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

Area of Science:

• Microbiology
• Molecular Biology
• Bacterial Pathogenesis

Background:

• Staphylococcus aureus adapts to low iron conditions in hosts.
• The ferric uptake transcriptional regulator (Fur) controls iron homeostasis in S. aureus.
• Iron availability impacts bacterial metabolism and virulence.

Purpose of the Study:

• To investigate the role of Fur and the regulatory RNA IsrR in S. aureus iron metabolism and virulence.
• To elucidate the regulatory network connecting Fur, IsrR, and iron-dependent enzymes.
• To understand how S. aureus copes with iron scarcity during infection.

Main Methods:

• Generating and analyzing S. aureus deletion mutants (Δfur, ΔisrR).
• Assessing gene expression (acnA, sdhC, mqo, citZ, citM) using transcriptional analysis.
• Performing suppressor analysis to identify genetic interactions.
• Conducting in vitro binding assays and whole-cell metal analysis.
• Evaluating bacterial growth and virulence in murine infection models.

Main Results:

• A Δfur mutant showed decreased expression of the iron-dependent aconitase gene (acnA), impairing growth.
• A mutation in isrR (a regulatory RNA) restored growth in the Δfur mutant by decreasing isrR transcription.
• IsrR directly binds to the acnA transcript and influences its expression, as well as other TCA cycle genes.
• IsrR enhances iron uptake and intracellular iron levels.
• Both Fur and IsrR contribute to S. aureus virulence in murine models of skin and pneumonia infections.

Conclusions:

• IsrR acts as a post-transcriptional regulator, impacting iron homeostasis and bacterial metabolism.
• The Fur-IsrR regulatory axis is crucial for S. aureus adaptation to iron-limited environments and pathogenesis.
• Targeting this regulatory pathway could offer novel strategies against S. aureus infections.