Abstract
Group B Streptococcus (GBS) is a β-hemolytic, Gram-positive bacterium that commonly colonizes the female lower genital tract and is associated with fetal injury, preterm birth, spontaneous abortion, and neonatal infections. A major factor promoting GBS virulence is the β-hemolysin/cytolysin, which is cytotoxic to several host cells. We recently showed that the ornithine rhamnolipid pigment, Granadaene, produced by the gene products of the cyl operon, is hemolytic. Here, we demonstrate that heterologous expression of the GBS cyl operon conferred hemolysis, pigmentation, and cytoxicity to Lactococcus lactis, a model non-hemolytic Gram-positive bacterium. Similarly, pigment purified from L. lactis is hemolytic, cytolytic, and identical in structure to Granadaene extracted from GBS, indicating the cyl operon is sufficient for Granadaene production in a heterologous host. Using a systematic survey of phyletic patterns and contextual associations of the cyl genes, we identify homologs of the cyl operon in physiologically diverse Gram-positive bacteria and propose undescribed functions of cyl gene products. Together, these findings bring greater understanding to the biosynthesis and evolutionary foundations of a key GBS virulence factor and suggest that such potentially toxic lipids may be encoded by other bacteria.
Highlights
For the first time, we show that heterologous expression of the Group B Streptococcus (GBS) cyl operon is sufficient to confer the production of functional Granadaene in Lactococcus lactis, a generally recognized as safe (GRAS) Grampositive bacterial strain (Cavanagh et al, 2015)
Given that GBS colonizes the human host with other commensal microbes, we wondered whether horizontal gene transfer of this operon would enable production of the hemolytic lipid pigment [ known as Granadaene (Rosa-Fraile et al, 2006)] to non-hemolytic bacteria
These results indicate that expression of the cyl operon is necessary and sufficient for hemolysis and pigmentation in GBS and even in L. lactis
Summary
Hemolytic activity is a key determinant of colonization and pathogenesis in Group B Streptococcus (GBS) (Nizet et al, 1996; Doran et al, 2002, 2003; Patras et al, 2013; Whidbey et al, 2013, 2015b; Boldenow et al, 2016), a Gram-positive bacterium that resides in the lower genital and/or gastrointestinal tract of approximately 18% of women and is a major cause of preterm birth and severe neonatal infections (Russell et al, 2017a,b; Seale et al, 2017a,b). Phyletic analysis revealed previously undescribed functional categories of cyl gene products, indicated that the cyl operon genes are present in a diverse range of Gram-positive bacteria, and suggested that pigment biosynthesis evolved in free-living bacteria, likely as a photoprotectant or as a defense mechanism against competing organisms. These findings provide biosynthetic and evolutionary insight into a critical GBS virulence factor
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