Mechanobiology of Neisseria Microcolonies

奈瑟菌微菌落的机械生物学

• 批准号: 9097400
• 负责人: Nicolas Biais
• 金额: $ 15.7万
• 依托单位: BROOKLYN COLLEGE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9097400
• 关键词: Address; Adhesions; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Architecture; Attention; Bacteria; Behavior; Biological Models; Cell Differentiation process; Cell Maturation; Cell-Cell Adhesion; Cells; Cellular biology; Cephalosporin Resistance; Cephalosporins; Chemicals; Communities; Complex; Cues; DNA; Data; Development; Diffusion; Disease; Drug resistance; Environment; Eukaryotic Cell; Event; Fiber; Foundations; Funding Opportunities; Gene Expression; Genes; Gonorrhea; Health; Human; Indium; Infection; International; Laboratories; Lead; Life; Microbial Biofilms; Neisseria; Neisseria gonorrhoeae; Nutrient; Pharmaceutical Preparations; Physiology; Pilot Projects; Pilum; Play; Process; Resolution; Resort; Role; Sexually Transmitted Diseases; Shapes; Signal Transduction; Staging; System; Testing; Time; United States National Institutes of Health; Work; arm; base; biological systems; biophysical properties; cancer cell; cell motility; fighting; human disease; innovation; novel therapeutics; pathogen; resistance allele; resistant strain; uptake; weapons

DESCRIPTION (provided by applicant): Neisseria gonorrhoeae (Ng) is the etiologic agent of gonorrhea. With over 100 million annual cases worldwide, gonorrhea is one of the most common sexually transmitted diseases. In recent years, an alarming increase in antibiotic resistance among Neisseria gonorrhoeae strains has been a cause for great concern among all national and international health agencies. The current emergence of cephalosporin-resistant strains (so far cephalosporins are our last resort antibiotic treatment for gonorrhea) around the world emphasizes the need for both new treatments for gonorrhea, as well as a better understanding of the basic mechanisms behind antibiotic resistance. As with many other bacteria, Ng bacteria are rarely found as single cells. Instead they are first found in small clusters or microcolonies of a few tens to a few thousands bacteria and then in fully formed biofilms of up to millions of cells. Bacteria within biofilms are more resistant to antibiotic treatment than their free-living counterparts. Biofilms also play a major role in pathogen colonization and disease. While much progress has been made in understanding the architecture of the mature biofilm, the process by which biofilms develop remains less well understood. Understanding the early stages of biofilm development may lead to new therapies and treatments of important human diseases. Similarly to what has been shown between human cells, we postulate that the impact of physical forces is crucial in the formation and architecture of Ng microcolonies, the precursors of Ng biofilms. A key element in the formation of Ng microcolonies is the Type IV pilus (Tfp). Tfp are retractable bacterial fibers involved in many aspects of Ng physiology including motility, adhesion, infection, DNA uptake and biofilm formation. We have shown that the retraction of Tfp from Ng microcolonies can exert forces in the nanoNewton range (approximately 100,000 times the bodyweight of a single bacteria) and that these forces are capable of triggering signaling events in human cells. The objective of this study is to discover how the extreme forces of Tfp retraction shape Ng microcolony formation and the behavior of Ng bacteria within these communities. We will obtain this objective by pursuing three aims: identify how Tfp retraction forces shape microcolonies, determine the role of Tfp retraction forces in the initial steps of biofilm differentiation, and determine the role ofTfp retraction forces in the resistance to antibiotics and the spreading of antibiotic resistance. This work is of particular significance as it addresses a largely unknown and important stage of biofilm development. The findings here will lay the groundwork for future research on an important topic of human health. The proposed project is innovative as it will, for the first time, assess the role of physical forces in the formation and function of Ng microcolonies and achieve this at the single cell level.

