Regulation of Salmonella Resistance to Oxidative and Nitrosative Stress

Calvin A. Henard; Andrés Vázquez-Torres

doi:10.1128/9781555818524.ch22

Chapter 22 : Regulation of Salmonella Resistance to Oxidative and Nitrosative Stress

Authors: Calvin A. Henard¹, Andrés Vázquez-Torres¹

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Affiliations: 1: Department of Microbiology, University of Colorado Denver School of Medicine, Aurora, CO 80045

Content Type: Monograph

Publication Year: 2013

Category: Bacterial Pathogenesis

Book DOI: 10.1128/9781555818524

Chapter DOI: 10.1128/9781555818524.ch22

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Abstract:

This chapter presents the molecular mechanisms used by Salmonella to sense and respond to reactive species encountered at various phases during the infectious cycle. Salmonellae are exposed to reactive oxygen species (ROS) produced endogenously through the univalent or divalent reduction of O2 by enzymes of the electron transport chain or cytoplasmic flavoproteins. Oxyradicals generated by the NADPH phagocyte oxidase react with sulfur compounds in the gut lumen, generating the alternative electron acceptor tetrathionate. The effect of ROS on Salmonella central metabolism may be especially pertinent in phagosomes of macrophages, where nutrients might be a limited resource. The importance of thiol-mediated sensing of ROS and reactive nitrogen species (RNS) has been established in both prokaryotes and eukaryotes. Of interest to this chapter, SPI2 lessens the oxidative and nitrosative stress that Salmonella must endure within macrophages. A section briefly discusses the sources of NO and the chemistry of RNS relevant to Salmonella pathogenesis. The formation of dinitrosyliron complexes in fumarate/nitrate reduction (FNR) derepresses genes involved in the antinitrosative response of Salmonella. ROS and RNS have distinct biological chemistries, but they also share some common molecular targets. The realization that the SPI2 master regulator SsrB can be a sensor of RNS illustrates the complex strategies used by intracellular Salmonella to sense reactive species engendered in the course of the infection.

Citation: Henard C, Vázquez-Torres A. 2013. Regulation of Salmonella Resistance to Oxidative and Nitrosative Stress, p 425-440. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch22

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Regulation of Salmonella Resistance to Oxidative and Nitrosative Stress

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Figure 1

Molecular targets of RNS- and ROS-mediated anti-Salmonella activity. N2O3 formed in the reaction of NO with molecular oxygen O2 is one of the indirect means by which NO causes cytotoxicity (blue box). NO forms ONOO− through its interactions with superoxide anion (O2 ·−), and dinitrosyl-iron complexes (DNIC) by reacting with iron and low-molecularweight thiols (-SH). The strong oxidant ONOO− targets [4Fe-4S] clusters of dehydratases. The NO radical can also react directly with the sulfenyl radical (-S·) to form S-nitrosylated protein derivatives. Moreover, N2O3 and DNIC are common sources of transnitrosation reactions and nitrosative stress. NO2 ·, N2O3, ONOO−, O2 ·−, and H2O2 are common sources of oxidative stress (purple box). These species damage [Fe-S] clusters, liberating catalytically active Fe2+. In turn, Fe2+ reduces H2O2 to the highly reactive hydroxyl radical (·OH), which causes extensive DNA damage. H2O2 also oxidizes reactive cysteine residues in proteins to form sulfenic acid derivatives (-SOH). O2 and NO also target copper and heme cofactors in terminal cytochromes of the electron transport chain; however, hemoprotein targets are not depicted because heme-based sensors of O2 or NO have not yet been identified in Salmonella. doi:10.1128/9781555818524.ch22f1

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Figure 1

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Figure 2

Sensors of oxidative and nitrosative stress. The dedicated NO sensors NsrR and NorR react with NO (yellow box). Dinitrosyl-iron complex formation in the NsrR [2Fe-2S] cluster derepresses transcription of target genes such as hmp, encoding a flavohemoglobin that detoxifies NO to NO3 −. The NorR metalloprotein containing a nonheme iron center is also activated by NO. The N-terminal regulatory domain of NorR represses norVW, encoding flavorubredoxin and associated oxidoreductase. The formation of a mononitrosyl-iron species in NorR activates transcription. The redox-active thiol of Cys203 of the SsrB response regulator that controls SPI2 gene transcription is the first thiol-based sensor of RNS to be identified in Salmonella. Some sensors such as Fur, FNR, SoxR, and OxyR can respond to both oxidative and nitrosative stress (green box). The transcriptional repressors Fur and FNR bind to DNA as homodimers. Dinitrosyl-iron complexes disrupt the DNA binding activity of Fur and FNR, derepressing transcription. Fur can be indirectly activated by oxidative stress-mediated disruption of iron homeostasis (not shown). O2 and O2 ·− oxidize the [4Fe-4S] cluster of FNR (not shown). The [2Fe-2S] cluster of SoxR is primarily dedicated to sensing and redox changes in the cell. Conformational changes associated with the oxidation or nitrosylation of SoxR [2Fe-2S]+ activate soxS transcription. OxyR Cys199 is a primary sensor of H2O2. H2O2 oxidizes the Cys199 thiolate to sulfenic acid, which condenses with Cys208 to form an intramolecular disulfide. OxyR Cys199 can also be S nitrosylated and form a mixed disulfide with glutathione (-SG). Both oxidized and RNS-modified OxyR are transcriptionally active. doi:10.1128/9781555818524.ch22f2

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Figure 2

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