Collective Dynamics and Collaborative Killing: Synergistic Elimination of Bacteria by Immune Cells and Viruses

集体动力与协同杀伤：免疫细胞和病毒协同消除细菌

• 批准号: 1806606
• 负责人: Jennifer Curtis
• 金额: $ 53.76万
• 依托单位: Georgia Tech Research Corporation
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1806606&HistoricalAwards=false
• 关键词: Collective; Dynamics; Collaborative; Killing; Synergistic

Bacteriophage ('phage') - viruses that exclusively infect and lyse bacteria - are highly abundant in the environment. Phage infections of bacteria can release matter, nutrients, and toxins, mediate the transfer of genes, and transform ecosystem function. In practice, phage are increasingly used as a form of biological control, to eliminate or prevent the proliferation of targeted bacteria - usually pathogens - from colonizing surfaces and organisms. The PI recently proposed a model of "immunophage synergy" to explain how phage and innate immune effector cells can, together, eliminate target bacteria in animal hosts, even when neither can do so alone. This model has been tested and validated in animal hosts. This project will integrate novel experimental methods with theory to transform our physical and systems-level understanding of how viruses and innate immune cells jointly modulate the dynamics of bacterial microcolonies and biofilms. It is also highly interdisciplinary, combining the fields of quantitative viral ecology, nonlinear dynamics, cellular biophysics, and soft matter physics. Thus it provides strong interdisciplinary training for students.As a first step, the project will extend a novel theory for synergistic elimination of bacteria by phage and neutrophils (a key component of the mammalian innate immune system). The theory combines principles of quantitative viral ecology, nonlinear dynamics, and mathematical immunology. This project will translate these principles into an explicitly spatial and individual-based context. This new framework will enable analysis of the basis for emergent, collective dynamics given tripartite interactions between phage, bacteria, and neutrophils. Second, this project will enable new in vitro experiments to probe the mechanistic basis for synergistic elimination of bacteria. Integrated research will assess the importance of nonlinear feedback, cellular biophysics, and soft-matter physics in governing tripartite dynamics via the visualization and quantification of interactions. Third, via an iterative and integrative approach, the project will combine new theoretical methods and in vitro techniques to evaluate principled mechanisms for combined use of phage and neutrophils to eliminate entire biofilms at different stages of development. This project will further the interdisciplinary study of the physics of viral and microbial systems, combining the fields of quantitative viral ecology, nonlinear dynamics, cellular biophysics, and soft matter physics. Two physics PhD students will be trained in an interdisciplinary context, i.e., including theory, large-scale computational modeling, and experimental studies of living systems. Research advances will be translated into reproducible software methods for use by the community, disseminated as protocols on protocols.io, with additional training materials and results presented as part of a collaborative workshop to be held in Year 3. The translation of discoveries to the public will be furthered by annual presentation of general interest talks to local communities, including elementary school, middle school and high school students, leveraging established contacts of the PIs. Discoveries of new principles underlying synergistic elimination of bacteria by phage and neutrophils also have the potential to influence the ongoing study of phage therapy for clinical use to treat multi-drug resistant bacterial infections in animals and humans. In immunophage synergy - the catalyzing discovery for this project - nonlinear feedback mechanisms are essential to understand system-level fates. The goal of this project is to develop an integrated approach to understand the physics of complex interactions amongst phage, bacteria, and innate immune effector cells. This project will combine theory of nonlinear dynamics, computational simulations of living systems, and in vitro experiments to: (i) Extend immunophage synergy to an explicitly spatial framework, including the analysis of emergent, collective dynamics. (ii) Establish and characterize physical interactions amongst phage, bacteria, and innate effector cells during bacteria microcolony and biofilm formation. (iii) Test principled combinations of phage and neutrophils to eliminate growing biofilms given environmental and strain heterogeneity. Together, these aims will deepen efforts to understand physical principles and feedback mechanisms by which phage transform bacterial populations given interactions with eukaryotic host organisms.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

