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

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。该领域继续将微生物组（微生物群落）作为控制人类和环境健康的许多生物过程的潜在关键致病因子。该领域面临的一个主要挑战是超越相关的方法，并建立对形成微生物组动力学和功能的力量的机制和定量理解。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，并设计出新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稳健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（噬菌体）。该项目研究了微生物组如何在短时间尺度（通过行为变化）和长时间尺度（通过生态和进化变化）上对病毒做出反应。该项目采用理论和实验相结合的方法，验证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。该项目通过多种与社会相关的成果，包括科学素养、研究参与、STEM教育和微生物组管理，产生了更广泛的影响。单个物种通常通过修改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实质性影响。从合成菌群的角度来看，噬菌体暴露后的表面因子修饰有损害菌群功能的风险。细菌也可以通过CRISPR-Cas进化出对噬菌体的抗性，使细胞的功能能力保持完整，但这种获得性耐药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作为获得性耐药的主要机制的理解提出了挑战。该项目假设CRISPR-Cas免疫获得是细胞内和细胞间特异性信号机制和社区依赖的适应度成本的一个新兴特性，它们共同促进了强大的社区功能。该项目通过确定合成微生物群落设计的一般原理，数学模型和工具具有重要意义，这些微生物群落具有抗噬菌体攻击的功能。这些工具反过来又促进微生物组辅助的环境健康、人类健康和应用环境中不可避免的噬菌体暴露工业的社会目标。这个英美合作项目由美国国家科学基金会（NSF）和英国生物技术和生物科学研究委员会（BBSRC）支持，其中NSF资助美国研究者，BBSRC资助英国的合作伙伴。该奖项反映了美国国家科学基金会的法定使命，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。

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.