Phenotypic diversification within pathogen populations can enhance survival in stressful environments, broaden niche colonization, and expand the ecological range of infectious diseases due to emerging collective pathogenicity characteristics. We describe a gene regulatory network property in the opportunistic pathogen Pseudomonas aeruginosa that generates diversity of gene expression and pathogenicity behavior at the single-cell level and that is stabilized by epigenetic cellular memory. The resulting heterogeneity in the expression of the glpD gene-an indicator of host-derived glycerol metabolism and intra-host presence-shapes adaptive processes that are subject to natural selection. Our work on how epigenetics generates phenotypic variation in response to the environment and how these changes are inherited to the next generation provides insights into phenotypic diversity and the emergence of unique functionalities at higher levels of organization. These could be crucial for controlling infectious disease outcomes.

Cluster of Excellence Resolving Infection Susceptibility EXC 2155 Hannover Medical School Hannover 30625 Germany

Department of Cell Biology Helmholtz Centre for Infection Research Braunschweig 38124 Germany

Department of Clinical Microbiology Copenhagen University Hospital Rigshospitalet Copenhagen 2100 Denmark

Department of Molecular Bacteriology Helmholtz Centre for Infection Research Braunschweig 38124 Germany

Department of Molecular Bacteriology TWINCORE Centre for Experimental and Clinical Infection Research a Joint Venture of the Hannover Medical School and the Helmholtz Centre for Infection Research Hannover 30625 Germany

Department of Nanoscale Infection Biology Helmholtz Centre for Infection Research Braunschweig 38124 Germany

Department of Systems Immunology Helmholtz Centre for Infection Research Braunschweig 38124 Germany

Laboratoy of Anoxygenic Phototrophs Institute of Microbiology of the Czech Academy of Science Třeboň 379 01 Czechia

Leibniz Institute Deutsche Sammlung von Mikroorganismen und Zellkulturen Braunschweig 38124 Germany

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Epigenetic cellular memory in Pseudomonas aeruginosa generates phenotypic variation in response to host environments