Rewiring capsule production by CRISPRi-based genetic oscillators demonstrates a functional role of phenotypic variation in pneumococcal-host interactions

Phenotypic variation is the phenomenon in which clonal cells display different traits even under identical environmental conditions. This plasticity is thought to be important for processes including bacterial virulence, but direct evidence for its relevance is often lacking. For instance, variation in capsule production in the human pathogen Streptococcus pneumoniae has been linked to different clinical outcomes, but the exact relationship between variation and pathogenesis is not well understood due to complex natural regulation. In this study, we used synthetic oscillatory gene regulatory networks (GRNs) based on CRISPR interference to show that variation in capsule production is beneficial for bacterial fitness in traits associated with pathogenesis. Our results demonstrate that engineered GRNs can be used to mimic and test the biological functions of natural phenotypic variable systems.