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.

eLife digest

While in hospital, patients can be unwittingly exposed to bacteria that can cause disease. These hospital-associated bacteria can lead to potentially life-threatening infections that may also complicate the treatment of the patients’ existing medical conditions. Staphylococcus aureus is one such bacterium, and it can cause several types of infection including pneumonia, blood infections and long-term infections of prosthetic devices.

It is thought that S. aureus is able to cause so many different types of infection because it is capable of colonizing distinct tissues and organs in various parts of the body. Understanding the biological processes that drive the different infections is crucial to improving how these infections are treated.

S. aureus lives either as an independent, free-swimming cell or as part of a community known as a biofilm. These different lifestyles dictate the type of infection the bacterium can cause, with free-swimming cells producing toxins that contribute to intense, usually short-lived, infections and biofilms promoting longer-term infections that are difficult to eradicate. However, it is not clear how a population of S. aureus cells chooses to adopt a particular lifestyle and whether there are any environmental signals that influence this decision.

Here, Garcia-Betancur et al. found that S. aureus populations contain small groups of cells that have already specialized into a particular lifestyle. These groups of cells collectively influence the choice made by other cells in the population. While both lifestyles will be represented in the population, environmental factors influence the numbers of cells that initially adopt each type of lifestyle, which ultimately affects the choice made by the rest of the population. For example, if the bacteria colonize a tissue or organ that contains high levels of magnesium ions, the population is more likely to form biofilms.

In the future, the findings of Garcia-Betancur et al. may help us to predict how an infection may develop in a particular patient, which may help to diagnose the infection more quickly and allow it to be treated more effectively.