Fluorescent Staphylococcus aureus (magenta) is taken up into sphingomyelin-containing vesicles (yellow). The cells’ nuclei are stained in blue. Image credit: Rühling et al. (CC BY 4.0)
Staphylococcus aureus bacteria cause several – often serious – conditions, including skin and soft-tissue infections. Some strains are also resistant to multiple antibiotics and are better known as MRSA, or ‘methicillin-resistant S. aureus’.
One important aspect of chronic staph infections is the bacteria’s ability to hide from the immune system inside host cells. To enter cells, Staphylococcus can bind to many proteins on the cell surface that act as entry receptors, triggering the host cell to engulf the bacteria in membrane-bound compartments called vesicles. Because the bacteria can use a variety of receptors, they can enter cells through several different pathways. Until now, however, it was unclear whether the route they take into a cell affects what happens to them afterwards.
To find out, Rühling et al. investigated whether the pathway bacteria use to enter host cells determines their fate inside them. The researchers focused on a previously unknown pathway that depends on sphingomyelin, a lipid that is abundant in mammalian cell membranes. They infected endothelial cells, a cell type that lines blood vessels, with S. aureus and used cell-based assays and microscopy to track bacterial entry, survival and growth.
Rühling et al. found that the sphingomyelin-dependent pathway activates within minutes of bacterial contact. It begins with the release of calcium ions from lysosomes – cell compartments involved in breaking down and recycling cellular material. This triggers lysosomes to fuse with the cell surface and release their contents, including the enzyme acid sphingomyelinase. The enzyme breaks down sphingomyelin in the cell membrane, helping the bacteria to be taken up rapidly by the host cell.
Compared with the ‘slow’ bacterial internalisation pathways that operate at the same time, bacteria entering through the rapid sphingomyelin-dependent pathway remained inside their enclosing vesicles for longer before escaping. In contrast, bacteria entering through slower pathways escaped from their vesicles earlier.
This difference had important consequences for the infection. Bacteria that escaped their vesicles later gained access to nutrients in the host cell at a later stage, delaying their replication and the subsequent death of the host cell. In contrast, bacteria that escaped earlier could begin replicating sooner, leading to earlier host-cell death. Together, the findings show that how S. aureus enters a cell can influence what happens to the bacteria afterwards – effectively determining the timing of key stages of infection.
Understanding how these bacteria invade host cells and behave once inside may eventually help researchers develop new ways to tackle chronic S. aureus infections. The findings are particularly interesting because several approved drugs inhibit acid sphingomyelinase. These drugs could potentially be repurposed to alter how bacteria enter cells and make them easier to clear. However, more research is needed to determine whether blocking this pathway actually reduces infection severity in living organisms. The many alternative routes that S. aureus can use to enter cells may make this challenging.
