Tick extracellular vesicles undermine epidermal wound healing during hematophagy

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. Here, we unveil a strategy by which extracellular vesicles (EVs) ensure blood-feeding and arthropod survival in three medically relevant tick species. We demonstrate through single cell RNA sequencing and murine genetics that wildtype animals infested with EV-deficientIxodes scapularisdisplay a unique population of keratinocytes with an overrepresentation of pathways connected to wound healing. Tick feeding affected keratinocyte proliferation in a density-dependent manner, which relied on EVs and dendritic epidermal T cells (DETCs). This occurrence was linked to phosphoinositide 3-kinase activity, keratinocyte growth factor (KGF) and transforming growth factor β (TGF-β) levels. Collectively, we uncovered a strategy employed by a blood-feeding arthropod that impairs the integrity of the epithelial barrier, contributing to ectoparasite fitness.