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: 10495242
• 负责人: Danielle A Garsin
• 金额: $ 23.4万
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10495242
• 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.

项目概要/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 这些细菌编码其分解代谢所必需的 EA 利用 (eut) 基因。在许多病原体中 经研究发现，EA 的利用对存活和致病性有积极贡献。许多 EA- 利用细菌还可以编码形成类似细胞器的蛋白质结合结构，称为细菌 EA 分解代谢发生的微区室 (BMC)。目前，严重缺乏相关知识 关于 EA 的产生方式以及宿主细胞中 EA 分解代谢的时间和地点。我们的长期目标是 了解 EA 在细菌中的利用情况。此应用程序的目的是阐明 EUT BMC 中的关键差距 动力学和 EA 分解代谢，重点关注细胞内环境。中心假设是 BMC 在宿主细胞吞噬体内组装，并通过 PEA 的分解代谢产生 EA。具体目标#1 将 确定 BMC 在宿主细胞内形成的时间和地点。单核细胞增生李斯特氏菌是一种天然的细胞内 逃避吞噬细胞吞噬体并在宿主细胞细胞质中复制的病原体。立足于强 初步数据表明，Eut BMC 是在吞噬体中形成的。具体目标 #2 将阐明 EA 如何从磷脂来源中提取。假设利用 EA 的细菌通过以下方式获得它： PEA 分解，因此编码 PEA 分解代谢所需的酶。候选基因是 其中一项的确定和初步研究证明了其在 EA 利用中的作用。总体而言，本研究将 显着影响 BMC 生物学、EA 利用和宿主-病原体相互作用领域。此外， 因为它将识别产生 EA 所需的细菌酶，这是抗菌药物的潜在目标 发展将得到精准定位。拟议的研究在概念上具有创新性，因为它试图破译 宿主细胞中的 BMC 动态。此外，它将研究 EA 如何在宿主细胞中发挥作用，这是一个不请自来的问题 这个问题在很大程度上已经被该领域掩盖了。