Norepinephrine derepresses the Fur regulon of <i>Neisseria gonorrhoeae</i> to enable growth in iron-limited conditions

<i>Neisseria gonorrhoeae</i> (Gc) is the gram-negative bacterium that causes gonorrhea, a prevalent sexually transmitted infection that can have life-threatening clinical sequelae. Gc requires iron for human infection and uses the iron-responsive, iron-binding transcriptional repressor Fur to maintain iron homeostasis. Gc infects mucosal sites, where the neuroendocrine hormone norepinephrine (NE) is produced by the autonomic nervous system and various epithelial and immune cell types. Here, we show that NE derepresses the Fur regulon to alter bacterial iron homeostasis and increase Gc survival. By RNA-seq, we determined that NE rewires gonococcal gene expression to increase capacity for iron uptake while enabling increased intracellular iron availability. Of the 30 genes that were differentially expressed in NE-treated compared to untreated bacteria, 27 have Fur box-containing promoters. A possible mechanism for how NE derepresses the Fur regulon is through direct demetalation of Fur, as NE directly decreased binding of Fur <i>in vitro</i> to a DNA amplicon containing the Fur-binding sequence from Gc <i>tbpB</i>. NE increased the labile intracellular iron pool in Gc, evidenced by increased streptonigrin sensitivity, without significantly increasing the total bacterial iron content, suggesting that NE leads to the redistribution of cellular iron. The work presented here provides a novel mechanism for how Gc survives iron limitation within its obligate human host.IMPORTANCE<i>Neisseria gonorrhoeae</i> (Gc) is the bacterial pathogen that causes gonorrhea, a sexually transmitted infection with an estimated global annual incidence of 87 million individuals. During infection, Gc must overcome iron limitation imposed by nutritional immunity. Here, we show that the host neuroendocrine hormone norepinephrine, which is present at the mucosal surfaces Gc infects, promotes the survival of iron-limited Gc. Our results support a novel mechanism by which norepinephrine works through the ferric uptake regulator, Fur, to enhance the capacity of Gc to take up iron and make it bioavailable. Our findings show that Gc responds to host-derived cues that enable it to resist iron limitation.