Abstract
Bacteria of the Spiroplasma ixodetis clade are well characterized as reproductive parasites and defensive endosymbionts of arthropods. Nevertheless, clinical evidence indicates that they can also infect humans, causing neonatal ocular disease and acute febrile illness in adults. Using metagenomic assembly and phylogenomic analyses of Spiroplasma ixodetis-related human infections (SiRHIs), combined with a systematic meta-analysis of public datasets, we identified 25 human cases across ten European countries. Despite the frequent detection of multiple S. ixodetis strains in ticks, our data provide no evidence implicating tick-associated strains in human infections. Instead, SiRHI constitute a distinct monophyletic lineage within the S. ixodetis clade, consistent with a shared evolutionary origin with arthropod-associated relatives. Notably, SiRHI genomes harbor horizontally acquired chaperone genes absent from most arthropod-associated Spiroplasma, while retaining conserved effector genes typical of endosymbionts, suggesting the preservation of ancestral symbiotic traits alongside newly acquired molecular adaptations.