Co-evolved Partners of Immunity: A Trait-Based Map of Human Keystone Organisms

Humans remain subject to ancient ecological forces in which persistent, human-adapted microbes act as partners and threats. We operationalize “key-stone organisms” as pathogens whose control requires coordinated engagement of multiple immune arms and whose residence is structured across tissue niches. Using 18 curated immunological and evolutionary traits across 43 organisms, unsupervised analyses resolved four archetypes; keystones score high on multi-arm coordination, co-evolutionary history and structured tropism, whereas non-human-specific pathogens and opportunists do not (Fig.1). Independent pairwise matrices (pathogen×immune-perturbation; pathogen×niche) yielded an interpretable systems readout—diagnostic breadth—which, together with niche use, separated keystones with 93% cross-validated accuracy and showed significant group differences (Kruskal-Wallis p = 0.026) (Fig. 2). At the micro level, focusing of memory on keystone-patterned epitopes creates niche-matched vulnerability to modified-self ligands, offering a mechanism for autoimmune and drug-hypersensitivity syndromes. In the same way, fast-evolving RNA viruses exploit keystone-established hierarchies by inflating immunodominant but mutable decoy epitopes that re-engage familiar memory while offering little control; unless immunogens exclude such decoys and force recognition of conserved, functionally constrained sites, vaccine responses are diverted and outpaced by host-specific adaptation [1–6].