An innate ability: How do basal invertebrates manage their chronic exposure to microbes?

Abstract

Homologs of mammalian innate immune sensing and downstream pathway proteins have been discovered in a variety of basal invertebrates, including cnidarians and sponges, as well as some single-celled protists. Although the structures of these proteins vary among the basal organisms, many of the activities found in their mammalian counterparts are conserved. This is especially true for the Toll-like receptor (TLR) and cGAS-STING pathways that lead to downstream activation of transcription factor NF-κB. In this short perspective, we describe the evidence that TLR and cGAS-STING signaling to NF-κB is also involved in immunity in basal animals, as well as in the maintenance of microbial symbionts. Different from terrestrial animals, immunity in many marine invertebrates might have a constitutively active state (to protect against continual exposure to resident or waterborne microbes), as well as a hyperactive state that can be induced by pathogens at both transcriptional and posttranscriptional levels. Research on basal immunity may be important for (1) understanding different approaches that organisms take to sensing and protecting against microbes, as well as in maintaining microbial symbionts; (2) the identification of novel antimicrobial effector genes and processes; and (3) the molecular pathways that are being altered in basal marine invertebrates in the face of the effects of a changing environment.

Fig 1. TLR and cGAS-STING signaling molecules in basal organisms.

(A) General phylogenetic tree of the basal organisms discussed in this review. Capsaspora and choanoflagellates are protists. Porifera comprises the sponges, and Cnidaria includes sea anemones, jellyfish, corals, and hydra. (B) From the limited sampling of basal invertebrates, it is clear that there is great diversity in the TLR and cGAS-STING pathways, as compared to flies and vertebrates. For example, mammalian-like TLRs with extracellular pathogen recognition LRRs, TMs, and intracellular TIR domains are even present in some choanoflagellates. Nevertheless, there are also LRR- and TIR-only proteins in other phyla, including Cnidaria and Porifera. Similarly, cGAS and STING homologs are found among a variety of basal eukaryotes. However, these basal cGAS and STING homologs are sometimes missing domains found in vertebrates (e.g., for double-stranded DNA binding in cGAS or IRF3->interferon signaling in STING). The cyclic GAMP molecules preferred by STING can differ among basal organisms. See text for further details. LRR, leucine-rich region; TIR, Toll/interleukin-1 receptor domain; TLR, Toll-like receptor; TM, transmembrane domain.

Fig 2. Mammalian and basal innate immune signaling via NF-κB.

(A) In a simplified mammalian immune pathway, the innate immune pathway is OFF in the resting state, especially as indicated by no nuclear NF-κB-dependent transcription of immune genes. In the pathogen-induced state—either via activation of TLRs or cGAS-STING—the nuclear translocation of active NF-κB leads to rapid and robust activation of immune effector genes. (B) In many basal invertebrates, in the resting state, it appears that there is constitutive activation of the NF-κB pathway, either due to resident microbes or presumably chronic exposure to microbes in marine environments. An acute exposure to pathogens can lead to a hyperimmune state, which is characterized by further nuclear translocation of NF-κB, as well as increased transcription of innate immune pathway components (indicated by the larger TLR and NF-κB fonts in the right half of the figure). Further details can be found in the text.