The Yin and Yang of Streptococcus Lung Infections in Cystic Fibrosis: a Model for Studying Polymicrobial Interactions

Abstract

The streptococci are increasingly recognized as a core component of the cystic fibrosis (CF) lung microbiome, yet the role that they play in CF lung disease is unclear. The presence of the Streptococcus milleri group (SMG; also known as the anginosus group streptococci [AGS]) correlates with exacerbation when these microbes are the predominant species in the lung. In contrast, microbiome studies have indicated that an increased relative abundance of streptococci in the lung, including members of the oral microflora, correlates with impacts on lung disease less severe than those caused by other CF-associated microflora, indicating a complex role for this genus in the context of CF. Recent findings suggest that streptococci in the CF lung microenvironment may influence the growth and/or virulence of other CF pathogens, as evidenced by increased virulence factor production by Pseudomonas aeruginosa when grown in coculture with oral streptococci. Conversely, the presence of P. aeruginosa can enhance the growth of streptococci, including members of the SMG, a phenomenon that could be exacerbated by the fact that streptococci are not susceptible to some of the frontline antibiotics used to treat P. aeruginosa infections. Collectively, these studies indicate the necessity for further investigation into the role of streptococci in the CF airway to determine how these microbes, alone or via interactions with other CF-associated pathogens, might influence CF lung disease, for better or for worse. We also propose that the interactions of streptococci with other CF pathogens is an ideal model to study clinically relevant microbial interactions.

Keywords: Streptococcus; Streptococcus milleri group; cystic fibrosis; exacerbation; polymicrobial.

FIG 1

Streptococci can influence cystic fibrosis airway disease. In CF airways, an increased prevalence of Streptococcus spp. has been correlated with clinical stability, lower inflammation, and/or less severe outcomes (2, 9, 12, 21, 29), but it is unclear whether this is due to direct interactions with the airway epithelium, is due to interactions between the streptococci and the microbiome that lead to increased microbial diversity, or is a consequence of less damage to the airway. Oral streptococci have been demonstrated to inhibit P. aeruginosa growth through the production of hydrogen peroxide and reactive nitrogenous intermediates (49–51); by inhibiting P. aeruginosa, streptococci could open up niches for increased microbial diversity in the lung, which could aid clinical stability. In contrast, the predominance of SMG isolates has been correlated with exacerbation (1, 7, 17, 30), and this may be due to interactions between the SMG isolates and other CF pathogens, such as P. aeruginosa. Oral streptococci have been demonstrated to stimulate increased virulence factor production by P. aeruginosa (43–45) through AI-2 signaling (43), and this could lead to dysbiosis in the lung and eventual exacerbation. The arrows indicate both direct and indirect interactions that are suggested to occur in the CF airways. The blue arrows indicate generally positive effects, the red arrows indicate generally negative effects, and the arrows are labeled with the factors (if known) involved in these effects. (Copyright William Scavone, Kestrel Studio; reproduced with permission.)