaera stadtmanae 能够诱导比 Methanobrevibacter smithii 明显更高的炎症细胞因子反应。根据我们第一个资助期的结果，我们假设 M. stadtmanae 有可能促进人类肠道的炎症过程，因此可能是迄今为止被忽视的人类肠道病理状况的贡献者。相比之下，史密斯氏菌似乎已经进化出了抑制肠道炎症过程的机制，而且可能对人类肠道生态系统具有免疫调节影响。我们获得的数据进一步有力地证明了人类中存在特定的古细菌相关模式识别受体。最后，我们证明了甲烷古菌像细菌一样容易受到抗菌肽（AMP）的溶解作用，并且能够调节人类免疫细胞的释放。因此，古细菌菌株对人类整体免疫稳态的影响程度可能与细菌的影响程度相当。因此，我们现在的目标是（1）识别所涉及的甲烷古菌相关分子模式以及参与信号传导过程的相应人类模式识别受体和介质，（2）通过比较甲烷古菌与人类上皮细胞和外周血细胞接触时的转录组变化来分析人类肠道内甲烷古菌的免疫调节过程，（3）评估潜在的通过监测健康和患病个体的肠道活检和粪便样本中的总细胞数，了解 M. stadtmanae 的存在与炎症性肠道疾病之间的相关性，(4) 阐明 M. stadtmanae 和 M. smithii 对人类细胞释放的 AMP 和细胞因子的细胞应激反应，以及 (5) 分析 M. smithii 和 M. stadtmanae 在人类上皮上形成生物膜的能力一般来说，这些研究将扩展我们在分子和免疫学水平上的最新发现，并评估 M. stadtmanae 对人类肠道病理状况的假设贡献，从而强调甲烷古菌作为人类微生物群一部分的功能重要性。