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Eukaryotic nucleosomes have critical regulatory roles in mediating access to DNA. Differential regulation of nucleosome distribution is necessary for generating a rapid response to pathogens in the innate immune response and other stimuli. However, this genomic reorganization event is largely uncharacterized. Our lab has proposed that early, widespread, and transient reorganization of the genomic structure potentiates the appropriate responses of the cell to insult. We have identified chromatin structural changes in THP-1 human macrophage-like cell line induced by S. aureus stimulation. We measured nucleosome distribution high temporal resolution through the course of infection at more than 800 inflammation and immunity related genes. Herein we show that S. aureus indeed does induce rapid widespread changes in nucleosome distribution. This work supports a new model in which widespread changes potentiate a robust immune response.