Staphylococcus aureus Infection Reduces Nutrition Uptake and Nucleotide Biosynthesis in a Human Airway Epithelial Cell Line

Abstract

Abstract:The Gram positive opportunistic human pathogen Staphylococcus aureus induces a variety of diseases including pneumonia. S. aureus is the second most isolated pathogen in cystic fibrosis patients and accounts for a large proportion of nosocomial pneumonia. Inside the lung, the human airway epithelium is the first line in defence with regard to microbial recognition and clearance as well as regulation of the immune response. The metabolic host response is, however, yet unknown. To address the question of whether the infection alters the metabolome and metabolic activity of airway epithelial cells, we used a metabolomics approach. The nutrition uptake by the human airway epithelial cell line A549 was monitored over time by proton magnetic resonance spectroscopy ( 1 H-NMR) and the intracellular metabolic fingerprints were investigated by gas chromatography and high performance liquid chromatography (GC-MS) and (HPLC-MS). To test the metabolic activity of the host cells, glutamine analogues and labelled precursors were applied after the infection. We found that A549 cells restrict uptake of essential nutrients from the medium after S. aureus infection. Moreover, the infection led to a shutdown of the purine and pyrimidine synthesis in the A549 host cell, whereas other metabolic routes such as the hexosamine biosynthesis pathway remained active. In summary, our data show that the infection with S. aureus negatively affects growth, alters the metabolic composition and specifically impacts the de novo nucleotide biosynthesis in this human airway epithelial cell model.

Intracellular Staphylococcus aureus Modulates Host Central Carbon Metabolism To Activate Autophagy

“…In addition, we also observed activation of both AMPK and ERK signaling pathways in HeLa cells after MRSA infection. In accordance with these findings, a recent study has shown that the levels of ATP in human alveolar epithelial cells were significantly decreased during early time points of S. aureus infection ( 74 ), further pointing to a starvation-induced response. Crucially, once we inhibited the host AMPK pathway using dorsomorphin, intracellular MRSA survival was significantly hampered and autophagy levels were decreased, supporting our hypothesis that the activation of autophagy is caused by the state of starvation induced by the intracellular pathogen, and this autophagy benefits the intracellular survival of MRSA.…”

Evolution of ARDS biomarkers: Will metabolomics be the answer?

“…However, some of the cellular responses that occur in ARDS can be inferred from studying cultured human cell models. For example, the effect of bacterial infection on the metabolome of A549 cultured human airway epithelial cells (mimics an infection-related direct lung injury) demonstrated an increase in extracellular secretion of glutamate and pyruvate (28). The study also revealed that concentrations of glycine, aspartate, and alanine were increased in the extracellular space suggesting a reduction in the cellular usage of these amino acids with consequent intracellular overflow and secretion (28).…”

Host-Targeted Therapeutics against Multidrug Resistant Intracellular Staphylococcus aureus

“…Moreover, host cholesterol import is required by intracellular Mycobacterium tuberculosis to persist inside both macrophages and mice lungs [88]. On the other hand, a reduction in nutrient uptake as well as nucleotide biosynthesis has been recently observed in human airway epithelial cells infected with S. aureus [89].…”