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  • Review Article
  • Published:

Interferon-inducible effector mechanisms in cell-autonomous immunity

Nature Reviews Immunology volume 12, pages 367–382 (2012)Cite this article

Subjects

Key Points

  • At least two forms of cell-autonomous immunity operate in higher organisms such as vertebrates: constitutive and inducible. The interferon (IFN) family of cytokines stimulates the inducible gene programme for mobilizing effector functions inside individual host cells.

  • IFN-induced effector proteins operate against most pathogen classes, especially bacteria, protozoan parasites and viruses.

  • Individual bacteria, protozoa and viruses occupy only a tiny fraction of the interior volume of a vertebrate cell. Hence, many IFN-inducible proteins are directly targeted to the site of microbial replication or generate toxic products capable of diffusing large intracellular distances to reach these microorganisms.

  • IFN-induced proteins inhibit intracellular bacteria and protozoa through a variety of mechanisms. These include: oxidative and nitrosative damage caused by cytotoxic gases (generated via IFN-inducible oxidoreductases); the recruitment of the autophagic machinery to deliver microorganisms to lysosomes (by IFN-inducible GTPases and cytosolic receptors); and the depletion of essential amino acids and divalent cations needed for microbial growth (by IFN-induced catabolic enzymes and efflux pumps, respectively).

  • IFN-induced antiviral mechanisms operate across most nucleated cells and at all stages of the viral life cycle, including entry, replication, capsid assembly and release. Several new proteins have recently been discovered that fulfil these different functions.

  • Much scientific effort over the last two decades has focused on how the innate immune system recognizes microbial pathogens. Attention is now beginning to turn towards understanding the effector mechanisms needed to sterilize these infections.

Abstract

Interferons (IFNs) induce the expression of hundreds of genes as part of an elaborate antimicrobial programme designed to combat infection in all nucleated cells — a process termed cell-autonomous immunity. As described in this Review, recent genomic and subgenomic analyses have begun to assign functional properties to novel IFN-inducible effector proteins that restrict bacteria, protozoa and viruses in different subcellular compartments and at different stages of the pathogen life cycle. Several newly described host defence factors also participate in canonical oxidative and autophagic pathways by spatially coordinating their activities to enhance microbial killing. Together, these IFN-induced effector networks help to confer vertebrate host resistance to a vast and complex microbial world.

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Figure 1: Evolution of IFN-induced cell-autonomous host defence.
Figure 2: Cell-autonomous mechanisms used by IFN-induced proteins against intracellular bacteria.
Figure 3: Cell-autonomous mechanisms used by IFN-induced proteins against intracellular protozoa.
Figure 4: Cell-autonomous mechanisms used by IFN-induced proteins against viruses.

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Acknowledgements

The author apologizes to colleagues whose work has not been cited owing to space constraints. J.D.M. is supported by the US National Institutes of Health (R01AI068041-06), a Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Disease Award (1007845), a Crohn's and Colitis Foundation of America Senior Research Award (R09928) and a W.W. Winchester Award.

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    John D. MacMicking

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IFN-inducible enzymes in oxidative and nitrosative defense. (PDF 277 kb)

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FURTHER INFORMATION

Interferome

Glossary

Autophagy

A specialized process involving the degradative delivery of a portion of the cytoplasm or of damaged organelles to the lysosome. Internalized pathogens can also be eliminated by this pathway.

Reactive oxygen species

(ROS). Aerobic organisms derive their energy from the reduction of oxygen. The metabolism of oxygen, and in particular its reduction through the mitochondrial electron-transport chain, generates by-products such as superoxide (O2−) and downstream intermediates such as hydrogen peroxide (H2O2) and hydroxyl radicals (·OH). These three species are referred to as ROS. ROS can damage important intracellular targets, such as DNA, lipids or proteins.

Reactive nitrogen species

(RNS). Nitric oxide (NO) chemistry is complex because of the extreme reactivity of NO, which can result in the formation of different reactive nitrogen intermediates (RNI) depending on the amount of NO that is produced by cells. At low concentrations, NO reacts directly with metals and other radicals. At higher concentrations, indirect effects prevail, and these include several oxidation or nitrosylation reactions with oxygen that result in the production of various congeners. NO and related RNI are effective antimicrobial agents and signal-transducing molecules.

Phagolysosomes

Intracellular vesicles that result from the fusion of phagosomes, which enclose extracellular material that has been ingested, with lysosomes, which contain lytic enzymes and antimicrobial peptides.

NADPH oxidases

Enzyme systems that consist of multiple cytosolic and membrane-bound subunits. The complex is assembled in activated phagocytic cells on the plasma and phagosomal membranes. NADPH oxidase uses electrons from NADPH to reduce molecular oxygen to form superoxide anions. Superoxide anions are enzymatically converted to hydrogen peroxide, which in neutrophils can undergo further conversion by myeloperoxidase to hypochloric acid, a highly toxic and microbicidal agent.

Respiratory burst

The process by which molecular oxygen is reduced by the NADPH oxidase system to produce reactive oxygen species.

Chronic granulomatous disease

An inherited disorder caused by defective oxidase activity in the respiratory burst of phagocytes. It results from mutations in any of five genes that are necessary to generate the superoxide radicals required for normal phagocyte function. Affected patients suffer from increased susceptibility to recurrent infections.

Galectins

Lectins that bind a wide variety of glycoproteins and glycolipids containing β-galactoside. They have extracellular and intracellular functions, including the regulation of apoptosis, RAS signalling, cell adhesion and angiogenesis.

SNARE proteins

(Soluble N-ethylmaleimide-sensitive factor attachment protein receptor proteins). A class of proteins that is required for membrane fusion events that occur in the course of vesicle trafficking and secretion.

ISGylation

The attachment of the ubiquitin-like modifier ISG15 to either pathogen or host protein targets to regulate their function rather than stimulate degradation.

MicroRNAs

Single-stranded RNA molecules of approximately 21–23 nucleotides in length that are thought to regulate the expression of other genes.

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MacMicking, J. Interferon-inducible effector mechanisms in cell-autonomous immunity. Nat Rev Immunol 12, 367–382 (2012). https://doi.org/10.1038/nri3210

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