The Small Non-coding RNA IsrR Regulates TCA Cycle Activity and Virulence

has evolved mechanisms to cope with low iron (Fe) availability in host tissues. uses the ferric uptake transcriptional regulator (Fur) to sense titers of cytosolic Fe. Upon Fe depletion, apo-Fur relieves transcriptional repression of genes utilized for Fe uptake. We demonstrate that an Δ mutant has decreased expression of , which codes for the Fe-dependent enzyme aconitase. Decreased expression prevented the Δ mutant from growing with amino acids as sole carbon and energy sources. Suppressor analysis determined that a mutation in , which produces a regulatory RNA, permitted growth by decreasing transcription. The decreased AcnA activity of the Δ mutant was partially relieved by an Δ mutation. Directed mutation of bases predicted to facilitate the interaction between the transcript and IsrR, decreased the ability of IsrR to control expression and IsrR bound to the transcript . IsrR also bound to the transcripts coding the alternate TCA cycle proteins , , , and . Whole cell metal analyses suggest that IsrR promotes Fe uptake and increases intracellular Fe not ligated by macromolecules. Lastly, we determined that Fur and IsrR promote infection using murine skin and acute pneumonia models.