Chapter 19 : Reactive Oxygen and Reactive Nitrogen Metabolites as Effector Molecules against Infectious Pathogens

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This chapter focuses on the sources, the regulation, the spectrum of activities, and the viral and microbial targets of reactive oxygen intermediates (ROIs) and reactive nitrogen intermediates (RNIs) generated by mammalian host cells. With respect to the control of infectious agents, the two most important oxygen-dependent pathways for the generation of antiviral or antimicrobial effector molecules are the phagocyte NADPH oxidase (Phox) and the inducible nitric oxide synthase (iNOS) pathways. One of the most intriguing discoveries in the field of ROIs in recent years was the observation by Wentworth and colleagues that antibodies, independent of their source or antigen specificity, can catalyze the generation of ROIs. Members of all groups of infectious pathogens (viruses, bacteria, protozoa, helminths, and fungi) were found to be controlled by RNIs. The significant improvement of certain infectious diseases after inhibition or genetic deletion of iNOS, which was without negative effects on the pathogen clearance, was unexpected. It can be explained by the inhibition of T-cell proliferation or induction of T-cell apoptosis via iNOS-positive suppressor cells (macrophages and dendritic cells) or by the tissue-damaging properties of RNIs. Transgenic mouse models have been extremely helpful to elucidate the relative contributions of ROIs and RNIs for the control of infectious pathogens. Viruses, bacteria, parasites, and fungi have developed multiple strategies to evade killing by oxygen-dependent effector mechanisms. Current research projects aim at the development of ROI or RNI precursors that enter only certain types of host cells and are activated by the infectious pathogens themselves.

Citation: Bogdan C. 2004. Reactive Oxygen and Reactive Nitrogen Metabolites as Effector Molecules against Infectious Pathogens, p 357-396. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch19
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Image of FIGURE 1

Key pathways for the generation of ROIs and RNIs (for details see text).

Citation: Bogdan C. 2004. Reactive Oxygen and Reactive Nitrogen Metabolites as Effector Molecules against Infectious Pathogens, p 357-396. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch19
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Image of FIGURE 2

Enzymatic and nonenzymatic generation of ROIs in the phagosomes or exocytosed granules of neutrophils.The NADPH oxidase (Phox) is assembled in the plasma membrane (forming phagosomes) or in the membrane of specific granules (which can be exocytosed). The produced superoxide (O ) enters the iron (Fe)-catalyzed Fenton–Weiss reaction (which leads to the release of hydroxyl radical [OH·] or hydroxyl anions [OH]) or dismutates into hydrogen peroxide (HO) and molecular oxygen (in the triplet or singlet state). HO is a substrate for the MPO, which leads to the generation of halogen-containing oxidants. Singlet oxygen (O), which is also derived from the reaction of HO with OCl, is transformed into ozone (O) and other ROIs by catalytic antibodies that are specifically bound to phagocytosed microbes or attached to the surface of neutrophils.

Citation: Bogdan C. 2004. Reactive Oxygen and Reactive Nitrogen Metabolites as Effector Molecules against Infectious Pathogens, p 357-396. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch19
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Image of FIGURE 3

Substrates, intermediates, and products of the iNOS reaction (modified from ). -Arginine is transformed into -citrulline and nitric oxide (NO) via the intermediate -hydroxy--arginine (LOHA). The reaction involves a five-electron reduction of the guanidino-nitrogen of arginine, in which NADPH and four redox active groups (FAD, FMN, heme, and tetrahydrobiopterin [THB]) participate in the electron transport to oxygen (O).

Citation: Bogdan C. 2004. Reactive Oxygen and Reactive Nitrogen Metabolites as Effector Molecules against Infectious Pathogens, p 357-396. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch19
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Image of FIGURE 4

Cytokine regulation and function of iNOS and arginase as alternative arginineconsuming pathways. For the production of NO by iNOS, the cells (e.g., macrophages, fibroblasts) require the uptake of extracellular -arginine via cationic amino acid transporters (CAT). Arginine can enter either the iNOS pathway or the arginase pathway. Arginase degrades arginine into urea and ornithine. Ornithine is a substrate for two enzymes: the ornithine-decarboxylase (ODC), which leads to the generation of polyamines that support cell proliferation but also exert immunosuppressive functions; and the ornithine aminotransferase (OAT), which leads to the production of proline, a precursor of collagen synthesis by fibroblasts. iNOS and arginase are regulated antagonistically by overlapping sets of cytokines and also fulfill complementary functions.THB, tetrahydrobiopterin.

Citation: Bogdan C. 2004. Reactive Oxygen and Reactive Nitrogen Metabolites as Effector Molecules against Infectious Pathogens, p 357-396. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch19
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