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Toll-like receptors — taking an evolutionary approach

Key Points

  • Toll-like receptors (TLRs) are type-I transmembrane proteins with extracellular leucine-rich repeat (LRR) motifs and an intracellular Toll/interleukin-1R (TIR) domain.

  • TLR genes are restricted to eumetazoans and probably originated at the dawn of animal evolution more than 700 million years ago.

  • With rare exceptions, both TLR and nuclear factor-kappaB (NF-κB) genes are found in sequenced animal genomes, pointing to the ancient origin of the TLR–NF-κB signalling module.

  • Early diversification of TLR structures resulted in two forms of the protein: multiple cysteine cluster TLRs found mostly in protostomes and single cysteine cluster TLRs found mostly in deuterostomes.

  • Three distinct functions of TLRs have been identified: TLRs are essential during host immune responses through NF-κB signalling in insects and vertebrates; they contribute to normal patterning and organogenesis during development through NF-κB signalling in insects; and they contribute to cell adhesion during embryonic development, apparently independently of NF-κB activation in both insects and nematodes.

  • The lack of functional information on TLRs in several lineages such as lophotrocozoans and cnidarians precludes the drawing of a robust evolutionary scenario for the emergence of TLR-mediated immunity or the ancestral function of TLRs. However, two hypotheses can explain the observed similarities and differences in TLR-mediated immunity in vertebrates and insects: an ancient origin of TLR-mediated immunity in the bilaterian ancestor followed by a substantial diversification along the lineages; or a convergent evolution based on the independent recruitment of TLRs to mediate immunity in deuterostomes and insects.

  • The recurrent use of similar protein modules (the TIR domain and LRR motifs) and signalling pathways (NF-κB) in the immune response is observed in phylogenetically distant lineages.

  • Future challenges include analysing TLR function in invertebrate deuterostomes, lophochotrozoan and cnidarian model organisms, and further dissection of the NF-κB-independent role of TLRs during development.

Abstract

The Toll receptor was initially identified in Drosophila melanogaster for its role in embryonic development. Subsequently, D. melanogaster Toll and mammalian Toll-like receptors (TLRs) have been recognized as key regulators of immune responses. After ten years of intense research on TLRs and the recent accumulation of genomic and functional data in diverse organisms, we review the distribution and functions of TLRs in the animal kingdom. We provide an evolutionary perspective on TLRs, which sheds light on their origin at the dawn of animal evolution and suggests that different TLRs might have been co-opted independently during animal evolution to mediate analogous immune functions.

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Figure 1: Toll-like receptors and downstream signalling pathways.
Figure 2: Origins, distribution and functions of Toll-like receptors in the animal kingdom.
Figure 3: Toll-like receptor functions in development.
Figure 4: Toll-like receptor functions in immunity.

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Acknowledgements

We are grateful to B. Prud'homme, J. Bangham, J. Casanova and colleagues at the Centre de Génétique Moléculaire for discussions and insights on our manuscript. We apologise to the many authors whose work has not been directly cited because of space limitation.

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Glossary

Metazoans

Heterotrophic multicellular organisms (that is, animals).

Deuterostomes

Animal taxon including all animal species in which the blastopore forms the anus.

Eumetazoans

The clade comprising all major animal groups except sponges (that is, cnidarians to vertebrates).

Protostomes

Animal taxon including all animal species in which the blastopore forms the mouth.

Bilaterians

Animals with bilateral symmetry.

Fat body

The functional equivalent, in insects, of the mammalian liver.

Haemolymph

Insect blood.

Avoidance behaviour

C. elegans worms that are fed on bacterial lawn in experimental conditions have the capacity to discriminate between bacterial species and avoid pathogenic bacteria such as Serratia marcescens, while being attracted by non-pathogenic species such as Escherichia coli.

Paneth cells

Specialized epithelial cells of the small intestine, which provide host defence against microorganisms.

Endotoxin shock

A medical condition that is caused by decreased tissue perfusion and oxygen delivery as a result of lipopolysaccharide contamination of the blood stream.

Morpholinos

A synthetic molecule used to modify gene expression.

Coelomocytes

Circulating cells that are present in the body cavity (coelome) of sea urchins and other invertebrates.

Adaptive immune system

The long-lasting host defence response to infection, which is acquired during the life of the host.

Chordates

The phylum of animals that is defined by the presence of a notochord.

Complement system

A complex system of proteins that interact in a proteolytic cascade, leading to pathogen clearance in the serum.

Innate immune response

The first line of defence against invading organisms, which is inherited.

Clade

A taxonomic group of organisms comprising a single common ancestor and all the descendants of that ancestor.

Convergent evolution

The process whereby organisms that are not closely related (not monophyletic) independently evolve similar traits as a result of having to adapt to similar environments or ecological niches.

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Leulier, F., Lemaitre, B. Toll-like receptors — taking an evolutionary approach. Nat Rev Genet 9, 165–178 (2008). https://doi.org/10.1038/nrg2303

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