Evolution of host innate defence: insights from Caenorhabditis elegans and primitive invertebrates

Abstract

The genetically tractable model organism Caenorhabditis elegans was first used to model bacterial virulence in vivo a decade ago. Since then, great strides have been made in identifying the host response pathways that are involved in its defence against infection. Strikingly, C. elegans seems to detect, and respond to, infection without the involvement of its homologue of Toll-like receptors, in contrast to the well-established role for these proteins in innate immunity in mammals. What, therefore, do we know about host defence mechanisms in C. elegans and what can they tell us about innate immunity in higher organisms?

Figure 1. Schematic representation of the C. elegans intestine

The C. elegans intestine is composed of 20 intestinal epithelial cells. These cells are organized in 9 rings: ring 1 contains four cells and rings 2–9 contain two cells each. The apical surface of each of the intestinal epithelial cells forms the microvillar brush border and faces the intestinal lumen. The intestinal epithelium is the major interface of interaction between C. elegans and ingested microbes.

Figure 2. Parts of mammalian TLR signalling are conserved in C. elegans

a | model of Toll-like receptor (TLR)-dependent signalling. Engagement of TLRs by cognate ligands such as lipopolysaccharide (LPS) trigger the recruitment of scaffolding proteins, such as MyD88. MyD88 and interleukin-1 receptor-associated kinase (IRAK) recruit and activate the scaffold tumor necrosis factor receptor-associated factor (TRAF)6, which, in turn, activates transforming growth factor-β (TGFβ)-activated kinase 1 (TAK1). TAK1 activates inhibitor of nuclear factor κB (NF-κB) kinase (IKKβ/γ), which phosphorylates inhibitor of NF-κB (IκB) resulting its degradation, thus releasing NF-κB from inhibition. Free NF-κB translocates into the nucleus and drives the transcription of inflammatory host responses, including cytokines and defensins. TAK1 also activates the p38 mitogen-activated protein kinase (MAPK) cascade, which comprises ASK-1/MAPK kinase kinase (MAPKKK), MKK3/6/4/7/MAPKK, and p38 and Jun N-terminal kinase (JNK). p38 and JNK target the activator protein-1 (AP-1) transcription factor to drive the transcription of host response genes. b | C. elegans has homologues for some components of TLR signalling, but notably lacks MyD88, IKKβ/γ and NF-κB homologues. MOM-4 (TAK1) functions during embryonic development in non-canonical Wnt signalling. The NSY-1–SEK-1–PMK-1 cassette is a central regulator of host defence, and depends on the upstream scaffold TIR-1 for activity. In mammals, the TIR-1 homologue sterile α- and armadillo-motif-containing protein (SARM) negatively regulates TLR signalling, showing how the same protein can have opposite roles in different organisms.

Figure 3. Components of Toll-like receptor signalling in bilaterians and cnidarians

Cnidarians and bilaterians diverged from the common eumetazoan ancestor (E) ~600–630 million years ago (2). One cnidarian branch, represented by N. vectensis, conserves nuclear factor κB (NF-κB), whereas a second branch, represented by H. magnipapillata, does not. Deuterostomes (including vertebrates) and protostomes (including nematodes and arthropods) diverged from the common bilaterian ancestor (B) ~570–582 million years ago., Because D. melanogaster and N. vectensis both possess NF-κB and MyD88, the most likely scenario is the loss of NF-κB and MyD88 from the nematode lineage. The presence or absence of other components of Toll-like receptor (TLR) signalling, including sterile α- and armadillo-motif-containing protein (SARM), inhibitor of NF-κB (IκB) and p38 mitogen-activated protein kinase (MPAK), is indicated.

Figure 4. Parallel signalling pathways in the induction of C. elegans host defence

The transforming growth factor (TGF)-β homologue DBL-1 signals to SMA-3 in the epidermis through the heterodimeric receptor DAF-4–SMA-6 for the induction of caenacin (CNC) genes during D. coniospora infection. Unknown upstream signals induce the transcription of neuropeptide-like peptide (NLP) genes in the epidermis through a signalling cascade involving the heterotrimeric G-protein subunits GPA-12 and RACK-1, the phospholipase C proteins PLC-3 and EGL-8, the protein kinase C proteins TPA-1 and PKC-3 and PMK-1 during D. coniospora infection. During wounding, death-associated protein kinase (DAPK-1) functions as an upstream negative regulator of the PMK-1 cassette in the epidermis; however, the exact point of input is unknown. In the intestine, TPA-1 and DKF-2 (protein kinase D) activate the PMK-1 cassette for the induction of host defence genes during infection by P. aeruginosa. The MAPKK MEK-1 increases PMK-1 phosphorylation. The phosphatase VHP-1 downregulates PMK-1 by dephosphorylation. Insulin (such as INS-7, which is upregulated during P. aeruginosa infection) acitvates the insulin receptor DAF-2, which sequentially activates AGE-1 (phosphoinositide 3-kinase), PDK-1 (phosphoinositide-dependent kinase-1), AKT-1, AKT-2, and SGK-1 (protein kinase B) to phosphorylate, and thereby inhibit, the FOXO transcription factor DAF-16.