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The iron-regulated sRNA IsrR is involved in the display of full Staphylococcus aureus virulence in part via SaeRS activation

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Staphylococcus Aureus

TISSUE(S): Cell Culture

SUBMITTER: Larissa Busch

LAB HEAD: Uwe Völker

PROVIDER: PXD055092 | Pride | 2025-04-11

REPOSITORIES: Pride

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Source:

			Action	DRS
	2021_01__uniprot_sp_Bsubtilis_168_incl_isoforms.fasta	Fasta
	20230811_Bacillus_heavy_lib_fix_mod.kit	Other
	20230816_Exp_AG_Fur_DisrR_exp_BR1_21.raw	Raw
	20230816_Exp_AG_Fur_DisrR_exp_BR2_22.raw	Raw
	20230816_Exp_AG_Fur_DisrR_exp_BR3_23.raw	Raw

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Project description:As integral parts of gene regulatory networks, small regulatory RNAs (sRNAs) play important roles in the adaptation of bacteria to environmental conditions. To adapt to iron limitation, many bacteria exploit an "iron-sparing" response mediated by Fur-regulated sRNAs such as RyhB of E. coli, allowing them to reduce the synthesis of iron-utilizing proteins not essential for growth. In this study, we aimed to confirm the regulatory role of the sRNA IsrR (Iron-sparing response Regulator) of S. aureus and to characterize the IsrR targetome in order to better understand the pathogens adaptation to iron-limited conditions often encountered in the host. To identify potential IsrR targets, two different experimental approaches were used. In the first, proteome profiles of S. aureus HG001 were compared to those of an isogenic ΔisrR mutant under iron-limited conditions. In the second approach, the effects of IsrR on the proteome under iron-rich conditions were analyzed using a strain in which IsrR was constitutively expressed from a plasmid. In silico target prediction was performed using the CopraRNA2 tool. Presence of IsrR caused a large number of consistent changes in protein levels both under iron-limited or iron-rich conditions. Among the proteins exhibiting significantly different abundance, 63 were in common between both experiments. Since sRNAs can have direct and indirect effects on global gene expression, the experimental approach was combined with in silico target prediction. In this way, very likely direct IsrR targets were identified, which include catalase (KatA) and three tricarboxylic acid (TCA) cycle enzymes (CitB, SdhA, SucA). Follow-up analyses confirmed that IsrR negatively affects KatA and CitB enzymatic activities. In contrast to most identified IsrR targets, the predicted interaction region of IsrR with the katA mRNA does not overlap the ribosome binding site, suggesting that IsrR cannot only inhibit translation, but also directly affect mRNA stability. A putative IsrR targetome was identified. In agreement with Fur-regulated sRNAs of other organisms, IsrR negatively affects the expression of TCA cycle and heme biosynthesis enzymes.

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The iron-regulated sRNA IsrR is involved in the display of full Staphylococcus aureus virulence in part via SaeRS activation

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