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Antimicrobial reactive oxygen and nitrogen species: concepts and controversies

Key Points

  • The mechanisms by which phagocytes kill microorganisms are still not completely understood. Phagocyte-derived reactive oxygen species (ROS) and reactive nitrogen species (RNS) are undoubtedly important molecules in this process. Here, Ferric Fang reviews the biology of these molecules, with particular emphasis on aspects of their biology that remain controversial.

  • ROS and RNS are important molecules in host innate immunity. The author briefly reviews the diseases that occur when these molecules cannot be produced, including the roles of ROS in chronic granulomatous disease (CGD); RNS and inducible nitric oxide synthase (iNOS) promoter polymorphisms; and deficiencies in cytokine production or responses.

  • The NADPH phagocyte oxidase (phox)-mediated generation of ROS and the iNOS-mediated generation of RNS are described. The range of ROS and RNS species that are produced, and their cellular target molecules are also discussed.

  • Microorganisms can sometimes overcome the production of ROS and RNS to avoid being killed. The strategies that are used are reviewed, including evasion of ROS and RNS, suppression of ROS and RNS production, enzymic detoxification of reactive species, scavenging of the species to remove them, iron sequestration, stress responses and repairing the damage that the molecules cause.

  • Controversies in this field include the mechanisms by which nitric oxide is produced by macrophages, the roles of myeloperoxidase and xanthine oxidase, the importance of vesicular transport, the synergy between ROS and RNS, the synergy between ROS and proteases, and the generation of ROS by antibodies — all of which are discussed here.

Abstract

Phagocyte-derived reactive oxygen and nitrogen species are of crucial importance for host resistance to microbial pathogens. Decades of research have provided a detailed understanding of the regulation, generation and actions of these molecular mediators, as well as their roles in resisting infection. However, differences of opinion remain with regard to their host specificity, cell biology, sources and interactions with one another or with myeloperoxidase and granule proteases. More than a century after Metchnikoff first described phagocytosis, and more than four decades after the discovery of the burst of oxygen consumption that is associated with microbial killing, the seemingly elementary question of how phagocytes inhibit, kill and degrade microorganisms remains controversial. This review updates the reader on these concepts and the topical questions in the field.

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Figure 1: Antimicrobial mechanisms of phagocytes.
Figure 2: Reactive oxygen and nitrogen intermediate production in mammalian cells.
Figure 3: Microbial targets of reactive oxygen and nitrogen species.

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Acknowledgements

The author is deeply grateful for the insight and suggestions provided by M. Dinauer, S. Holland, C. Lowenstein, C. Nathan, W. Nauseef, H. Rosen and A. Vazquez-Torres, as well as the members of the Fang laboratory. Space limitations prevented the inclusion of many noteworthy citations — in such instances, the author has cited a representative article or referred the reader to a relevant review. Research support was provided by the US National Institutes of Health.

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DATABASES

Infectious Disease Information

leishmaniasis

tuberculosis

OMIM

CGD

xanthinuria

SwissProt

DtxR

Fur

glucose-6-phosphate dehydrogenase

gp91-phox

iNOS

MPO

p22-phox

p47-phox

p67-phox

Rac1

Rac2

Rap1A

xanthine oxidase

YopE

YopH

FURTHER INFORMATION

Ferric C. Fang's laboratory

Glossary

PATHOPHYSIOLOGICAL

Functional changes that are associated with, or result from, disease or injury.

POLYMORPHONUCLEAR PHAGOCYTES

White blood cells with multi-lobed nuclei and cytoplasmic granules that are involved in inflammatory responses.

PROINFLAMMATORY CYTOKINES

Secreted proteins with autocrine or paracrine action that regulate the inflammatory response. There are many types of cytokine, which elicit different cellular responses, including the control of cell proliferation and differentiation, the regulation of immune responses and haematopoiesis.

AGONIST PEPTIDES

Peptides that mimic cognate antigen, which results in cellular activation.

ELECTROGENIC

Generating an electrical potential across a membrane.

DENDRITIC CELLS

'Professional' antigen-presenting cells that are found in the T-cell areas of lymphoid tissues and as minor cellular components in most tissues. They have a branched or dendritic morphology and are the most potent stimulators of T-cell responses.

ISOFORMS

Forms of a protein with slightly different amino-acid sequences that often have diverse activities, functions and/or distributions.

HYPOHALOUS

A compound in which a hydroxyl group is combined with a halogen atom.

FENTON REACTION

The reduction of hydrogen peroxide by ferrous iron.

PEROXIDATION

A type of reaction in which oxygen atoms are formed, which leads to the production of peroxides.

MYELOPEROXIDASE

Peroxidase from neutrophils that takes part in the bactericidal activity of these cells. The name originates from the first isolation from the blood of patients with myeloid leukaemia.

PROTEASOME

In eukaryotes the 26S proteasome is a large multisubunit protease complex that selectively degrades multi-ubiquitylated proteins. It contains a 20S particle that carries the catalytic activity and two regulatory 19S particles.

IONOPHORE

Small hydrophobic molecules that dissolve in lipid bilayers and increase the permeability of membranes to ions.

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Fang, F. Antimicrobial reactive oxygen and nitrogen species: concepts and controversies. Nat Rev Microbiol 2, 820–832 (2004). https://doi.org/10.1038/nrmicro1004

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