噬菌体（“噬菌体”）-专门感染和裂解细菌的病毒-在环境中非常丰富。细菌的噬菌体感染可以释放物质、营养物质和毒素，介导基因转移，并改变生态系统功能。在实践中，噬菌体越来越多地被用作生物控制的一种形式，以消除或防止目标细菌（通常是病原体）在表面和生物体上的繁殖。PI最近提出了一个“免疫噬菌体协同作用”模型，以解释噬菌体和先天免疫效应细胞如何共同消除动物宿主中的靶细菌，即使两者都不能单独做到这一点。该模型已在动物宿主中进行了测试和验证。该项目将把新的实验方法与理论相结合，以改变我们对病毒和先天免疫细胞如何共同调节细菌小菌落和生物膜动态的物理和系统水平的理解。它也是高度跨学科的，结合了定量病毒生态学，非线性动力学，细胞生物物理学和软物质物理学领域。 作为第一步，该项目将扩展一种新的理论，通过噬菌体和中性粒细胞（哺乳动物先天免疫系统的关键组成部分）协同消除细菌。该理论结合了定量病毒生态学、非线性动力学和数学免疫学的原理。该项目将把这些原则转化为明确的空间和个人为基础的背景。这个新的框架将使分析的基础上出现的，集体动力学之间的三方相互作用噬菌体，细菌和中性粒细胞。其次，该项目将使新的体外实验能够探索协同消除细菌的机制基础。综合研究将评估非线性反馈，细胞生物物理学和软物质物理学在管理三方动态通过可视化和量化的相互作用的重要性。第三，通过迭代和综合的方法，该项目将联合收割机结合新的理论方法和体外技术，以评估联合使用噬菌体和中性粒细胞消除不同发育阶段的整个生物膜的原理机制。该项目将进一步病毒和微生物系统物理学的跨学科研究，结合定量病毒生态学，非线性动力学，细胞生物物理学和软物质物理学领域。两名物理学博士生将在跨学科背景下接受培训，即，包括理论、大规模计算建模和生命系统的实验研究。研究进展将转化为可复制的软件方法供社区使用，并作为协议在protocols.io上传播，并提供额外的培训材料和结果，作为第三年举行的协作研讨会的一部分。将通过每年向当地社区（包括小学、初中和高中学生）介绍一般兴趣讲座，利用PI的既定联系，进一步将发现转化为公众。通过噬菌体和嗜中性粒细胞协同消除细菌的新原理的发现也有可能影响正在进行的噬菌体治疗临床使用以治疗动物和人类中的多药耐药细菌感染的研究。在免疫噬菌体协同作用中-这个项目的催化发现-非线性反馈机制对于理解系统级命运至关重要。该项目的目标是开发一种综合方法来了解噬菌体，细菌和先天免疫效应细胞之间复杂相互作用的物理学。该项目将结合非线性动力学联合收割机理论、生命系统的计算模拟和体外实验，以：（i）将免疫噬菌体协同作用扩展到明确的空间框架，包括对涌现的集体动力学的分析。(ii)建立和表征细菌微菌落和生物膜形成过程中噬菌体，细菌和先天效应细胞之间的物理相互作用。(iii)测试噬菌体和中性粒细胞的原则性组合，以消除环境和菌株异质性下生长的生物膜。这些目标将共同深化理解噬菌体与真核宿主生物相互作用的物理原理和反馈机制的努力。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Heterogeneity in susceptibility dictates the order of epidemic models

• DOI: 10.1016/j.jtbi.2021.110839
• 发表时间: 2021-08-05
• 期刊: JOURNAL OF THEORETICAL BIOLOGY
• 影响因子: 2
• 作者: Rose, Christopher;Medford, Andrew J.;Peterson, Andrew A.
• 通讯作者: Peterson, Andrew A.

The time scale of asymptomatic transmission affects estimates of epidemic potential in the COVID-19 outbreak

• DOI: 10.1016/j.epidem.2020.100392
• 发表时间: 2020-06-01
• 期刊: EPIDEMICS
• 影响因子: 3.8
• 作者: Park, Sang Woo;Cornforth, Daniel M.;Weitz, Joshua S.
• 通讯作者: Weitz, Joshua S.