Iron, RNA, and Adaptation: How Staphylococcus aureus Uses IsrR to Survive Host-Imposed Iron Limitation
- Ray Sullivan
- 20 hours ago
- 2 min read
Updated: 3 hours ago
At the 2025 Theobald Smith Society Spring Symposium, Gustavo Rios-Delgado from Jeff Boyd’s Lab at Rutgers University–New Brunswick presented new insights into how Staphylococcus aureus responds to iron starvation—an environmental stress commonly imposed by the host immune system. His work centers on a small regulatory RNA called IsrR and its role in repressing iron-dependent metabolism when iron becomes scarce.
During infection, hosts restrict bacterial access to essential metals like iron by deploying iron-binding proteins such as transferrin and lactoferrin. In response, S. aureus uses the ferric uptake regulator, Fur, to sense and manage iron availability. Traditionally, Fur is known to repress iron uptake genes when iron is abundant. However, Rios-Delgado's work uncovers a more nuanced function—how Fur indirectly supports the tricarboxylic acid (TCA) cycle and overall metabolism by repressing a small RNA that limits iron use.
The project began with the observation that S. aureus mutants lacking Fur had no aconitase activity—an iron-sulfur enzyme essential to the TCA cycle. Further analysis revealed that these Fur-deficient mutants could not grow in minimal media where amino acids were the only carbon source. To uncover what might be repressing aconitase in the absence of Fur, Rios-Delgado performed a suppressor screen and identified a consistent mutation in a previously uncharacterized small RNA gene, now called IsrR.
Functional studies showed that removing IsrR from the Fur mutant background restored aconitase expression and bacterial growth. IsrR appears to bind directly to the ribosome binding site of the aconitase mRNA, blocking its translation. This was confirmed through GFP fusion assays and electrophoretic mobility shift assays (EMSAs), demonstrating physical interaction between IsrR and target transcripts.
IsrR also represses other iron-dependent TCA cycle enzymes, including succinate dehydrogenase, and was shown to bind additional transcripts related to heme biosynthesis and oxidative stress. The emerging model suggests that when iron is scarce, Fur repression is lifted, IsrR is expressed, and it systematically shuts down iron-intensive metabolic processes—conserving iron for critical cellular functions.
The story doesn’t end at the bench. In a mouse model of acute pneumonia, S. aureus strains lacking IsrR showed significantly reduced colonization, linking this regulatory RNA to in vivo virulence. These findings reveal how S. aureus fine-tunes metabolism under iron limitation, positioning IsrR as a key player in bacterial adaptation and a potential target for anti-virulence therapies.
See Gustavo’s talk at: https://youtu.be/O7meVf1VtjA
Rios-Delgado G, McReynolds AKG, Pagella EA, Norambuena J, Briaud P, Zheng V, Munneke MJ, Kim J, Racine H, Carroll RK, Zelzion E, Skaar E, Bose JL, Parker D, Lalaouna D, Boyd JM. The Staphylococcus aureus non-coding RNA IsrR regulates TCA cycle activity and virulence. Nucleic Acids Res. 2025 Feb 8;53(4):gkae1243. doi: 10.1093/nar/gkae1243. PMID: 39704109; PMCID: PMC11879123.