Tick Extracellular Vesicles Alter Epidermal Keratinocyte Function

Wound healing has been extensively studied through the lens of inflammatory disorders and cancer, but limited attention has been given to hematophagy and arthropod-borne diseases. Hematophagous ectoparasites, including ticks, subvert the wound healing response to maintain prolonged attachment and facilitate blood feeding. In this study, we unveil a strategy through which extracellular vesicles ensure blood feeding and arthropod survival in 3 medically relevant tick species. Through single-cell RNA sequencing and murine genetics, we demonstrate that wild-type animals infested with Ixodes scapularis that produce fewer extracellular vesicles display a unique epidermal subpopulation with a mesenchymal-like transcriptional program and an overrepresentation of pathways connected to wound healing. Furthermore, tick extracellular vesicles inhibit proliferation and diminish the capacity of gap closure in keratinocytes using an in vitro scratch assay. This occurrence was linked to phosphoinositide 3-kinase activity, keratinocyte GF 1, and TGF-β levels. Collectively, we uncovered a strategy employed by a blood-feeding arthropod that disrupts the circuitry in cutaneous wound healing, contributing to ectoparasite fitness.