ABSTRACTStaphylococcus aureusis a facultative intracellular pathogen that invades and replicates within many types of phagocytic and nonphagocytic cells. During intracellular infection,S. aureusis capable of subverting xenophagy and escaping to the cytosol of the host cell. Furthermore, drug-induced autophagy facilitates the intracellular replication ofS. aureus, but the reasons behind this are unclear. Here, we have studied the host central carbon metabolism duringS. aureusintracellular infection. We found extensive metabolic rerouting and detected several distinct metabolic changes that suggested starvation-induced autophagic flux in infected cells. These changes included increased uptake but lower intracellular levels of glucose and low abundance of several essential amino acids, as well as markedly upregulated glutaminolysis. Furthermore, we show that AMP-activated protein kinase (AMPK) and extracellular signal-regulated kinase (ERK) phosphorylation levels are significantly increased in infected cells. Interestingly, while autophagy was activated in response toS. aureusinvasion, most of the autophagosomes detected in infected cells did not contain bacteria, suggesting thatS. aureusinduces the autophagic flux during cell invasion for energy generation and nutrient scavenging. Accordingly, AMPK inhibition haltedS. aureusintracellular proliferation.IMPORTANCEStaphylococcus aureusescapes from immune recognition by invading a wide range of human cells. Once the pathogen becomes intracellular, the most important last resort antibiotics are not effective. Therefore, novel anti-infective therapies against intracellularS. aureusare urgently needed. Here, we have studied the physiological changes induced in the host cells byS. aureusduring its intracellular proliferation. This is important, because the pathogen exploits the host cell’s metabolism for its own proliferation. We find thatS. aureusseverely depletes glucose and amino acid pools, which leads to increased breakdown of glutamine by the host cell in an attempt to meet its own metabolic needs. All of these metabolic changes activate autophagy in the host cell for nutrient scavenging and energy generation. The metabolic activation of autophagy could be used by the pathogen to sustain its own intracellular survival, making it an attractive target for novel anti-infectives.
Copper stress in Staphylococcus aureus leads to adaptive changes in central carbon metabolism
