Lag phase-associated iron accumulation is likely a microbial counter-strategy to host iron sequestration: Role of the ferric uptake regulator (fur)

Abstract

Iron is an essential metal for almost all forms of life, but potentiates oxidative stress via Fenton catalysis. During microbial lag phase there is a rapid influx of iron with concomitant oxidative hypersensitivity. How and why iron accumulation occurs remains to be elucidated. Iron homeostasis in prokaryotes is mediated by the ferric uptake regulator (Fur), an iron-activated global regulator that controls intracellular iron levels by feedback inhibition with the metal. Herein it is postulated, based on the expression profiles of antioxidant enzymes within the Fur regulon as observed in wild type and Δfur mutants, that iron accumulation is mediated by a transitively low concentration of the Fur protein during lag phase. Vertebrate hosts sequester iron upon ‘sensing’ an infection in order to retard microbial proliferation through a process known as ‘nutritional immunity’. It is herein argued that the purpose of iron accumulation is not principally a preparative step for the replicative phase, as suggested elsewhere, but an evolved behavior that counteracts host iron sequestration. This interpretation is supported by multiple clinical and animal studies that demonstrate that iron surplus in hosts advances progression and susceptibility to infection, and vice versa. Contextualizing iron accumulation as a counter-immune behavior adds impetus to the development of antibiotics targeting pathogenic modes of iron acquisition.