Similarities in the induction of the intracellular pathogen response in Caenorhabditis elegans and the type I interferon response in mammals

Abstract

Although the type‐I interferon (IFN‐I) response is considered vertebrate‐specific, recent findings about the Intracellular Pathogen Response (IPR) in nematode Caenorhabditis elegans indicate that there are similarities between these two transcriptional immunological programs. The IPR is induced during infection with natural intracellular fungal and viral pathogens of the intestine and promotes resistance against these pathogens. Similarly, the IFN‐I response is induced by viruses and other intracellular pathogens and promotes resistance against infection. Whether the IPR and the IFN‐I response evolved in a divergent or convergent manner is an unanswered and exciting question, which could be addressed by further studies of immunity against intracellular pathogens in C. elegans and other simple host organisms. Here we highlight similar roles played by RIG‐I‐like receptors, purine metabolism enzymes, proteotoxic stressors, and transcription factors to induce the IPR and IFN‐I response, as well as the similar consequences of these defense programs on organismal development.

C. elegansRIG-I-like receptor DRH-1 signals via CARDs to activate anti-viral immunity in intestinal cells

“…A hallmark of anti-viral immunity in mammals is the induction of systemic immunity triggered by secreted IFN-I ligands signaling through IFN receptors, which are ostensibly absent in C. elegans , although other ligand-receptor systems likely mediate systemic immunity as part of the IPR (32). Our work, however, supports the notion that RLR activation of the IFN-I response in mammals, and the IPR in C. elegans, resulted from divergent evolution of an ancient immune pathway for sensing cytosolic nucleic acid (43). Proteins involved in co-evolutionary host/pathogen battles commonly undergo amino acid sequence diversification (51).…”

“…IPR activation by DRH-1(2CARD) conferred increased resistance to viral infection and increased survival following heat shock (Fig. 3), which are both phenotypes that have been previously linked to IPR activation (43). Prior to this study, the tissue requirement for DRH-1 in the context of Orsay virus infection remained unclear, although recent findings support a role for DRH-1 acting in the intestine to combat age-related pathology (44).…”

“…Canonical RLR signaling in mammals involves MAVS filament formation, as described above, followed by activation of the TBK-1 kinase, then phosphorylation and nuclear localization of the IRF3 transcription factor, which induces IFN-I gene expression and a systemic innate immune response (15). C. elegans lacks known homologs of TBK-1, IRF3 as well as MAVS, so its downstream signaling mechanisms are unknown (43). ZIP-1 is the only signaling factor identified so far that activates transcription downstream of DRH-1.…”

Proteasome inhibition triggers tissue-specific immune responses against different pathogens in C. elegans

“…elegans [ 10 ]. Likewise, the IPR can be induced either by inhibition of the purine salvage pathway as seen in pnp-1 mutants [ 14 , 15 ] or by blockade of the major protein degradation machinery in the cell, the proteasome [ 4 , 16 ].…”

CUL-6/cullin ubiquitin ligase-mediated degradation of HSP-90 by intestinal lysosomes promotes thermotolerance

“…In C. elegans , we recently described the Intracellular Pathogen Response (IPR) as a stress resistance pathway that appears to promote thermotolerance in a manner that is separate from the upregulation of chaperones by HSF-1. 7-10 The IPR comprises a common set of genes induced by natural intracellular pathogens of the intestine, including microsporidia and the Orsay virus, as well as by abiotic stressors like proteasome blockade and chronic heat stress. 11 A negative regulator of the IPR is pals-22 , a protein of unknown biochemical function but nonetheless serves a critical physiological function to repress IPR mRNA expression in the absence of infection or stress.…”