Munneke, M. J. | bioRxiv Science

bioRxiv2024

The Staphylococcus aureus small non-coding RNA IsrR regulates TCA cycle activity and virulence

Staphylococcus aureus has evolved mechanisms to cope with low iron (Fe) availability in host tissues. S. aureus 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 S. aureus {Delta}fur mutant has decreased expression of acnA, which codes for the Fe-dependent enzyme aconitase. Decreased acnA expression prevented the {Delta}fur mutant from growing with amino acids as sole carbon and energy sources. Suppressor analysis determined that a mutation in isrR, which produces a regulatory RNA, permitted growth by decreasing isrR transcription. The decreased AcnA activity of the {Delta}fur mutant was partially relieved by an {Delta}isrR mutation. Directed mutation of bases predicted to facilitate the interaction between the acnA transcript and IsrR, decreased the ability of IsrR to control acnA expression in vivo and IsrR bound to the acnA transcript in vitro. IsrR also bound to the transcripts coding the alternate TCA cycle proteins sdhC, mqo, citZ, and citM. 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. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/601953v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@1ec27b2org.highwire.dtl.DTLVardef@1224b64org.highwire.dtl.DTLVardef@83cd49org.highwire.dtl.DTLVardef@11a9cea_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2023

Iron acquisition by a commensal bacterium modifies host nutritional immunity during Salmonella infection

During intestinal inflammation, host nutritional immunity starves microbes of essential micronutrients such as iron. Pathogens scavenge iron using siderophores, which is counteracted by the host using lipocalin-2, a protein that sequesters iron-laden siderophores, including enterobactin. Although the host and pathogens compete for iron in the presence of gut commensal bacteria, the roles of commensals in nutritional immunity involving iron remain unexplored. Here, we report that the gut commensal Bacteroides thetaiotaomicron acquires iron in the inflamed gut by utilizing siderophores produced by other bacteria including Salmonella, via a secreted siderophore-binding lipoprotein termed XusB. Notably, XusB-bound siderophores are less accessible to host sequestration by lipocalin-2 but can be "re-acquired" by Salmonella, allowing the pathogen to evade nutritional immunity. As the host and pathogen have been the focus of studies of nutritional immunity, this work adds commensal iron metabolism as a previously unrecognized mechanism modulating the interactions between pathogen and host nutritional immunity.

microbiology↗