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Repair of Iron Centers RIC protein contributes to the virulence of Staphylococcus aureus.

ABSTRACT: RICs are a family of bacterial proteins involved in the repair of iron centers containing proteins damaged by the antimicrobial reactive species liberated by the innate immune system of infected hosts. Staphylococcus aureus is a human pathogen with increasing antibiotic resistance that also contains a RIC-like protein. In this work, we show that the survival of S. aureus within macrophages decreases upon inactivation of ric, and that the viability was restored to levels similar to the wild-type strain by reintroduction of ric via in trans complementation. Importantly, in macrophages that do not produce reactive oxygen species, the lower survival of the ric mutant was no longer observed. In lung epithelial cells, the intracellular viability of the S. aureus ric mutant was also shown to be lower than that of the wild-type. The wax moth larvae Galleria mellonella infected with S. aureus ric mutant presented an approximately 2.5-times higher survival when compared to the wild-type strain. Moreover, significantly lower bacterial loads were determined in the larvae hemolymph infected with strains not expressing ric, and complementation assays confirmed that this behavior was related to RIC. Furthermore, expression of the S. aureus ric gene within the larvae increased along the course of infection with a ~20-fold increase after 8 h of infection. Altogether, the data show that RIC is important for the virulence of S. aureus.

SUBMITTER: Silva LO

PROVIDER: S-EPMC5955197 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Repair of Iron Centers RIC protein contributes to the virulence of Staphylococcus aureus.

Silva Liliana O LO Nobre Lígia S LS Mil-Homens Dalila D Fialho Arsénio A Saraiva Lígia M LM

Virulence 20171208 1

RICs are a family of bacterial proteins involved in the repair of iron centers containing proteins damaged by the antimicrobial reactive species liberated by the innate immune system of infected hosts. Staphylococcus aureus is a human pathogen with increasing antibiotic resistance that also contains a RIC-like protein. In this work, we show that the survival of S. aureus within macrophages decreases upon inactivation of ric, and that the viability was restored to levels similar to the wild-type ...[more]

PMID: 29020514

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Project description:Staphylococcus aureus causes a wide spectrum of disease, with the site and severity of infection dependent on virulence traits encoded within genetically distinct clonal complexes (CCs) and bacterial responses to host innate immunity. The production of nitric oxide (NO) by activated phagocytes is a major host response to which S. aureus metabolically adapts through multiple strategies that are conserved in all CCs, including an S. aureus nitric oxide synthase (Nos). Previous genome analysis of CC30, a lineage associated with chronic endocardial and osteoarticular infections, revealed a putative NO reductase (Nor) not found in other CCs that potentially contributes to NO resistance and clinical outcome. Here, we demonstrate that Nor has true nitric oxide reductase activity, with nor expression enhanced by NO stress and anaerobic growth. Furthermore, we demonstrate that nor is regulated by MgrA and SrrAB, which modulate S. aureus virulence and hypoxic response. Transcriptome analysis of the S. aureus UAMS-1, UAMS-1 Δnor, and UAMS-1 Δnos strains under NO stress and anaerobic growth demonstrates that Nor contributes to nucleotide metabolism and Nos to glycolysis. We demonstrate that Nor and Nos contribute to enhanced survival in the presence of human human polymorphonuclear cells and have organ-specific seeding in a tail vein infection model. Nor contributes to abscess formation in an osteological implant model. We also demonstrate that Nor has a role in S. aureus metabolism and virulence. The regulation overlap between Nor and Nos points to an intriguing link between regulation of intracellular NO, metabolic adaptation, and persistence in the CC30 lineage.IMPORTANCEStaphylococcus aureus can cause disease at most body sites, and illness spans asymptomatic infection to death. The variety of clinical presentations is due to the diversity of strains, which are grouped into distinct clonal complexes (CCs) based on genetic differences. The ability of S. aureus CC30 to cause chronic infections relies on its ability to evade the oxidative/nitrosative defenses of the immune system and survive under different environmental conditions, including differences in oxygen and nitric oxide concentrations. The significance of this work is the exploration of unique genes involved in resisting NO stress and anoxia. A better understanding of the functions that control the response of S. aureus CC30 to NO and oxygen will guide the treatment of severe disease presentations.

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Repair of Iron Centers RIC protein contributes to the virulence of Staphylococcus aureus.

Publications

Repair of Iron Centers RIC protein contributes to the virulence of Staphylococcus aureus.

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