A high-frequency phenotypic switch links bacterial virulence and environmental survival in Acinetobacter baumannii

Abstract

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, harbors 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, and whose overexpression abrogated virulence. Further, the overexpression strain vaccinated 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.

Coping with low water activities and osmotic stress in Acinetobacter baumannii: significance, current status and perspectives

“…One of them has a translucent colony phenotype and is avirulent (named AV‐T by the authors), the other produces opaque colonies (VIR‐O). Bacteria isolated from patients' blood streams always belong to the VIR‐O subpopulation (Chin et al ., ). This is not only the subpopulation responsible for outbreak of disease, but also important for its endemic spread and for persistence of the bacteria.…”

“…This is not only the subpopulation responsible for outbreak of disease, but also important for its endemic spread and for persistence of the bacteria. The VIR‐O subpopulation has a thick capsule and is much more resistant against desiccation, host antimicrobials and disinfectants, whereas the AV‐T form might be advantageous in environments outside the host due to higher biofilm formation and better growth in nutrient poor medium (Chin et al ., ). This phenotypic switch links virulence and environmental persistence.…”

“…This phenotypic switch links virulence and environmental persistence. Interestingly, besides depending on a transcriptional master regulator, switching also involves the OmpR‐EnvZ two‐component system, which is furthermore involved in osmotic stress response of A. baumannii (see below) (Tipton and Rather, ; Chin et al ., ).…”

Spontaneous mutations in a regulatory gene induce phenotypic heterogeneity and adaptation of Ralstonia solanacearum to changing environments

“…The molecular mechanisms that lead to phenotypic heterogeneity in bacteria are very diverse and include phase variation, gene expression noise, post-transcriptional modification or epigenetic mechanisms (Hallet, 2001;Acar et al, 2008;Veening et al, 2008;Fraser and Kaern, 2009;Casadesús and Low, 2013). Phenotypic heterogeneity has been widely reported for bacterial pathogens with the description of co-existing virulent and avirulent (or less virulent) subpopulations (Diard et al, 2013;Mouammine et al, 2017;Ronin et al, 2017;Chin et al, 2018).…”

The UDP‐GalNAcA biosynthesis genes gna‐gne2 are required to maintain cell envelope integrity and in vivo fitness in multi‐drug resistant Acinetobacter baumannii

“…Until recently, just a subset of virulence factors had been identified, including capsule, lipooligosaccharide, metal acquisition systems (iron and zinc), secretion systems (Type I, II and VI), the phenotypic switch and a lytic transglycosylase (Wong et al, 2017;Chin et al, 2018;Crépin et al, 2018;Harding et al, 2018;Waack et al, 2018;Runci et al, 2019). However, the regulation of these factors and their specific roles in the pathobiology of A. baumannii infections are yet to be elucidated.…”