An Integrative Framework Identifies Cooperative Targeting of Host Pathways by Tick Salivary miRNAs

Abstract Ticks are ectoparasites that modulate host responses to sustain prolonged blood feeding, and in Ixodes ricinus , salivary microRNAs (miRNAs) represent promising candidates for manipulating host gene expression. Using phylogenetic footprinting combined with cooperative targeting analysis, we identified deeply conserved miRNA–mRNA interactions that appear essential for the tick lifecycle and its ability to parasitize diverse vertebrate hosts. Our findings show that conserved tick miRNAs can mimic host miRNAs by exploiting shared target sites on host transcripts, allowing them to modulate regulatory circuits critical during tick feeding. We identified twelve core salivary miRNAs—highly expressed and enriched in conserved target sites—that cooperatively target twenty-two human genes predominantly expressed in skin and neural tissues. This cooperative suppression converges on host hub genes like PDGFRA and NRG1 , linking tick miRNA activity to MAPK and PI3K–AKT pathways that regulate immune defense, tissue repair, and sensory responses. Overall, our results demonstrate that I. ricinus miRNAs can synergistically disrupt host homeostasis, and they introduce a broadly applicable framework that leverages evolutionary conservation to detect meaningful cross-species miRNA–mRNA interactions. Highlights The study shows that tick miRNAs with Bilaterian node of origin mimic host miRNAs to exploit conserved target sites of host mRNAs. It demonstrates that these conserved tick miRNAs cooperatively repress key host defense and repair pathways. It introduces a framework that leverages evolutionary conservation to detect and explain functional, conserved cross-species miRNA–mRNA regulation. Abstract Figure