Repeat tick exposure elicits distinct immune responses in guinea pigs and mice.

Ticks deposit salivary proteins into the skin during a bite to mediate acquisition of a blood meal. Acquired resistance to tick bites has been demonstrated to prevent Borrelia burgdorferi sensu lato (s.l.) transmission. However, the mechanism of resistance, as well as the protective antigens, have remained elusive. To address these unknowns, we utilized a guinea pig model of tick resistance and a mouse model of permissiveness. Guinea pigs developed immunity after multiple Ixodes scapularis tick infestations, characterized by rapid tick detachment and impaired feeding. In comparison, mice tolerated at least 6 infestations with no significant impact on feeding. We analyzed the bite sites by RNA-sequencing and histology, identifying several inflammatory pathways in tick immune animals, such as FcεRI signaling and complement activation, and activation of coagulation pathways that could impair local blood flow. Together, these results identify important pathways altered during tick rejection and potential tick proteins that could serve as vaccine candidates.