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

Georgia Tech Research Corporation, Atlanta GA

Investigators

Abstract

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.