Flavohemoglobin requires microaerophilic conditions for nitrosative protection of <i>Staphylococcus aureus</i>

Gonçalves, Vera L.; Nobre, Lígia S.; Vicente, João B.; Teixeira, Miguel; Saraiva, Lı́gia M.

doi:10.1016/j.febslet.2006.02.039

Cited by 49 publications

(26 citation statements)

References 26 publications

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“…First, SrrAB is essential for full induction of the flavohemoprotein Hmp. This enzyme detoxifies NO˙to nitrate, thereby reducing intracellular NOl evels such that respiration can resume (58). Reduced Hmp production in a ⌬srrAB mutant presumably extends the period of time during which NO˙levels surpass the threshold that limits respiration.…”

Section: Resultsmentioning

confidence: 99%

Regulatory Requirements for Staphylococcus aureus Nitric Oxide Resistance

et al. 2016

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The ability of Staphylococcus aureus to resist host innate immunity augments the severity and pervasiveness of its pathogenesis. Nitric oxide (NO˙) is an innate immune radical that is critical for the efficient clearance of a wide range of microbial pathogens. Exposure of microbes to NO˙typically results in growth inhibition and induction of stress regulons. S. aureus, however, induces a metabolic state in response to NO˙that allows for continued replication and precludes stress regulon induction. The regulatory factors mediating this distinctive response remain largely undefined. Here, we employ a targeted transposon screen and transcriptomics to identify and characterize five regulons essential for NO˙resistance in S. aureus: three virulence regulons not formerly associated with NO˙resistance, SarA, CodY, and Rot, as well as two regulons with established roles, Fur and SrrAB. We provide new insights into the contributions of Fur and SrrAB during NO˙stress and show that the S. aureus ⌬sarA mutant, the most sensitive of the newly identified mutants, exhibits metabolic dysfunction and widespread transcriptional dysregulation following NO˙exposure. Altogether, our results broadly characterize the regulatory requirements for NO˙resistance in S. aureus and suggest an intriguing overlap between the regulation of NO˙resistance and virulence in this well-adapted human pathogen. IMPORTANCEThe prolific human pathogen Staphylococcus aureus is uniquely capable of resisting the antimicrobial radical nitric oxide (NO˙), a crucial component of the innate immune response. However, a complete understanding of how S. aureus regulates an effective response to NO˙is lacking. Here, we implicate three central virulence regulators, SarA, CodY, and Rot, as major players in the S. aureus NO˙response. Additionally, we elaborate on the contribution of two regulators, SrrAB and Fur, already known to play a crucial role in S. aureus NO˙resistance. Our study sheds light on a unique facet of S. aureus pathogenicity and demonstrates that the transcriptional response of S. aureus to NO˙is highly pleiotropic and intrinsically tied to metabolism and virulence regulation. The versatile Gram-positive pathogen Staphylococcus aureus is the leading cause of skin and soft tissue infections (SSTIs) in the United States but can also cause more severe illnesses, including pneumonia, osteomyelitis, endocarditis, and bacteremia (1-5). The ability of S. aureus to infect virtually every tissue of the body can be partially attributed to its extensive capacity for subverting host immunity. One unique defense of S. aureus against the immune system is resistance to nitric oxide (NO˙), a membrane-permeable radical and broad-spectrum innate immune effector required for the clearance of bacterial, viral, and fungal pathogens (6). The ability of S. aureus to continue growth in the presence of NO˙at concentrations that are inhibitory to other bacteria, including closely related staphylococci, contributes to its invasiveness and pathogenic success. For example...

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Section: Resultsmentioning

confidence: 99%

Regulatory Requirements for Staphylococcus aureus Nitric Oxide Resistance

et al. 2016

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“…Previous work had shown that the primary mechanism of action of flavohemoglobins, such as HmpA, is through dinitrosylation of NO, a reaction that is dependent on O 2 (28). Hmp of Escherichia coli also possesses an O 2 -independent NO reductase activity in vitro (29), but the activity is slow, and its physiological relevance is uncertain (30). Thus, we hypothesized that under anaerobic conditions, the effect of HmpA in V. cholerae might be less dominant and NnrS might become more important.…”

