Cell differentiation defines acute and chronic infection cell types in Staphylococcus aureus

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.

Stochastic Expression of Sae-Dependent Virulence Genes during Staphylococcus aureus Biofilm Development Is Dependent on SaeS

“…This secreted enzyme was shown to mediate the degradation of the extracellular DNA (eDNA) matrix of biofilm, resulting in the detachment of cells during the early stages of biofilm development and allowing microcolony formation. In contrast to the previous dogma, which was based on the presumption that all S. aureus cells within a population are similar with respect to virulence gene expression, our current results support a growing awareness that expression of some virulence genes is limited to a subpopulation of cells under (33,34). We also demonstrated that the stochastic expression of these genes is likely to be mediated by the well-known SaePQRS regulatory system.…”

Chronic Staphylococcus aureus lung infection correlates with proteogenomic and metabolic adaptations leading to an increased intracellular persistence

“…These abilities are likely to contribute to the persistence of S. aureus in airways of patients with chronic lung diseases despite appropriate antimicrobial treatments [18, 19]. S. aureus persistence is associated with a drastic decrease in metabolism [20], a decrease in the expression of virulence factors and an increase in the expression of bacterial adhesins [21]. Such profile is typical of small-colony variants (SCVs) that are defined by small-sized colonies [15, 22, 23].…”

“…S. aureus persistence is linked to a drastic decrease in metabolism (such as a reduction in the Krebs cycle activity) [27] and is generally associated with a decrease in the expression of virulence factors and an increase in the expression of bacterial adhesins [28]. Such profile is typical of small-colony variants (SCVs) that are defined by their slow growth rate resulting in small-sized colonies [22, 29, 30].…”

“…Such profile is typical of small-colony variants (SCVs) that are defined by their slow growth rate resulting in small-sized colonies [22, 29, 30]. Beside SCVs, strains with normal colony morphology can exhibit similar patterns of “low toxicity” which allow them to persist intracellularly without being cleared by host cell defense mechanisms [28]. A “low toxicity” pattern can be achieved either transiently, by changes in the expression of genes encoding toxins and/or regulators, or permanently, by mutations in global regulators [31-33].…”

Dynamical Task Switching in Cellular Computers

“…Clusters essentially act like plasmid reservoirs and generate non-linear dynamics around overall plasmid copy number, which favours robustness. In addition, these clusters add a different viewpoint to the analysis of bacterial differentiation within a population [26] - often a knowledge gap - which is advantageous to us.…”