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  • Review Article
  • Published:

Genetic analysis of resistance to viral infection

Nature Reviews Immunology volume 7, pages 753–766 (2007)Cite this article

Key Points

  • The Toll-like receptors (TLRs) and retinoic-acid-inducible gene I (RIG-I)-like receptors (RLRs) both participate in sensing viral infection, but do so in different cells and fill different 'niches'. Whereas the RLRs detect viral nucleic acids within the cytoplasm of infected cells and are therefore cell-autonomous sensors, the TLRs can allow non-infected cells to detect infection in other cells, perhaps even in cells at a considerable distance.

  • The biochemical pathways for TLR-induced and RLR-induced signalling have been largely deciphered, and are described here. These pathways are both capable of activating nuclear factor-κB (NF-κB) and interferon-regulatory factor 3 (IRF3) and/or IRF7, which are central regulators of inflammatory-cytokine induction and type I interferon (IFN) production, respectively.

  • A division of labour exists among immune cells, in that plasmacytoid dendritic cells (pDCs), conventional DCs, natural killer (NK) cells, lymphocytes and other cell types all mediate host resistance to viral infection, and each cell type has non-redundant functions in the containment of specific viral infections.

  • For a defined β-herpesvirus infection, multiple classes of DCs have a vital sensory role, whereas NK cells are of key importance as effectors. Numerous viral-evasion mechanisms have been identified, many mutations in the 'resistome' cause susceptibility to infection and many other mutations yet to be identified cause resistance to infection.

  • Studies using the invertebrate model Drosophila melanogaster show that insects sense viral infection and respond by inducing gene expression. Some of the genes that are induced by viral infection are controlled by the Janus kinase–signal transducer and activator of transcription (JAK–STAT) pathway, establishing a parallel with IFN signalling.

  • RNA interference is an intrinsic defence against viral infections in invertebrates. The RNaseIII enzyme Dicer-2 processes viral double-stranded RNAs, and generate small interfering RNAs that guide the RNaseH-like enzyme Argonaute-2 to viral RNA molecules, providing sequence-specific immunity.

Abstract

As machines that reprogramme eukaryotic cells to suit their own purposes, viruses present a difficult problem for multicellular hosts, and indeed, have become one of the central pre-occupations of the immune system. Unable to permanently outpace individual viruses in an evolutionary footrace, higher eukaryotes have evolved broadly active mechanisms with which to sense viruses and suppress their proliferation. These mechanisms have recently been elucidated by a combination of forward and reverse genetic methods. Some of these mechanisms are clearly ancient, whereas others are relatively new. All are remarkably adept at discriminating self from non-self, and allow the host to cope with what might seem an impossible predicament.

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Figure 1: Principles and applications of forward and reverse genetic analysis.
Figure 2: Signalling through TLR3, TLR7, TLR8 and TLR9 in response to endosomal nucleic acids of viral origin.
Figure 3: Signalling through cytoplasmic helicases leads to the activation of both NF-κB and IRF3.
Figure 4: Central roles of NK cells and DCs in the defence against MCMV.
Figure 5: Schematic overview of antiviral defences in Drosophila melanogaster.

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Acknowledgements

We thank M. Hashimoto and B. Layton for their assistance in completing this manuscript, and C. Hetru for discussions and preparation of Fig. 5. This work was supported in part by grants from the Special Coordination Funds of the Japanese Ministry of Education, Culture, Sports, Science and Technology, and from the 21st Century Center of Excellence Program of Japan, and by the National Institutes of Health, USA (P01 AI070,167).

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Author notes

  1. Celine Eidenschenk, Karine Crozat, Osamu Takeuchi and Shizuo Akira: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Genetics, The Scripps Research Institute, IMM-3-1, 10550 N. Torrey Pines Road, La Jolla, 92037, California, USA

    Bruce Beutler, Celine Eidenschenk & Karine Crozat

  2. UPR9022 Centre National de la Recherche Scientifique, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, 67000, France

    Jean-Luc Imler & Jules A. Hoffmann

  3. Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 31 Yamada-oka, Suita, 565-0871, Osaka, Japan

    Osamu Takeuchi & Shizuo Akira

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  1. Bruce Beutler
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Cross-presentation

The ability of certain antigen-presenting cells to load peptides that are derived from exogenous antigens onto MHC class I molecules. This property is atypical, because most cells exclusively present peptides from their endogenous proteins on MHC class I molecules. Cross-presentation is essential for the initiation of immune responses to viruses that do not infect antigen-presenting cells.

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Hypomorphic

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

Orthologous genes

Genes that are present in a different species but are derived from a common ancestral gene.

Haemolymph

The insect equivalent of blood.

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Beutler, B., Eidenschenk, C., Crozat, K. et al. Genetic analysis of resistance to viral infection. Nat Rev Immunol 7, 753–766 (2007). https://doi.org/10.1038/nri2174

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