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PerR is a positive regulator of staphyloferrin B-mediated iron acquisition in Staphylococcus aureus

ABSTRACT: Staphylococcus aureus is a globally prevalent Gram-positive pathogen with the remarkable ability to cause infection in numerous tissues. Due to the concerted action of host iron (Fe) sequestration mechanisms, the ability of bacterial pathogens to overcome this nutritional immunity is required for infection. S. aureus expresses an arsenal of Fe acquisition systems the expression of which are coordinated primarily through a well-characterized Fe-sensing transcriptional regulator, Fur. Here, from a screen to identify S. aureus mutants defective for iron-restricted growth, we identified several where genome sequencing identified mutations in the perR gene, encoding a transcriptional regulator involved in resistance to oxidative stress. RNA-seq identified that perR mutants express significantly less transcript from the staphyloferrin B biosynthetic operon, sbn, during growth under Fe starvation. These results were consistent with our finding that perR mutants grew poorly in iron-deficient media in a staphyloferrin B-dependent manner. In a subcutaneous model of S. aureus infection, a perR mutant demonstrated significantly smaller lesion sizes, and this was consistent with our finding that perR mutant had decreased expression of alpha-hemolysin when grown under iron-restriction. All of these findings are consistent with the hypothesis that perR acts to fine tune access to iron as a means to avoid Fe-dependent toxicity. The importance of PerR function to S. aureus was further highlighted by examination of over 8000 bloodstream isolates of S. aureus from humans, showing that PerR sequence was highly conserved among this large cohort of isolates. Together, these findings demonstrate the importance of PerR to S. aureus in providing an additional level of regulation of iron homeostasis beyond Fur-dependent iron sensing.

ORGANISM(S): Staphylococcus aureus

PROVIDER: GSE318095 | GEO | 2026/06/11

REPOSITORIES: GEO

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Project description:The Gram-positive pathogenic bacterium Staphylococcus aureus permanently colonizes the nasal mucosa in about 30% of the healthy population. However, as an opportunistic pathogen, S. aureus can also cause a variety of diseases, the treatment of which is becoming increasingly difficult due to antibiotic resistance. Adaptation to changing environmental conditions during colonization and infection of the host requires precise regulation of the expression of genes for virulence factors and metabolic functions. The host conditions essentially include low iron availability, with the majority of iron in the human organism being present intracellularly in the form of haemoglobin. Therefore, S. aureus has various adaptive mechanisms, in particular iron uptake systems, which are regulated by the global iron uptake regulator Fur (ferric-uptake regulator). Iron deficiency conditions lead to the derepression of Fur-dependent genes. In many bacteria, these genes also include regulatory RNAs (small regulatory RNAs, sRNAs), which mediate an iron-sparing response by inhibiting the synthesis of non-essential iron-containing proteins. A Fur-dependent sRNA (S596) was identified in a transcriptome analysis of S. aureus. In a study by Coronel-Tellez et al. (2022) it was shown that S596/IsrR (“iron sparing response regulator”) is necessary for the virulence of S. aureus. In the presented secretome analysis, the S. aureus HG001 wild type (WT) was compared with an isogenic isrR mutant (ΔisrR) under iron-limiting conditions and a constitutively isrR-expressing strain (HG001 pJLisrR) with an empty vector control (HG001 pJLctrl) under iron-rich conditions as well as corresponding sae mutant (Δsae) strains. Culture supernatants were collected in the exponential and stationary growth phases and extracellular proteins were subsequently analyzed by mass spectrometry. Statistical data analysis was performed to identify proteins with significantly altered amounts between the respective strains. We demonstrate that IsrR positively influences the protein levels of numerous virulence factors which in particular belong to the Sae regulon.

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PerR is a positive regulator of staphyloferrin B-mediated iron acquisition in Staphylococcus aureus

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