Abstract
A central question to biology is how pathogenic bacteria initiate acute or chronic infections. Here we describe a genetic program for cell-fate decision in the opportunistic human pathogen Staphylococcus aureus, which generates the phenotypic bifurcation of the cells into two genetically identical but different cell types during the course of an infection. Whereas one cell type promotes the formation of biofilms that contribute to chronic infections, the second type is planktonic and produces the toxins that contribute to acute bacteremia. We identified a bimodal switch in the agr quorum sensing system that antagonistically regulates the differentiation of these two physiologically distinct cell types. We found that extracellular signals affect the behavior of the agr bimodal switch and modify the size of the specialized subpopulations in specific colonization niches. For instance, magnesium-enriched colonization niches causes magnesium binding to S. aureusteichoic acids and increases bacterial cell wall rigidity. This signal triggers a genetic program that ultimately downregulates the agr bimodal switch. Colonization niches with different magnesium concentrations influence the bimodal system activity, which defines a distinct ratio between these subpopulations; this in turn leads to distinct infection outcomes in vitro and in an in vivo murine infection model. Cell differentiation generates physiological heterogeneity in clonal bacterial infections and helps to determine the distinct infection types.
Highlights
Nosocomial pathogens often cause a broad range of diseases using diverse virulence factors, such as production of tissue-damaging toxins or production of adhesins during biofilm formation (Bush et al, 2011)
We found that colonization niches with higher Mg2+ concentrations, which is inherent in tissues colonized preferentially by S. aureus (Gunther, 2011; Jahnen-Dechent and Ketteler, 2012), influenced the bimodal switch and increased the size of the subpopulation of cells specialized in biofilm formation, as Mg2+ binding to teichoic acids increases cell wall rigidity and triggered a sB stress-induced genetic cascade that downregulates agr
Staphylococcus aureus multicellular aggregates differentiate cell types We explored the role of agr-mediated antagonistic regulation of planktonic and biofilm-associated lifestyles in S. aureus aggregates growing on Mg2+-enriched TSB medium (TSBMg), in which most S
Summary
Nosocomial pathogens often cause a broad range of diseases using diverse virulence factors, such as production of tissue-damaging toxins or production of adhesins during biofilm formation (Bush et al, 2011). Staphylococcus aureus is one such pathogen that is able to cause different types of life-threatening infections in hospital settings, from acute bacteremia to endocarditis, pneumonia and chronic biofilm-associated infections in prosthetic devices (Otto, 2012). The underlying cellular processes that enable S. aureus to provoke these disparate types of infections is likely driven by host-microbe interactions (Casadevall et al, 2011), in which specific, yet-to-be-described extracellular signals play a role to generate distinct, locally defined types of infections (Veening et al, 2008; Lopez and Kolter, 2010). Determining the cellular processes and the nature of the extracellular
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