Impact of Streptococcus parasanguinis-Generated Reactive Nitrogen Species on Pseudomonas aeruginosa Virulence and the Host Response

Abstract

Streptococcus parasanguinis is an oral commensal bacterium that produces hydrogen peroxide. Hydrogen peroxide can react with endogenous molecules such as nitrite to form reactive nitrogen intermediates (RNI). These S. parasanguinis-mediated RNI have been shown to inhibit oral pathogens such as Streptococcus mutans, Enterococcus faecalis, and Aggregatibacter actinomycetemcomitans. As such, S. parasanguinis plays a protective role in the oral microbial ecosystem by antagonizing and preventing colonization by oral pathogens.

In addition to being an important organism for the health of the oral cavity, S. parasanguinis has also been associated with improved outcomes for people with cystic fibrosis. There are two explanations for S. parasanguinis-mediated protection of the airway addressed within this work: 1) S. parasanguinis antagonizes CF pathogens in an RNI-dependent manner and 2) S. parasanguinis modulates the host inflammatory response to reduce damage and subsequent lung deterioration.  

In the first part of this work, we demonstrate that nitric oxide reductase in P. aeruginosa is critical for both CF and non CF isolates to withstand S. parasanguinisgenerated RNI. We also found that CF isolates of P. aeruginosa are particularly sensitive to nitrosative stress. In the second part of this work, we demonstrate that S. parasanguinis attenuates the host inflammatory response to P. aeruginosa and modulates nitrite flux in an airway epithelial model. In the third part of this work, we demonstrate that S. parasanguinis biofilm physiology is modulated by its pyruvate oxidase, the enzyme responsible for its hydrogen peroxide production, and by nitrite.

Taken together, these studies revealed important mechanisms that define the relationship between S. parasanguinis and P. aeruginosa: that nitric oxide reductase is critical for the P. aeruginosa nitrosative stress response, that S. parasanguinis can modulate the host immune response to P. aeruginosa, and that nitrite modulates S. parasanguinis physiology and behavior.