Interferon-inducible effector mechanisms in cell-autonomous immunity

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.

Supplementary information

The online version of this article (doi:10.1038/nri3210) contains supplementary material, which is available to authorized users.

Abstract

Here, John MacMicking provides a broad overview of the recently described functional properties of interferon-inducible effector proteins that mediate cell-autonomous host defence against internalized bacteria, protozoa and viruses.

Supplementary information

The online version of this article (doi:10.1038/nri3210) contains supplementary material, which is available to authorized users.

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.

Supplementary information

The online version of this article (doi:10.1038/nri3210) contains supplementary material, which is available to authorized users.