Evolution of hematophagy in blood-sucking parasites likely involves communication with their hosts. We find that Ixodes ticks are responsive to IFNg acquired in a blood meal from mice infected with the Lyme disease-causing bacteria Borrelia burgdorferi, leading to induction of antimicrobial responses. Ixodes ticks parasitizing B. burgdorferi-infected mice upregulated an I. scapularis Rho-like GTPase (IGTPase). IGTPase knockdown enhanced B. burgdorferi levels in postfed ticks, suggesting this protein controls spirochete survival. Notably, IGTPase was only induced during pathogen acquisition from mice and not upon transmission to naive hosts. Microinjection of ticks with IFNg induced IGTPase, and ticks parasitizing IFNg knockout mice, failed to upregulate IGTPase. Additionally, ticks lacking the transcription factor STAT, which signals downstream of IFNg, did not induce IGTPase. IGTPase expression induced antimicrobial peptides, including Dae2, previously shown to inhibit B. burgdorferi. These results identify an interspecies signaling cascade allowing ticks to detect invading bacteria and mount microbicidal responses.