CAD and Sepsis: We envision that during infection, changes in metabolism driven by oxygen and sugar availability, in turn, drive changes in the concentration(s) of the as-of-yet unknown SpxR ligand(s) to facilitate pneumococcal lung-to-blood transition and sepsis, possibly including quaternary changes, to ultimately allow RNA polymerase and/or other TFs access to the cps core promoter/regulatory region (Fig 7).