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

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 predicted deeply conserved miRNA-mRNA interactions that appear to contribute to tick lifecycle completion and tick's ability to parasitize diverse vertebrate hosts. Our analysis suggests that conserved tick miRNAs may mimic host miRNAs by exploiting shared target sites on host transcripts, potentially influencing regulatory circuits active during tick feeding and cross-kingdom communication. We identified 12 core tick salivary miRNAs-highly expressed and enriched in conserved target sites-predicted to cooperatively target 22 human genes, several of which are associated with processes relevant to parasitism establishment. These predicted cooperative interactions involve hub genes such as PDGFRA and NRG1, which are components of MAPK and PI3K-AKT pathways that regulate immune defense, tissue repair, and sensory responses. Our results suggest that I. ricinus miRNAs could potentially influence host homeostasis through cooperative targeting mechanisms, and they introduce a broadly applicable framework that leverages evolutionary conservation to detect meaningful cross-species miRNA-mRNA interactions.