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Abstract
Rggs are a group of transcriptional regulators with diverse roles in metabolism and virulence. Here, we present work on the Rgg1518/SHP1518 quorum sensing system of Streptococcus pneumoniae. The activity of Rgg1518 is induced by its cognate peptide, SHP1518. In vitro analysis showed that the Rgg1518 system is active in conditions rich in galactose and mannose, key nutrients during nasopharyngeal colonization. Rgg1518 expression is highly induced in the presence of these sugars and its isogenic mutant is attenuated in growth on galactose and mannose. When compared with other Rgg systems, Rgg1518 has the largest regulon on galactose. On galactose it controls up- or downregulation of a functionally diverse set of genes involved in galactose metabolism, capsule biosynthesis, iron metabolism, protein translation, as well as other metabolic functions, acting mainly as a repressor of gene expression. Rgg1518 is a repressor of capsule biosynthesis, and binds directly to the capsule regulatory region. Comparison with other Rggs revealed inter-regulatory interactions among Rggs. Finally, the rgg1518 mutant is attenuated in colonization and virulence in a mouse model of colonization and pneumonia. We conclude that Rgg1518 is a virulence determinant that contributes to a regulatory network composed of multiple Rgg systems.
Highlights
Streptococcus pneumoniae causes a diverse array of infections
A significant promoter induction was detected on galactose (969 ± 6 MU, n = 3), and mannose (503 ± 13 MU, n = 3; p < .001 and p < .01, for galactose and mannose) compared to no sugar control. These results show that the rgg1518 promoter is inducible by galactose and mannose (Figure 2)
Under these conditions 80 were downregulated and 298 were upregulated in the mutant (Supporting information Table S1). This suggests that Rgg1518/SHP1518 acts mainly as a repressor, at least in the condition tested (CDM-galactose, mid-log phase). These genes are organized into 61 operons with an annotated role in the synthesis of capsule, fatty acid, hypothetical proteins, sugar and metal transporters, proteins involved in galactose metabolism as well as several transcriptional regulators
Summary
Streptococcus pneumoniae (pneumococcus) causes a diverse array of infections. It can exist as an asymptomatic colonizer of the upper respiratory tract or can spread to middle ear, lower respiratory tract, blood, and central nervous system, causing diseases such as otitis media, pneumonia, septicemia, and meningitis, respectively (Weiser et al, 2018). This suggests that Rgg1518/SHP1518 acts mainly as a repressor, at least in the condition tested (CDM-galactose, mid-log phase) These genes are organized into 61 operons with an annotated role in the synthesis of capsule, fatty acid, hypothetical proteins, sugar and metal transporters, proteins involved in galactose metabolism as well as several transcriptional regulators. In the production of glucuronic acid among the wild type, ∆rgg1518 and ∆rgg1518c (60 ± 6, 59 ± 6, and 60 ± 7 μg/109 CFU, n = 6, respectively; p > .05; Figure 5b) These results show that Rgg1518 is a repressor of capsule synthesis on galactose. There was no significant difference in the counts of the complemented strain, ∆rgg1518c, and the wild type (p < .001) at 3 (Log10 2.83 ± 0.07 CFU/mg, n = 5) and 7 days (Log10 2.85 ± 0.087 CFU/mg n = 5) post-infection (p > .05) These results clearly prove the involvement of Rgg1518 in pneumococcal colonization of the murine nasopharynx. These finding demonstrate that Rgg1518 promotes colonization and pathogenesis of the pneumococcus
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