UKRI/BBSRC-NSF/BIO: Community-dependent CRISPR-cas evolution and robust community function

UKRI/BBSRC-NSF/BIO：群落依赖性 CRISPR-cas 进化和强大的群落功能

• 批准号: 2321502
• 负责人: Samuel Brown
• 金额: $ 83.4万
• 依托单位: Georgia Tech Research Corporation
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2321502&HistoricalAwards=false
• 关键词: UKRI; BBSRC; NSF; BIO; Community

Microbiome research has produced an incredible inventory of data from diverse human and environmental samples. The field continues to implicate microbiomes (microbial communities) as potentially key causal agents in many biological processes governing human and environmental health. A major challenge for the field is to move beyond correlative approaches and to establish mechanistic and quantitative understanding of the forces shaping the dynamics and functions of microbiomes. Rationally designed and experimentally assembled ‘synthetic microbiomes’ offer an exciting avenue to decipher basic rules of microbial organization and engineer novel microbial solutions to pressing applied societal challenges. Yet, the robustness of synthetic microbiomes to environmental perturbations remains relatively untested. A major class of microbiome perturbation stems from assault by parasites of microbes, such as bacteriophage viruses (phages). This project investigates how defined microbiomes respond to viruses on both short timescales (via behavioral shifts) and longer timescales (via ecological and evolutionary shifts). Using a combination of theory and experiment, the project tests the hypothesis that robust microbiome functions are predictably promoted by microbial communication systems, and costs of virus resistance. The project holds broader impact through multiple societally relevant outcomes, spanning scientific literacy, research participation, STEM education and microbiome management. Individual species commonly evolve resistance to phages by modifying or entirely deleting the surface receptor used by the phage. This can have substantial impacts on the functional capacities and species interactions of the bacterium, due to the importance of surface factors in mediating environmental interactions. From a synthetic community perspective, surface factor modifications in response to phage exposure risk damaging the functional capacities of the community. Bacteria can also evolve resistance to phages via CRISPR-Cas, leaving the functional capacity of the cell intact, yet this pathway of acquired resistance is rarely seen in a lab setting. The paucity of lab CRISPR-Cas evolution presents a challenge to the understanding of CRISPR-Cas as a primary mechanism of acquired resistance. This project hypotheses that CRISPR-Cas immunity acquisition is an emergent property of intra- and inter-specific cell-cell signaling mechanisms and community-dependent fitness costs, which together promote robust community functioning. This project holds significance by identifying general principles, math models and tools for the design of synthetic microbial communities that are functionally robust against phage attack. These tools in turn promote microbiome-assisted societal goals for environmental health, human health and industry in applied settings where phage exposure is inevitable.This collaborative US/UK project is supported by the US National Science Foundation (NSF) and the UK Biotechnology and Biological Sciences Research Council (BBSRC), where NSF funds the US investigator and BBSRC funds the partners in the UK.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.

微生物组研究已经从不同的人类和环境样本中产生了令人难以置信的数据清单。该领域继续涉及微生物组（微生物群落）作为潜在的关键致病因子在许多生物过程中管理人类和环境健康。该领域的一个主要挑战是超越相关方法，并建立对塑造微生物组动态和功能的力量的机械和定量理解。合理设计和实验组装的“合成微生物组”提供了一个令人兴奋的途径来破译微生物组织的基本规则，并设计新颖的微生物解决方案来应对紧迫的应用社会挑战。然而，合成微生物组对环境扰动的鲁棒性仍然相对未经测试。 一类主要的微生物组扰动源于微生物寄生虫的攻击，如噬菌体病毒（Bacteriophage virus，简称BTV）。该项目研究了定义的微生物组如何在短时间尺度（通过行为转变）和较长时间尺度（通过生态和进化转变）上对病毒做出反应。该项目将理论和实验相结合，测试了微生物通讯系统可预测地促进微生物组功能的假设，以及病毒抗性的成本。该项目通过多种社会相关成果产生更广泛的影响，涵盖科学素养，研究参与，STEM教育和微生物组管理。个别物种通常通过修饰或完全删除噬菌体使用的表面受体来进化对噬菌体的抗性。由于表面因子在介导环境相互作用中的重要性，这可能对细菌的功能能力和物种相互作用产生重大影响。从合成的社区的角度来看，表面因子的修改，以响应噬菌体暴露的风险，损害社区的功能能力。细菌也可以通过CRISPR-Cas进化出对细菌的抗性，使细胞的功能能力保持完整，但这种获得性抗性的途径在实验室环境中很少见到。实验室CRISPR-Cas进化的缺乏对CRISPR-Cas作为获得性抗性的主要机制的理解提出了挑战。该项目假设CRISPR-Cas免疫获得是种内和种间细胞间信号传导机制和社区依赖性适应性成本的一种新兴特性，它们共同促进了强大的社区功能。该项目具有重要意义，通过确定一般原则，数学模型和工具，用于设计功能强大的抗噬菌体攻击的合成微生物群落。这些工具反过来又促进了微生物组辅助的社会目标，以实现环境健康、人类健康和工业在噬菌体暴露不可避免的应用环境中的目标。这项美国/英国合作项目得到了美国国家科学基金会（NSF）和英国生物技术和生物科学研究理事会（BBSRC）的支持，该奖项反映了NSF的法定使命，并通过使用基金会的知识产权进行评估，被认为值得支持。优点和更广泛的影响审查标准。