Effect of combined oxidative and nitrosative stresses on Staphylococcus aureus transcriptome

Staphylococcus aureus is a pathogen responsible for severe community- and nosocomially acquired infections. To fight pathogen intrusion, the innate immune system uses a plethora of weapons, with the generation of oxidative and nitrosative stresses among the most efficient. In this work, the S. aureus genome-wide transcriptional responses to oxidative stress generated by hydrogen peroxide, to nitrosative stress imposed by S-nitrosoglutathione (GSNO), and to the combination of the two were investigated using microarray analysis. The results showed that these stresses have a significant impact on the transcriptome of S. aureus. Hydrogen peroxide modified mainly the mRNA abundance of genes involved in oxidative detoxification and DNA metabolism, which together represent 14 % of the total number of upregulated genes. GSNO caused significant alteration of the expression of gene products with regulatory function. However, the simultaneous addition of GSNO and hydrogen peroxide was found to cause the more significant transcriptomic alteration, affecting similar to 10 % of the total transcriptome. In particular, exposure of S. aureus to GSNO plus hydrogen peroxide modified the transcription of genes associated with cell envelope and iron metabolism, including induction of ftnA and dps genes that encode iron-storage and oxidative-protecting proteins. Further studies revealed that when exposed to combined GSNO-hydrogen peroxide stresses, S. aureus has decreased viability, which is enhanced in the presence of iron, and low siderophore activity. Altogether, this study revealed, for the first time, how the combined oxidative and nitrosative stresses inflicted during phagocytosis interfere at the transcriptional level with the S. aureus cellular metabolism.