Staphylococcus aureus Fur Regulates the Expression of Virulence Factors That Contribute to the Pathogenesis of Pneumonia

Abstract

The tremendous success of Staphylococcus aureus as a pathogen is due to the controlled expression of a diverse array of virulence factors. The effects of host environments on the expression of virulence factors and the mechanisms by which S. aureus adapts to colonize distinct host tissues are largely unknown. Vertebrates have evolved to sequester nutrient iron from invading bacteria, and iron availability is a signal that alerts pathogenic microorganisms when they enter the hostile host environment. Consistent with this, we report here that S. aureus senses alterations in the iron status via the ferric uptake regulator (Fur) and alters the abundance of a large number of virulence factors. These Fur-mediated changes protect S. aureus against killing by neutrophils, and Fur is required for full staphylococcal virulence in a murine model of infection. A potential mechanistic explanation for the impact of Fur on virulence is provided by the observation that Fur coordinates the reciprocal expression of cytolysins and a subset of immunomodulatory proteins. More specifically, S. aureus lacking fur exhibits decreased expression of immunomodulatory proteins and increased expression of cytolysins. These findings reveal that Fur is involved in initiating a regulatory program that organizes the expression of virulence factors during the pathogenesis of S. aureus pneumonia.

Staphylococcus aureus NorD, a Putative Efflux Pump Coregulated with the Opp1 Oligopeptide Permease, Contributes Selectively to Fitness In Vivo

“…In contrast, a shift to an acidic environment (pH 5.5) caused a 3-fold decrease in norD expression (data not shown). However, free iron restriction, which occurs at many sites of infection (7,30), upregulated norD expression. We compared norD expression in strain MW2 grown in TSB supplemented with 400 M dipyridyl (a ferrous iron chelator) with and without the addition of 50 M ferrous sulfate.…”

“…5-Bromo-4-chloro-3-indolyl-␤-D-galactopyranoside (X-Gal) (Sigma) was used at 60 g/ml in LB agar. To measure the induction of NorD in iron-restricted medium, strain MW2 was cultivated for 30 min in TSB supplemented with 400 M dipyridyl (Sigma) with or without the addition of 50 M ferrous sulfate (Sigma) (30).…”

The Bicomponent Pore-Forming Leucocidins of Staphylococcus aureus

“…S. aureus fur mutants significantly upregulate the production of LukED and HlgCB in broth culture (322). Whether the regulation of leucocidins by Fur occurs via direct or indirect mechanisms is yet to be determined.…”

“…In addition to the Agr, SarA, and Sae regulatory inputs, the master regulator of iron acquisition, Fur, provides additional regulatory control over leucocidin gene expression (322). S. aureus fur mutants significantly upregulate the production of LukED and HlgCB in broth culture (322).…”

Staphylococcus aureus Transporters Hts, Sir, and Sst Capture Iron Liberated from Human Transferrin by Staphyloferrin A, Staphyloferrin B, and Catecholamine Stress Hormones, Respectively, and Contribute to Virulence

“…Given its high virulence potential, it is of interest to define mechanisms by which this bacterium scavenges host iron sources. S. aureus has a system to acquire iron from heme via the secretion of toxins and hemolysins that provide access to hemoglobin, followed by the actions of several S. aureus proteins that function in an overall process which includes the extraction of heme from hemoglobin and the eventual internalization of heme, followed by the extraction of iron from the porphyrin ring (38,45,60,64,65).…”