Central Role of Manganese in Regulation of Stress Responses, Physiology, and Metabolism in Streptococcus pneumoniae†

The importance of Mn2 for pneumococcal physiology and virulence has been studied extensively. However, the specific cellular role(s) for which Mn2 is required are yet to be fully elucidated. Here, we analyzed the effect of Mn2 limitation on the transcriptome and proteome of Streptococcus pneumoniae D39. This was carried out by comparing a deletion mutant lacking the solute binding protein of the high-affinity Mn2 transporter, pneumococcal surface antigen A (PsaA), with its isogenic wild-type counterpart. We provide clear evidence for the Mn2-dependent regulation of the expression of oxidative-stress-response enzymes SpxB and Mn2-SodA and virulence-associated genes pcpA and prtA. We also demonstrate the upregulation of at least one oxidative-and nitrosative-stress-response gene cluster, comprising adhC, nmlR, and czcD, in response to Mn2 stress. A significant increase in 6-phosphogluconate dehydrogenase activity in the psaA mutant grown under Mn2-replete conditions and upregulation of an oligopeptide ABC permease (AppDCBA) were also observed. To-gether, the results of transcriptomic and proteomic analyses provided evidence for Mn2 having a central rol