摘要：

21 The streptococci are increasingly recognized as a core component of the cystic fibrosis 22 (CF) lung microbiome, yet the role that they play in CF lung disease is unclear. The 23 presence of Streptococcus milleri group (SMG, also known as the anginosus group 24 streptococci, AGS) correlates with exacerbation when these microbes are the 25 predominant species in the lung. In contrast, microbiome studies have indicated that 26 increased relative abundance of streptococci in the lung, including members of the oral 27 microflora, correlates with less severe impacts on lung disease compared to other CF- 28 associated microflora, indicating a complex role for this genus in the context of CF. 29 Recent findings suggest that streptococci in the CF lung microenvironment may 30 influence the growth and/or virulence of other CF pathogens as evidenced by increased 31 virulence factor production by Pseudomonas aeruginosa when grown in coculture with 32 oral streptococci. Conversely, the presence of P. aeruginosa can enhance the growth of 33 streptococci, including members of the SMG, a phenomenon that could be exacerbated 34 by the fact that streptococci are not susceptible to some of the front-line antibiotics used 35 to treat P. aeruginosa . Collectively, these studies indicate the necessity for further 36 investigation into the role of streptococci in the CF airway to determine how these 37 microbes, alone or via interactions with other CF-associated pathogens, might influence 38 CF lung disease, for better or for worse. We also propose that studying the interactions 39 of streptococci with other CF pathogens is an ideal model to study clinically relevant 40 microbial interactions. vitro P. aeruginosa co-aggregate a of our indicate both the potential for these provide a oral their lung disease in monoculture in the rat lung. These results are further supported by additional studies that demonstrate increased elastase, phenazine, and rhamnolipid production by P. aeruginosa strains exposed to streptococci, including S. anginosus 205 (44, 45). Interestingly, two lasR mutant variants of P. aeruginosa from patients with CF 206 showed more robust pyocyanin and elastase production, and associated host damage and inflammation, when grown in coculture with several SMG isolates (44), indicating that coculture with another microbial species can (at least in part) bypass the quorum sensing (QS) defect of the lasR mutant strains. Analogous observations have been made for P. aeruginosa lasR mutants growing in coculture with the fungus Candida albicans (46), indicating that the loss of QS signaling observed for pure strains of P. aeruginosa isolated from the CF airway may not accurately reflect the situation in the context of an in vivo , polymicrobial infection. Furthermore, a recent study also demonstrated that S. anginosus can stimulate P. aeruginosa to convert from a mucoid phenotype to a non-mucoid, high-pyocyanin producing phenotype in an in vitro , hypercapnic (10% CO 2 ) environment; this phenotype is associated with reduced survival of Galleria mellonella , an insect model of pathogenesis, during infection (47, 48). Taken together, these data call into question the strengths of conclusions that can be drawn regarding virulence potential of strains in the CF airway based solely on in vitro clinical culture data assaying single species.

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