描述（由申请人提供）：淋病奈瑟菌（Ng）是淋病的病原体。淋病是最常见的性传播疾病之一，全球每年有超过 1 亿病例。近年来，淋病奈瑟菌菌株中抗生素耐药性的惊人增加引起了所有国家和国际卫生机构的高度关注。目前世界各地出现的头孢菌素耐药菌株（到目前为止，头孢菌素是我们治疗淋病的最后抗生素治疗手段）强调了对淋病新疗法的需求，以及更好地了解抗生素耐药性背后的基本机制的必要性。与许多其他细菌一样，NG 细菌很少以单细胞形式存在。相反，它们首先在几十到几千个细菌的小簇或小菌落中发现，然后在多达数百万个细胞的完全形成的生物膜中发现。生物膜内的细菌比自由生活的细菌对抗生素治疗具有更强的抵抗力。生物膜在病原体定植和疾病中也发挥着重要作用。虽然在了解成熟生物膜的结构方面已经取得了很大进展，但生物膜形成的过程仍然不太了解。了解生物膜发育的早期阶段可能会带来重要人类疾病的新疗法和治疗方法。与人类细胞之间的情况类似，我们假设物理力的影响对于 Ng 微菌落（Ng 生物膜的前体）的形成和结构至关重要。 Ng 微菌落形成的关键因素是 IV 型菌毛 (Tfp)。 Tfp 是可伸缩的细菌纤维，参与 Ng 生理学的许多方面，包括运动、粘附、感染、DNA 摄取和生物膜形成。我们已经证明，Tfp 从 Ng 微菌落中收缩可以施加纳牛顿范围内的力（大约是单个细菌体重的 100,000 倍），并且这些力能够触发人体细胞中的信号事件。本研究的目的是发现 Tfp 收缩的极端力量如何影响 Ng 微菌落的形成以及这些群落中 Ng 细菌的行为。我们将通过追求三个目标来实现这一目标：确定Tfp回缩力如何塑造微菌落，确定Tfp回缩力在生物膜分化的初始步骤中的作用，并确定Tfp回缩力在抗生素耐药性和抗生素扩散中的作用反抗。这 这项工作具有特别重要的意义，因为它涉及生物膜发展的一个很大程度上未知且重要的阶段。这里的研究结果将为人类健康这一重要课题的未来研究奠定基础。拟议的项目具有创新性，因为它将首次 评估物理力在 Ng 微菌落形成和功能中的作用，并在单细胞水平上实现这一目标。

项目成果

Analyzing bacterial movements on surfaces.

分析表面上的细菌运动。

• DOI: 10.1016/bs.mcb.2014.10.014
• 发表时间: 2015
• 期刊: Methods in cell biology
• 作者: Munteanu,ELaura;Spielman,Ingrid;Biais,Nicolas
• 通讯作者: Biais,Nicolas

Pili mediated intercellular forces shape heterogeneous bacterial microcolonies prior to multicellular differentiation.

• DOI: 10.1038/s41598-018-34754-4
• 发表时间: 2018-11-08
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Pönisch W;Eckenrode KB;Alzurqa K;Nasrollahi H;Weber C;Zaburdaev V;Biais N
• 通讯作者: Biais N

Formation and dissolution of bacterial colonies.

细菌菌落的形成和溶解。

• DOI: 10.1103/physreve.92.032704
• 发表时间: 2015
• 期刊: Physical review. E, Statistical, nonlinear, and soft matter physics
• 作者: Weber,ChristophA;Lin,YenTing;Biais,Nicolas;Zaburdaev,Vasily
• 通讯作者: Zaburdaev,Vasily

Uncovering the mechanism of trapping and cell orientation during Neisseria gonorrhoeae twitching motility.

• DOI: 10.1016/j.bpj.2014.07.061
• 发表时间: 2014-10
• 期刊: Biophysical journal
• 影响因子: 3.4
• 作者: V. Zaburdaev;N. Biais;M. Schmiedeberg;J. Eriksson;A. Jonsson;M. Sheetz;D. Weitz