Ethanolamine utilizing bacterial microcompartments in host cells

乙醇胺利用宿主细胞中的细菌微区室

• 批准号: 10385013
• 负责人: Danielle A Garsin
• 金额: $ 19.5万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-24 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10385013
• 关键词: Bacteria; Binding Proteins; Biochemical; Biology; Candidate Disease Gene; Carbon; Catabolism; Cells; Cytoplasm; Data; Development; Drug Targeting; Enterococcus faecalis; Environment; Enzymes; Ethanolamines; Future; Genes; Goals; Harvest; Human; In Vitro; Intestines; Knowledge; Link; Listeria monocytogenes; Metabolism; Nitrogen; Organelles; Pathogenesis; Pathogenicity; Pathway interactions; Phagocytes; Phagosomes; Phosphatidylethanolamine; Phospholipids; Public Health; Quantitative Reverse Transcriptase PCR; Regulation; Research; Role; Source; Structure; Testing; Virulence; Visualization; Work; antimicrobial; antimicrobial drug; base; enzyme pathway; human pathogen; innovation; mutant; pathogen; phosphodiester; phosphoric diester hydrolase; targeted treatment; therapeutic development

PROJECT SUMMARY/ABSTRACT Within host environments, ethanolamine (EA) can serve as a key source of carbon, nitrogen and/or energy for those bacteria that encode the EA-utilizing (eut) genes necessary for its catabolism. In many of the pathogens in which it has been studied, EA utilization positively contributes to survival and pathogenicity. Many EA- utilizing bacteria also encode for the formation of an organelle-like, protein-bound structure called a bacterial microcompartment (BMC) in which EA catabolism takes place. Currently, there is a critical lack of knowledge regarding how EA is derived and when and where EA catabolism is utilized in host cells. Our long-term goal is to understand EA utilization in bacteria. The objective of this application is to elucidate key gaps in Eut BMC dynamics and EA catabolism with a focus on the intracellular environment. The central hypothesis is that BMCs assemble within the host cell phagosome and derive EA by catabolism of PEA. Specific Aim #1 will identify when and where BMCs are formed within host cells. L. monocytogenes is a natural intracellular pathogen that escapes the phagocytic phagosome to replicate in the host cell cytoplasm. Based on strong preliminary data, it is postulated that the Eut BMCs form in the phagosome. Specific Aim #2 will elucidate how EA is derived from phospholipid sources. The hypothesis is that bacteria that utilize EA obtain it by breakdown of PEA and therefore encode the enzymes necessary for PEA catabolism. Candidate genes were identified and preliminary studies of one demonstrated its role in EA utilization. Overall, this study will significantly impact the fields of BMC biology, EA utilization and host-pathogen interactions. Additionally, because it will identify the bacterial enzymes necessary to generate EA, potential targets for antimicrobial development will be pinpointed. The proposed research is conceptually innovative in that it seeks to decipher BMC dynamics in host cells. Moreover, it will examine how EA becomes available in host cells, an unasked question that has largely been swept under the rug by the field.

项目总结/摘要 在宿主环境中，乙醇胺（EA）可以作为碳、氮和/或能量的关键来源， 这些细菌编码的EA-利用（eut）基因的必要，其catalysts。在许多病原体中 在已经研究的环境中，EA利用积极地有助于存活和致病性。很多EA- 利用细菌还编码形成一种细胞器样的蛋白质结合结构，称为细菌 微区室（BMC），其中EA catalysts发生。目前，我们严重缺乏知识， 关于EA是如何衍生的以及何时何地在宿主细胞中使用EA催化剂。我们的长期目标是 了解EA在细菌中的利用。本申请的目的是阐明Eut BMC中的关键差距 动力学和EA catalysts与细胞内环境的重点。核心假设是， BMCs在宿主细胞吞噬体中组装，并通过PEA的催化作用获得EA。具体目标#1 确定何时何地在宿主细胞内形成BMC。L.单核细胞增多症是一种天然的细胞内 从吞噬细胞的吞噬体中逃脱而在宿主细胞质中复制的病原体。基于强 根据初步数据，推测Eut BMC在吞噬体中形成。具体目标#2将阐明 EA是如何从磷脂来源中衍生出来的。假设是利用EA的细菌通过以下方式获得它： PEA分解，因此编码PEA催化所必需的酶。候选基因 确定和初步研究表明，它在EA利用的作用之一。总的来说，这项研究将 显著影响BMC生物学、EA利用和宿主-病原体相互作用领域。此外，本发明还 因为它将确定产生EA所必需的细菌酶，抗菌剂的潜在靶点， 发展将被定位。拟议的研究在概念上是创新的，因为它试图破译 宿主细胞中的BMC动力学。此外，它将研究EA如何在宿主细胞中变得可用，这是一个未知的问题。 这个问题在很大程度上被这个领域扫到了地毯下面。