The MgaSpn global transcriptional regulator mediates the biosynthesis of capsular polysaccharides and affects virulence via the uracil synthesis pathway in Streptococcus pneumoniae

Uracil metabolism is an important step in the growth and metabolism of Streptococcus pneumoniae, and pyrimidine nucleotides play an important role in the expression and production of S. pneumoniae capsules. MgaSpn(spd_1587),as a transcriptional ragulator of host environment adaptation, regulates the biosynthesis of the capsules and phosphorylcholine. However, the underlying regulation mechanism between uracil metabolism and biosynthesis of capsules remains incompletely understood. Here, we first described the relationship between uracil metabolism and capsule expression via the pyrR gene(spd_1134) in S. pneumoniae. Electrophoretic mobility-shift assays (EMSAs) and DNase I footprinting assays showed a direct interaction between MgaSpn and the pyrR promoter (P_pyrR) at two specific binding sites. MgaSpn negatively regulated capsule production through pyrR as confirmed by complementing pyrR expression in D39ΔmgaSpnΔpyrR (mgaSpn and pyrR double-defective strain). Virulence experiments showed that the MgaSpn-pyrR interaction was necessary for both pneumococcal colonization and invasive infection. For the first time, the present study demonstrated that the de novo synthesis gene pyrR of S. pneumoniae is regulated by the MgaSpn transcriptional regulator.Taken together,these results provide an insight into the regulation of capsule production mediated by uracil metabolism and its important roles in pneumococcal pathogenesis.