The cellular mammalian clock regulates Staphylococcus aureus invasion in epithelial cells

An endogenous biological clock, the circadian clock, coordinates life with the 24-hour day/night cycle of the environment. The unit of this circadian clock is the cell but in multicellular organisms, such as mammals, a circadian timing system (CTS) with a central pacemaker orchestrates peripheral clocks and the overall finely tuned temporal order. For example, the CTS changes immune responses to infections depending on time-of-day, however, its role in controlling bacterial infections at a cellular level is not understood.

In this study, we investigated the role of the host cellular clock during infection by Staphylococcus aureus, a highly drug-resistant, facultatively intracellular human pathogen. Our findings revealed that S. aureus invasion into epithelial cells is dependent on the cellular circadian phase. Interestingly, in BMAL1, an essential clock protein, deficient cells bacterial uptake was significantly higher compared to parental A549 cells. RNA sequencing of BMAL1 knockdown (KD) cells showed a significant upregulation of GP340 , coding for the receptor of SraP, an S. aureus adhesin. An S. aureus mutant lacking SraP did not exhibit a circadian rhythm of uptake into A549 cells nor an increased uptake into BMAL1 KD compared to the parental A549 cells. Of note, bacterial mutants for other adhesins continued to show a rhythmic and higher uptake in BMAL1 KD cells.

Hence, we report that S. aureus invasion of epithelial cells is clock-modulated and mediated through S. aureus SraP, suggesting potential for host clock-directed therapy against this pathogen.