Diversity in CRISPR-based immunity protects susceptible genotypes by restricting phage spread and evolution

Diversity in host resistance often associates with reduced pathogen
spread. This may result from ecological and evolutionary processes, likely
with feedback between them. Theory and experiments on bacteria-phage
interactions have shown that genetic diversity of the bacterial adaptive
immune system can limit phage evolution to overcome resistance. Using the
CRISPR-Cas bacterial immune system and lytic phage, we engineered a
host-pathogen system where each bacterial host genotype could be infected
by only one phage genotype. With this model system, we explored how CRISPR
diversity impacts the spread of phage when they can overcome a resistance
allele, how immune diversity affects the evolution of the phage to
increase its host range, and if there was feedback between these
processes. We show that increasing CRISPR diversity benefits susceptible
bacteria via a dilution effect, which limits the spread of the phage. We
suggest that this ecological effect impacts the evolution of novel phage
genotypes, which then feeds back into phage population dynamics.

宿主抗性的多样性通常与病原体传播减少相关联。该现象可能源于生态与进化过程，且二者间大概率存在反馈调控。针对细菌-噬菌体互作的理论与实验研究表明，细菌适应性免疫系统的遗传多样性可限制噬菌体进化以突破宿主抗性。本研究借助CRISPR-Cas细菌免疫系统与裂解性噬菌体，构建了一套宿主-病原体实验系统，其中每一类细菌宿主基因型仅能被单一噬菌体基因型感染。利用该模型系统，我们探究了三个核心科学问题：当噬菌体可突破某一抗性等位基因时，CRISPR多样性如何影响噬菌体的传播；免疫系统多样性如何推动噬菌体进化以拓宽宿主范围；以及这些过程之间是否存在反馈调控。研究结果显示，提升CRISPR多样性可通过稀释效应使易感细菌获益，进而限制噬菌体的传播。我们推测，这一生态学效应会影响新型噬菌体基因型的进化，而该进化过程又会反过来作用于噬菌体种群动态。