Antibiotic-resistant infections lead to 700,000 deaths per year worldwide1. The roles of phenotypically diverse subpopulations of clonal bacteria in the progression of diseases are unclear. We found that the increasingly pathogenic and antibiotic-resistant pathogen Acinetobacter baumannii harbours a highly virulent subpopulation of cells responsible for disease. This virulent subpopulation possesses a thicker capsule and is resistant to host antimicrobials, which drive its enrichment during infection. Importantly, bacteria harvested from the bloodstream of human patients belong exclusively to this virulent subpopulation. Furthermore, the virulent form exhibits increased resistance to hospital disinfectants and desiccation, indicating a role in environmental persistence and the epidemic spread of disease. We identified a transcriptional ‘master regulator’ of the switch between avirulent and virulent cells, the overexpression of which abrogates virulence. Furthermore, the overexpression strain is capable of vaccinating mice against lethal challenge. This work highlights a phenotypic subpopulation of bacteria that drastically alters the outcome of infection, and illustrates how knowledge of the regulatory mechanisms controlling such phenotypic switches can be harnessed to attenuate bacteria and develop translational interventions.
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The authors thank staff at the Genomics Resource Center at the University of Maryland for help with RNA-Seq and analysis, H. Ratner for the mice experiments, D. Bonenberger for breeding the knockout mice and W. Shafer for comments on the manuscript. This study was supported in part by the Robert P. Apkarian Integrated Electron Microscopy Core, which is subsidized by the Emory College of Arts and Sciences and the Emory University School of Medicine, and is one of the Emory Integrated Core Facilities. Additional support was provided by the Georgia Clinical and Translational Science Alliance of the National Institutes of Health (NIH) under award number UL1TR000454. P.N.R is supported by NIH grants R21AI115183 and R01072219, VA Merit award I01 BX001725 and a Research Career Scientist Award from the Department of Veterans Affairs. D.S.W. is supported by a Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Disease award, VA Merit award I01 BX002788 and NIH grant AI098800. This content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH and Department of Veterans Affairs.
The authors declare no competing interests.
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Chin, C.Y., Tipton, K.A., Farokhyfar, M. et al. A high-frequency phenotypic switch links bacterial virulence and environmental survival in Acinetobacter baumannii. Nat Microbiol 3, 563–569 (2018). https://doi.org/10.1038/s41564-018-0151-5
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