Control of Virus Induced Lysis

病毒诱导裂解的控制

• 批准号: 7923494
• 负责人: RYLAND F YOUNG
• 金额: $ 13.91万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7923494
• 关键词: Address; Allolevivirus; Anti-Bacterial Agents; Antibiotics; Bacteriophages; Biochemical Genetics; Cell Wall; Cells; Chemicals; Complement; Consensus; Cues; Cytolysis; Dissection; Enzymes; Event; Genes; Genome; Goals; Infection; Investigation; Levivirus; Lipids; Membrane; Membrane Proteins; Microvirus; Molecular; Muramidase; Pathway interactions; Peptidoglycan; Physiological; Property; Proteins; Public Health; RNA Phages; Research; Resistance; Schedule; System; Virion; Virus; Work; base; combat; design; endolysin; killings; pathogen; programs; protein E; protein protein interaction; prototype; tool

The focus of this proposal is on the mechanism of host lysis by bacteriophage. Building on recent progress, it is proposed to investigate the biochemical and genetic properties of holins, smallphage-encoded membrane proteins that act as the timers of phage infections. Holins have the remarkable ability to accumulate during the phage infective cycle without harming the cell, then suddenly triggering to permeabilize the membrane. This terminates the infection and activatesmuralytic enzymes called endolysins, or lysozymes, resulting in degradationof the cell wall, leading to bursting of the cell and release of the progeny virions. The work is aimed at determining how these proteins can form holes inmembranes, and how the scheduling of the hole-forming event is programmed into the sequence of the holin. Fundamental issues of lipid-protein and protein-protein interactions in membranes will be addressed, including an investigation of how integral membranedomains of some lysis proteins actually are able to exit the membrane upon physiological cues. The holin-endolysin mode is completely general for all phages except those with very small genomes. However, single-stranded DMA and RNAphages, limited to 3 - 10genes for their entire genome complement, accomplish host lysis by expressing single genes. In two of these cases, recent progress has shown that the phage lysis protein causes lysis by inhibiting different enzymes in the murein precursor biosynthetic pathway. It is proposed to investigate the molecular basis by which these "protein antibiotics" effect inhibition of these conserved enzymes. Other small single-stranded RNA phages effect lysis by an unknown mechanism, the elucidation of which is another goal of this project. Public health implications: These studies are critical to our understanding of how bacterial viruses, or phages, kill their prey and effect dispersal of their progeny. This may have direct practical benefits because there is a growing consensus that phages, as natural antibacterial agents, will become an important tool in combating bacterial pathogens, which are increasingly resistant to available antibiotics. In addition, the research may reveal new modes for design of chemical antibiotics.

该建议的重点是噬菌体裂解宿主的机制。根据最近 进展，建议调查的生化和遗传特性的holins，小噬菌体编码的 作为噬菌体感染计时器的膜蛋白。Holins有非凡的能力， 在噬菌体感染周期中积累而不伤害细胞，然后突然触发， 使膜渗透。这终止了感染并激活了一种叫做 内溶素或溶菌酶，导致细胞壁降解，导致细胞破裂并释放 的后代病毒体。这项工作旨在确定这些蛋白质如何在膜上形成孔， 以及如何将孔形成事件的调度编程到孔的序列中。 膜中脂质-蛋白质和蛋白质-蛋白质相互作用的基本问题将得到解决， 包括一些溶解蛋白的完整膜蛋白如何实际上能够离开 生理信号的影响 孔蛋白-内溶素模式对于除了具有非常小的基因组的那些之外的所有微生物是完全通用的。 然而，单链DNA和RNA聚合酶，其整个基因组仅限于3 - 10个基因 补体，通过表达单个基因完成宿主裂解。在其中两个案例中，最近的进展 显示噬菌体裂解蛋白通过抑制胞壁蛋白前体中的不同酶而引起裂解 生物合成途径建议调查这些“蛋白质抗生素”的分子基础， 抑制这些保守的酶。其他小的单链RNA通过一种 未知的机制，阐明这是本项目的另一个目标。 公共卫生影响：这些研究对我们了解细菌病毒或 捕食，杀死猎物并分散它们的后代。这可能有直接的实际好处，因为 越来越多的人一致认为，作为天然抗菌剂，抗菌肽将成为治疗细菌感染的重要工具。 防治细菌病原体，这些病原体对现有抗生素的耐药性越来越强。此外该 研究可能揭示化学抗生素设计的新模式。