Impact of the C. difficile small acid soluble proteins on spore physiology

艰难梭菌小酸溶蛋白对孢子生理学的影响

基本信息

批准号：
10533031
负责人：
Joe Sorg
金额：
$ 57.34万
依托单位：
TEXAS A&M UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-08 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10533031
关键词：
Acids Affect Alleles Amino Acids Anaerobic Bacteria Bacillus subtilis Bacteria Binding Binding Proteins Biology Cells Characteristics Chemicals Chromosomes Clostridium Clostridium difficile Clostridium perfringens DNA DNA Binding DNA Sequence Data Desiccation Development Disease Endospore-Forming Bacteria Environment Event Formaldehyde Future Gel Genes Genetic Transcription Genome Germination Hamsters Healthcare Healthcare Systems Hospitals Hydrogen Peroxide In Vitro Individual Infection Lead Lesion Life Lyase Metabolism Minor Modeling Mothers Mutation Nature Nitrous Acid Organism Oxygen Pathogenesis Patients Peptide Hydrolases Phase Phase-Contrast Microscopy Phenotype Physiology Play Polymerase Process Production Property Proteins Publishing Reproduction spores Resistance Role Site Source Specificity Structure Surface Testing Thymidine Time Toxin UV Radiation Exposure UV induced DNA damage UV sensitive Ultraviolet Rays Ultraviolet Therapy United States Work adduct antibiotic-associated diarrhea cost crosslink design dimer experimental study extreme temperature genotoxicity health care settings mutant novel prevent programs repaired ultraviolet damage whole genome

项目摘要

Clostridioides difficile is the leading cause of antibiotic-associated diarrhea in the hospital and long term health care settings. In addition to the patient toll, the treatment-associated costs of C. difficile infections to the United States healthcare system have been estimated at $5 billion. Although the rate of C. difficile infection in the United States is rising, surprisingly little is known about the mechanisms by which C. difficile spores maintain their extreme resistance properties. C. difficile is believed to be acquired by the host in the form of a dormant spore which contaminates the nosocomial environment. In other organisms, a significant amount of resistant to UV and genotoxic chemicals is provided by the small acid soluble proteins (SASPs). SASPs are thought to nonspecifically bind to DNA and alter its form to prevent the formation of thymidyl-thymidine adducts (thymidine dimers) upon UV exposure. These proteins also provide resistances to reactive oxygen, acids, crosslinking agents and minor resistance to heat. In C. difficile, however, nothing is known about how these important proteins contribute to the C. difficile spore resistance spectrum. C. difficile SspA provides resistance to UV but SspA & SspB play a role in spore formation. The C. difficile ΔsspA ΔsspB double mutant strain does not produce mature spores suggesting that these SASPs regulate, at some level, the sporulation program. This application will analyze the impact of SASPs on spore biology in three aims. Aim 1 investigates how SspA & SspB contributes to spore formation and how the C. difficile SASPs protect the C. difficile genome from UV damage. Aim 2 investigates mechanisms by which the SASPs contribute to spore formation. Aim 3 investigates how the protease that degrades the SASPs during germination is regulated and its spectrum of activity in the spore. Successful completion of these aims will thoroughly characterize the impact of SASPs on spore resistance and lead to the future design of agents that can clean a contaminated environment.

梭状芽胞杆菌艰难梭菌是医院与抗生素相关腹泻的主要原因，长期医疗保健环境。除了患者损失外，与治疗相关的成本美国医疗保健系统的艰难梭菌感染估计为50亿美元。尽管美国艰难梭菌感染的速度正在上升，但令人惊讶的是鲜为人知关于艰难梭菌孢子保持其极端抗性特性的机制。据信，艰难梭菌是由宿主以休眠酱的形式获得的污染了医院环境。在其他生物体中，大量的抗性小酸固体蛋白（SASP）提供了紫外线和遗传毒性化学物质。 SASP 被认为是非特异性结合并改变其形式以防止形成的形式的紫外线暴露后，胸苷 - 胸腺苷加合物（胸苷二聚体）。这些蛋白质也提供对活性氧，酸，交联剂和对热的耐药性的抗性。在C. 然而，艰难梭菌对这些重要蛋白如何促进C。艰难的孢子抗性光谱。艰难梭菌SSPA对紫外线提供了抵抗力，但SSPA和SSPB 在散射形成中起作用。艰难梭菌δSSPAΔSSPB双重突变菌株不产生成熟的孢子，表明这些SASP在某种程度上调节了孢子形成程序。该应用程序将分析SASP对三个目标的散射生物学的影响。目的 1研究SSPA和SSPB如何促进散射形成以及艰难梭菌SASP 保护艰难梭菌基因组免受紫外线损伤。 AIM 2调查了机制 SASP有助于散射形成。 AIM 3调查了如何降解的蛋白酶调节发芽期间的SASP，并在调味料中的活性范围。成功的这些目标的完成将彻底表征SASP对散射阻力的影响并导致可以清洁受污染环境的代理商的未来设计。