Reactive oxygen and nitrogen species in microbial killing
THE CONTEXT
Activated phagocytes generate destructive oxygen- and nitrogen-derived molecules that damage microbial cellular constituents.
Generation of reactive oxygen species
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Reactive oxygen species (ROS)* are produced mainly in neutrophil phagolysosomes.
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Neutrophil activation rapidly assembles the multicomponent enzyme phagocyte oxidase, also called NADPH oxidase, in the phagolysosomal membrane.
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Phagocyte oxidase oxidizes NADPH and reduces oxygen to superoxide anion, which is subsequently converted to hydrogen peroxide.
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Production of ROS coupled with oxygen consumption is called the respiratory burst.
Microbicidal effects and clinical association
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Hydrogen peroxide does not efficiently kill microbes by itself. Myeloperoxidase in neutrophil azurophilic granules uses a halide, such as chloride, to convert hydrogen peroxide to hypochlorite.
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Hypochlorite destroys microbes through halogenation of cellular constituents or oxidation of proteins and lipids.
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The hydrogen peroxide–myeloperoxidase–halide system is the most efficient bactericidal system of neutrophils.
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Hydrogen peroxide can also be converted to the highly destructive hydroxyl radical.
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Oxygen-derived free radicals modify cellular lipids, proteins, and nucleic acids, thereby destroying cells such as microbes.
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Genetic defects in ROS generation cause chronic granulomatous disease.
Nitric oxide and reactive nitrogen species
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Nitric oxide is a soluble gas produced from arginine by nitric oxide synthase and contributes to microbial killing, especially in macrophages.
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Microbial products and cytokines such as interferon-gamma induce transcriptional activation of the inducible nitric oxide synthase gene in macrophages.
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Nitric oxide reacts with superoxide generated by phagocyte oxidase to form highly reactive peroxynitrite.
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These nitrogen-derived molecules damage microbial lipids, proteins, and nucleic acids.