Heme regulation of glucose metabolism in bloodstream infections

Abstract

Bloodstream infections are associated with hemolysis. Once released from red blood cells, extracellular hemoglobin auto-oxidizes and loses its prosthetic heme groups, generating labile heme. As it accumulates in plasma, labile heme is loosely bound to plasma acceptor proteins, macromolecules or low molecular weight ligands that fail to control its redox activity, which presumably explains its pathologic effects. We found that the pro-oxidant effect of labile heme suppresses de novo liver glucose production, inducing severe hypoglycemia and ultimately compromising host survival to bloodstream infections. This is countered via a complex host defense mechanism that converges at the induction of the heme catabolizing enzyme heme oxygenase-1 and the iron sequestering protein complex ferritin. The ferroxidase activity of ferritin H chain sustains de novo liver glucose production, via an anti-oxidant mechanism that promotes the transcription of gluconeogenic genes. These include glucose 6 phosphatase 1, the last rate-limiting step in the gluconeogenesis pathway, which we found to be required to confer host protection against bloodstream infections.