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 environmental cycle. In mammals, a central pacemaker in the suprachiasmatic nucleus of the hypothalamus coordinates timing between peripheral clocks and with the environment and, for example, modulates immune responses to infections. However, its role in controlling bacterial infections at a cellular level is not understood. Here, we investigate the role of the host cellular clock during infection by a highly drug-resistant human pathogen, Staphylococcus aureus. Our findings revealed that S. aureus invasion into epithelial cells was dependent on the host circadian phase. Interestingly, cells deficient in BMAL1, a transcriptional activator and an essential clock protein, demonstrated increased bacterial uptake compared to parental A549 cells. The BMAL1-knockdown (KD) cells showed significant induction of GP340, a receptor of the S. aureus adhesin, SraP. An S. aureus sraP mutant did not exhibit rhythmic uptake into A549 cells or an increased uptake into BMAL1-KD compared to parental A549 cells. Of note, other bacterial adhesin mutants showed rhythmic and higher uptake in BMAL1-KD cells. Hence, we report that S. aureus epithelial cell invasion is clock-modulated and mediated through the S. aureus SraP-GP340 pathway, suggesting potential for host clock-directed therapy against this pathogen.