Key Points
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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.
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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.
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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.
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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.
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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.
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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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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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Glossary
- 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.
- Plasmacytoid dendritic cells
-
(pDCs). A subset of DCs that was named 'plasmacytoid' because their appearance under the microscope is similar to that of plasmablasts. In humans, these DCs can be derived from lineage (Lin)− haematopoietic stem cells from the peripheral blood. These DCs are the main producers of type I interferons in response to viral infections.
- ENU-induced mutation
-
A point mutation that is induced by the alkylating agent N-ethyl-N-nitrosourea (ENU).
- Ubiquitylation
-
The attachment of the small protein ubiquitin to lysine residues that are present in other proteins; this often tags these proteins for rapid cellular degradation.
- Myeloid dendritic cells
-
A subset of CD8α− dendritic cells that might be important for initiating vigorous immune responses.
- SCID mice
-
(Severe combined immunodeficient mice). A naturally occurring mouse mutant with SCID disease owing to an inability to rearrange antigen-receptor-chain genes.
- Quantitative trait locus
-
A locus that specifies a phenotypic difference between two different strains of mice, which may be distinguished by millions of genetic differences in all.
- Hypomorphic
-
A type of mutation in which either the altered gene product has a decreased level of activity or the wild-type gene product is expressed at a decreased level.
- Ikaros family
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A family of zinc-finger-containing transcription factors. These factors are pleiotropic regulators of haematopoiesis and are required for the generation of lymphocyte and dendritic-cell lineages, as well as lymph nodes and Peyer's patches.
- Resistome
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The set of all genes with non-redundant function in the resistance to a particular microbial agent.
- SNARE proteins
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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
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Genes that are present in a different species but are derived from a common ancestral gene.
- Haemolymph
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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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DOI: https://doi.org/10.1038/nri2174
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