How does a bacterium make sense of the world?

Bacteria use a variety of sensing mechanisms to respond adaptively to changes in their environment. One important cue could be how many cells of their own species are present (a mechanism called ‘quorum sensing’). However, scientists disagree on whether bacteria really are able to assess their own population density and whether they care about this information or base their decisions on other factors. University of Groningen biologists combined experiments and a mathematical model to show just what counts for a bacterium. The results were published in Nature Communications on 11 October.

The bacterium Streptococcus pneumoniae (the pneumococcus) can frequently be found in the in the human body, the nasopharynx in particular, and is usually harmless. However, under certain conditions, it may become virulent and cause a dangerous infection like pneumonia. One of the factors that turns this harmless guest into a dangerous infectious agent is a small protein called Competence Stimulating Peptide (CSP). Under certain conditions, bacterial cells start making CSP, which stimulates the production of more CSP in neighbouring cells.

This chain reaction induces a state called competence, which increases the bacteria’s ability to take up DNA from their environment. ‘Competence therefore simulates the spread of genes, such as those for antibiotic resistance. But CSP also induces the production of toxins which will kill cells from other bacterial species’, says University of Groningen evolutionary biologist Sander van Doorn. He is senior author of the paper together with Jan-Willem Veening, who now works at the University of Lausanne, Switzerland.

The process leading to competence had, until recently, been interpreted as a representative example of a quorum-sensing mechanism; in other words, as a way for bacteria to sense how many cells of their own species are present. But recently, some microbiologists have suggested that competence isn’t simply induced by counting other cells, but that it functions as a probe which gives the bacteria information about their environment, such as the diffusion speed, the presence of antibiotics or the acidity of the environment.

The teams of Van Doorn and Veening joined forces and used experiments and theoretical modelling to end the confusion in the field. ‘We performed experiments in which we varied the number of cells, the antibiotic concentration or the acidity of the growth medium. We then used the results to create a mathematical model’, explains Van Doorn.

Increasing cell density did stimulate competence, but varying the antibiotic concentration or acidity meant the threshold density for competence induction could be raised or lowered, ‘even to the point where single cells became competent.’ The model also showed that competence development depends on the cell history in a bistable manner. The acidity of the medium in which cells are grown affects the amount of CSP needed to make the cells competent. Cells grown under acidic conditions need a lot of CSP (i.e. a high number of cells) to become competent, whereas cells grown under alkaline conditions become competent at much lower CSP concentrations. Van Doorn: ‘This prediction of the model was confirmed by subsequent experiments.’

The model increases our understanding of quorum sensing, says Van Doorn. ‘If you only look at results of experiments, you may miss some important interactions.’ The model makes them visible and thus advances our understanding of how quorum sensing works. ‘Furthermore, we are confident that the results we got from specific molecular interactions are valid for other forms of quorum sensing as well.’ It therefore follows that bacteria can make their decisions by counting cells, but that the critical quorum needed to trigger a response depends on other environmental cues.

This could lead to new ways to fight bacteria. ‘Competence development is a virulence factor in S. pneumoniae, so blocking this in some way could stop infections. This could also be an effective way to reduce the spread of antibiotic resistance.’ But to Van Doorn and his colleagues the most satisfying result is a better idea of how quorum sensing works. ‘The debate has been a bit chaotic recently, and we have now been able to clear up some of the confusion.’

Reference
Stefany Moreno-Gámez, Robin A. Sorg, Arnau Domenech, Morten Kjos, Franz J. Weissing, G. Sander van Doorn & Jan-Willem Veening: Quorum sensing integrates environmental cues, cell density and cell history to control bacterial competence. Nature Communications 11 October 2017