The Staphylococcus aureus two component system, SaeR/S, modulates monocyte production of TNF-alpha to influence neutrophil functions
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Date
2018
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Montana State University - Bozeman, College of Letters & Science
Abstract
Staphylococcus aureus (S. aureus) is a commensal organism that colonizes the anterior nares of more than half the population. Although most individuals colonized with S. aureus remain asymptomatic, showing no signs of complications, colonization is associated with a predisposition to infection. S. aureus infections include skin- and softtissue infections as well as life-threatening infections, such as necrotizing fasciitis, necrotizing pneumonia, and sepsis. To date, it is not clearly understood how S. aureus transitions from a commensal organism to a deadly pathogen but evidence highlights that this capacity is largely dependent on two-component gene-regulatory systems that control expression of cytolytic and immunomodulatory virulence factors. The SaeR/S twocomponent system (SaeR/S TCS) of S. aureus is critical for the regulation of virulence factors that enables immune evasion and attenuates killing of S. aureus by human neutrophils. However, the precise SaeR/S-dependent mechanisms used by S. aureus to overcome and effective neutrophil response remains incompletely define. To advance our understanding, we studied SaeR/S-dependent immunomodulation of TNF-alpha. TNF-alpha is an important inflammatory mediator because it can recruit neutrophils to the site of infection and promote increased neutrophil killing of S. aureus. Using primary human cells, we demonstrated that the SaeR/S system reduced early monocyte production of TNF-alpha and showed that this modulation influenced the neutrophil priming and subsequent staphylocidal activity. These results demonstrated that S. aureus could reduce TNF-alpha early during infection to diminish neutrophil production of reactive oxygen species. As increased TNF-alpha is associated with morbidity and mortality during systemic infections, we propose that SaeR/S modulation of monocyte-derived TNF-alpha is important for reducing protective immune responses during localized infections. These data add to our understanding of how S. aureus disrupts early inflammatory responses to initiate infection.