The immune modules conserved across the tree of life: Towards a definition of ancestral immunity

Abstract

Immune defence mechanisms exist across the tree of life in such diversity that prokaryotic antiviral responses have historically been considered unrelated to eukaryotic immunity. Mechanisms of defence in divergent eukaryotes were similarly believed to be largely clade specific. However, recent data indicate that a subset of modules (domains and proteins) from prokaryote defence systems are conserved in eukaryotes and populate many stages of innate immune pathways. In this Essay, we propose the notion of ancestral immunity, which corresponds to the set of immune modules conserved between prokaryotes and eukaryotes. After offering a typology of ancestral immunity, we speculate on the selective pressures that could have led to the differential conservation of specific immune modules across domains of life. The exploration of ancestral immunity is in its infancy and appears full of promises to illuminate immune evolution, and also to identify and decipher immune mechanisms of economic, ecological, and therapeutic importance.

Fig 1. Defining ancestral immunity.

(A) Modules of ancestral immunity can be proteins, as exemplified by viperins, as well as domains, such as TIR domains, which are present in antiphage Thoeris and in mammalian TLRs. Eukaryotes also encode defences that are unrelated to those of bacteria, the mechanisms of which can be analogous to prokaryotic defence systems. For example, CRISPR-Cas of bacteria and the piRNA pathway of animals are 2 evolutionarily unrelated mechanisms of nucleic acid-guided memory [10]. Top panels: examples of prokaryotic (blue) and eukaryotic (green) proteins of interest. Structural comparison for viperins and TIR domains (generated with AlphaFold). Bottom panels summarise the modules’ mechanisms of action; prokaryotes are labelled in blue and eukaryotes in green. (B) Proposed classification for the modules of ancestral immunity according to shared ancestry (homology) and mechanism of action. VDJ recombination is an innovation of jawed vertebrates absent in bacteria, with no shared ancestry nor mechanistic conservation. Viperins display shared ancestry and mechanistic conservation. The boundaries of ancestral immunity are highlighted. Unknown mechanism refers to an undetermined molecular mechanism in prokaryotes and/or eukaryotes, despite a known (experimentally assessed) function in immunity. (C) Conservation of the modules of ancestral immunity in different clades of eukaryotes and prokaryotes. Prokaryotes: the percentage of genomes in which the module is detected are represented by shades of blues (based on the DefenseFinder database [11]). Eukaryotes: as inferred from the literature, common (widely conserved), present (detected in some genomes), or absent. “?” indicates that the literature is insufficient to assess conservation. TIR, Toll-interleukin-1 receptor; TLR, Toll-like receptor.

Fig 2. Putative scenario to explain the evolution of ancestral immunity.

(A) The emergence of ancestral immune modules depends on the selection of immune modules within prokaryotes, subject to selective pressures (step 1). A subset of modules is acquired by eukaryotes through vertical inheritance and horizontal gene transfer (step 2). Modules are selected within a eukaryotic framework (step 3). (B) Acquired immune modules are then utilised (through selection) for the construction of immune pathways, with diversification through tinkering (step 1), and selection of a subset of “tinkered-with” modules (step 2), which are included in and completed by original, nonbacterial immune mechanisms (step 3).