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EcoSal Plus

Domain 8:


Nitric Oxide in and Infections

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  • Authors: AndrÉs VÁzquez-Torres1, and Ferric C. Fang2
  • Editor: Michael S. Donnenberg3
    Affiliations: 1: Department of Microbiology, University of Colorado Health Sciences Center, Denver, CO 80262; 2: Departments of Laboratory Medicine and Microbiology, University of Washington School of Medicine, Seattle, WA 98195-7242; 3: University of Maryland, School of Medicine, Baltimore, MD
  • Received 19 May 2005 Accepted 02 August 2005 Published 23 November 2005
  • Address correspondence to AndrÉs VÁzquez-Torres andres.vazquez-torres@uchsc.edu
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  • Abstract:

    This review discusses the role that nitric oxide (NO) and its congeners play on various stages in the pathophysiology of and infections, with special emphasis on the regulatory pathways that lead to high NO synthesis, the role of reactive nitrogen species (RNS) in host resistance, and the bacterial molecular targets and defense mechanisms that protect enteric bacteria against the nitrosative stress encountered in diverse host anatomical sites. In general, NO can react directly with prosthetic groups containing transition metal centers, with other radicals, or with sulfhydryl groups in the presence of an electron acceptor. Binding to iron complexes is probably the best characterized direct reaction of NO in biological systems. The targets of RNS are numerous. RNS can facilitate oxidative modifications including lipid peroxidation, hydroxylation, and DNA base and protein oxidation. In addition, RNS can inflict nitrosative stress through the nitrosation of amines and sulfhydryls. Numerous vital bacterial molecules can be targeted by NO. It is therefore not surprising that enteropathogenic bacteria are armed with a number of sensors to coordinate the protective response to nitrosative stress, along with an assortment of antinitrosative defenses that detoxify, repair, or avoid the deleterious effects of RNS encountered within the host. NO and NO-derived RNS play important roles in innate immunity to and . Enzymatic NO production by NO synthases can be enhanced by microbial and other inflammatory stimuli and it exerts direct antimicrobial actions as well as immunomodulatory and vasoregulatory effects.

  • Citation: VÁzquez-Torres A, Fang F. 2005. Nitric Oxide in and Infections, EcoSal Plus 2005; doi:10.1128/ecosalplus.8.8.8

Key Concept Ranking

Type III Secretion System
Tumor Necrosis Factor alpha
Bacterial Pathogenesis
Peyer's Patches


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This review discusses the role that nitric oxide (NO) and its congeners play on various stages in the pathophysiology of and infections, with special emphasis on the regulatory pathways that lead to high NO synthesis, the role of reactive nitrogen species (RNS) in host resistance, and the bacterial molecular targets and defense mechanisms that protect enteric bacteria against the nitrosative stress encountered in diverse host anatomical sites. In general, NO can react directly with prosthetic groups containing transition metal centers, with other radicals, or with sulfhydryl groups in the presence of an electron acceptor. Binding to iron complexes is probably the best characterized direct reaction of NO in biological systems. The targets of RNS are numerous. RNS can facilitate oxidative modifications including lipid peroxidation, hydroxylation, and DNA base and protein oxidation. In addition, RNS can inflict nitrosative stress through the nitrosation of amines and sulfhydryls. Numerous vital bacterial molecules can be targeted by NO. It is therefore not surprising that enteropathogenic bacteria are armed with a number of sensors to coordinate the protective response to nitrosative stress, along with an assortment of antinitrosative defenses that detoxify, repair, or avoid the deleterious effects of RNS encountered within the host. NO and NO-derived RNS play important roles in innate immunity to and . Enzymatic NO production by NO synthases can be enhanced by microbial and other inflammatory stimuli and it exerts direct antimicrobial actions as well as immunomodulatory and vasoregulatory effects.

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Image of Figure 1
Figure 1

NOS hemoproteins oxidize the guanidine group of -arginine to generate NO and -citrulline. The reaction consumes molecular oxygen and requires NADPH and tetrahydrobiopterin. -Hydroxy--arginine is an intermediate of this enzymatic reaction. Reproduced with permission from reference 18 .

Citation: VÁzquez-Torres A, Fang F. 2005. Nitric Oxide in and Infections, EcoSal Plus 2005; doi:10.1128/ecosalplus.8.8.8
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Image of Figure 2
Figure 2

Translated monomers of constitutive and inducible NOS (cNOS and iNOS) bind avin. The presence of -arginine, tetrahydrobiopterin, and heme stimulate dimerization of cNOS, resulting in the pairing of oxygenase and reductase domains of opposite monomers. Elevated cytosolic calcium (white) increases the affinity of calmodulin (green) for homodimeric cNOS. Binding of calmodulin to an exposed hydrophobic site (red) of cNOS induces a conformational change in the reductase domain, which allows electron flow to the heme oxygenase domain. In contrast to cNOS, the hydrophobic site (orange) of monomeric iNOS binds calmodulin at trace intracellular calcium concentrations. The enzymatic activity of iNOS is thus controlled by the availability of -arginine, tetrahydrobiopterin, and heme, which are normally plentiful in cells transcribing iNOS mRNA. Therefore, regulation of cNOS is controlled by cytosolic calcium levels, whereas regulation of iNOS is controlled primarily at the level of transcription. Reproduced with permission from reference 6 .

Citation: VÁzquez-Torres A, Fang F. 2005. Nitric Oxide in and Infections, EcoSal Plus 2005; doi:10.1128/ecosalplus.8.8.8
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Image of Figure 3
Figure 3

NO and superoxide radicals react avidly to form peroxynitrite, a species that is protonated under acidic conditions, giving rise to a reactive intermediate with properties of nitrogen dioxide and hydroxyl radicals. Through its reactions with oxygen, NO is oxidized ultimately to nitrate. In the process, other reactive species such as NO and NO are formed (not represented). NO can oxidize thiol groups to sulfenic acid or nitrosylate them to form nitrosothiols. Reproduced with permission from reference 48 .

Citation: VÁzquez-Torres A, Fang F. 2005. Nitric Oxide in and Infections, EcoSal Plus 2005; doi:10.1128/ecosalplus.8.8.8
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Image of Figure 4
Figure 4

Saliva accumulates NO from the diet and endogenous sources. Nitrate reductases (red) expressed by bacteria colonizing the posterior dorsal surface of the tongue generate NO from NO . Nitrites are reduced to NO in the stomach by its low pH or in the presence of vitamin C. NO serves as precursor of an array of reactive nitrogen species (RNS) including NO and RSNO (-nitrosothiols). RNS are beneficial in the gastric mucosa and have been associated with cytotoxicity against bacteria that include several members of the , as well as the stimulation of mucus secretion and vasodilation. On the other hand, -nitroso compounds (NOC) generated from RNS or by the actions of nitrate reductases expressed by overgrowing bacteria may be carcinogenic. Reproduced with permission from reference 132 .

Citation: VÁzquez-Torres A, Fang F. 2005. Nitric Oxide in and Infections, EcoSal Plus 2005; doi:10.1128/ecosalplus.8.8.8
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