Section: Nnrs Is Important For Resistance To No But Does Not Remove Nomentioning

confidence: 99%

A Novel Protein Protects Bacterial Iron-Dependent Metabolism from Nitric Oxide

et al. 2013

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Reactive nitrogen species (RNS), in particular nitric oxide (NO), are toxic to bacteria, and bacteria have mechanisms to allow growth despite this stress. Understanding how bacteria interact with NO is essential to understanding bacterial physiology in many habitats, including pathogenesis; however, many targets of NO and enzymes involved in NO resistance remain uncharacterized. We performed for the first time a metabolomic screen on NO-treated and -untreated bacteria to define broadly the effects of NO on bacterial physiology, as well as to identify the function of NnrS, a previously uncharacterized enzyme involved in defense against NO. We found many known and novel targets of NO. We also found that iron-sulfur cluster enzymes were preferentially inhibited in a strain lacking NnrS due to the formation of iron-NO complexes. We then demonstrated that NnrS is particularly important for resistance to nitrosative stress under anaerobic conditions. Our data thus reveal the breadth of the toxic effects of NO on metabolism and identify the function of an important enzyme in alleviating this stress. Vibrio cholerae causes cholera, a severe watery diarrhea responsible for millions of cases and thousands of deaths each year (Centers for Disease Control and Prevention [http://www.cdc .gov]). It is not, however, a member of the Enterobacteriaceae-its natural habitat is aquatic. It is thought that during most of its life cycle, when not infecting humans, V. cholerae resides in association with zooplankton, forming biofilms on the chitinous surfaces of crustaceans (1, 2). Thus, V. cholerae must display metabolic flexibility in order to thrive in these two different environments and respond to the different metabolic challenges therein.A commonly encountered metabolic stress for pathogenic and nonpathogenic bacteria is the presence of reactive nitrogen species (RNS), in particular the well-studied molecule nitric oxide (NO). NO is formed as a by-product of nitrogen metabolism for many bacteria as an intermediate in denitrification (3), as well as from dedicated nitric oxide synthases (NOSs) in both bacteria and eukaryotes (4, 5), and is present in micromolar concentrations in some bacterial biofilms (6). NO can also be formed by chemical decomposition of nitrite in acid environments, such as the human stomach (7). NO is also a prominent component of the mammalian innate immune system, part of a battery of reactive oxygen species (ROS) and RNS produced by phagocytes when they encounter bacteria (7).The mechanisms whereby NO inhibits bacterial growth are diverse, but one of the most important properties of NO is its ability to bind iron and form dinitrosyl iron complexes (DNICs) bound to iron-sulfur cluster proteins, inhibiting their function (8, 9). DNICs have also been shown to mediate the formation of nitrosothiols, another form of nitrosative stress that inhibits thiolcontaining proteins (10). Through this mechanism and others, NO has been shown to inhibit a few enzymes in vitro, including such central metabolic enzymes as ...

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“…Consequently, an srrAB mutant exhibited enhanced sensitivity to NO and this was partially attributed to dysregulation of the NO detoxification enzyme Hmp (see above), but the divergently transcribed ldh1 gene, encoding lactate dehydrogenase was subsequently shown to be essential for virulence and maintaining redox balance during nitrosative stress. 153,154 The overlap between the response to anoxia and exposure to NO could be accounted for by NO-mediated inhibition of aerobic respiration triggering the activation of the SrrAB two-component system and consequently the role of SrrAB could be extended beyond the control of hypoxic metabolic and major virulence factor genes to include NO resistance; a combination that readily explains the attenuation of the srrAB mutant.…”

Section: Nitric Oxide Responsesmentioning

confidence: 99%

Transcriptional regulation of bacterial virulence gene expression by molecular oxygen and nitric oxide

2014

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Molecular oxygen (O 2 ) and nitric oxide (NO) are diatomic gases that play major roles in infection. The host innate immune system generates reactive oxygen species and NO as bacteriocidal agents and both require O 2 for their production. Furthermore, the ability to adapt to changes in O 2 availability is crucial for many bacterial pathogens, as many niches within a host are hypoxic. Pathogenic bacteria have evolved transcriptional regulatory systems that perceive these gases and respond by reprogramming gene expression. Direct sensors possess iron-containing co-factors (iron-sulfur clusters, mononuclear iron, heme) or reactive cysteine thiols that react with O 2 and/or NO. Indirect sensors perceive the physiological effects of O 2 starvation. Thus, O 2 and NO act as environmental cues that trigger the coordinated expression of virulence genes and metabolic adaptations necessary for survival within a host. Here, the mechanisms of signal perception by key O 2 -and NO-responsive bacterial transcription factors and the effects on virulence gene expression are reviewed, followed by consideration of these aspects of gene regulation in two major pathogens, Staphylococcus aureus and Mycobacterium tuberculosis.

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Flavohemoglobin requires microaerophilic conditions for nitrosative protection of Staphylococcus aureus

Cited by 49 publications

References 26 publications

Regulatory Requirements for Staphylococcus aureus Nitric Oxide Resistance

Regulatory Requirements for Staphylococcus aureus Nitric Oxide Resistance

A Novel Protein Protects Bacterial Iron-Dependent Metabolism from Nitric Oxide

Transcriptional regulation of bacterial virulence gene expression by molecular oxygen and nitric oxide

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