Synthetic genetic oscillators demonstrate the functional importance of phenotypic variation in pneumococcal-host interactions

Anne-Stéphanie Rueff, Renske Raaphorst, Surya D. Aggarwal, Javier Santos-Moreno, Géraldine Laloux, Yolanda Schaerli, Jeffrey N. Weiser and Jan-Willem Veening ()
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Anne-Stéphanie Rueff: University of Lausanne, Biophore Building
Renske Raaphorst: University of Lausanne, Biophore Building
Surya D. Aggarwal: New York University School of Medicine
Javier Santos-Moreno: University of Lausanne, Biophore Building
Géraldine Laloux: de Duve Institute, UCLouvain
Yolanda Schaerli: University of Lausanne, Biophore Building
Jeffrey N. Weiser: New York University School of Medicine
Jan-Willem Veening: University of Lausanne, Biophore Building

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract 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 use synthetic oscillatory gene regulatory networks (GRNs) based on CRISPR interference (CRISPRi) together with live cell imaging and cell tracking within microfluidics devices to mimic and test the biological function of bacterial phenotypic variation. We provide a universally applicable approach for engineering intricate GRNs using only two components: dCas9 and extended sgRNAs (ext-sgRNAs). Our findings demonstrate that variation in capsule production is beneficial for pneumococcal fitness in traits associated with pathogenesis providing conclusive evidence for this longstanding question.

Date: 2023
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DOI: 10.1038/s41467-023-43241-y

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