The importance of Mn for pneumococcal physiology and virulence has been studied extensively. However, the specific cellular role(s) for which Mn is required are yet to be fully elucidated. Here, we analyzed the effect of Mn 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 Mn transporter, pneumococcal surface antigen A (PsaA), with its isogenic wild-type counterpart. We provide clear evidence for the Mn-dependent regulation of the expression of oxidative-stress-response enzymes SpxB and Mn-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 Mn stress. A significant increase in 6-phosphogluconate dehydrogenase activity in the psaA mutant grown under Mn-replete conditions and upregulation of an oligopeptide ABC permease (AppDCBA) were also observed. Together, the results of transcriptomic and proteomic analyses provided evidence for Mn having a central role in activating or stimulating enzymes involved in central carbon and general metabolism. Our results also highlight the importance of high-affinity Mn transport by PsaA in pneumococcal competence, physiology, and metabolism and elucidate mechanisms underlying the response to Mn stress. Copyright
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