Immune factor of bacterial origin protects ticks against host skin microbes

Hard ticks are blood-feeding arthropods that carry and transmit microbes to their vertebrate hosts¹. Tick-borne disease cases have been on the rise over the last several decades, drawing much-needed attention to the molecular interplay between transmitted pathogens and their human hosts. However, far less is known about how ticks control their own microbes, which is critical for understanding how zoonotic transmission cycles persist. We previously found that ticks horizontally acquired an antimicrobial toxin gene from bacteria known as<underline>d</underline>omesticated<underline>a</underline>midase<underline>e</underline>ffector 2(dae2)². Here we show that this effector from the tick vectorIxodes scapularis(Dae2^Is) has structurally and biochemically diverged from ancestral bacterial representatives, expanding its antibacterial targeting range to include host skin microbes. Disruption ofdae2^Isincreases the burden of skin-associated staphylococci withinI. scapularisand adversely affects tick fitness, suggesting resistance of host microbes may be important for the parasitic blood-feeding lifestyle. In contrast, Dae2^Ishas no intrinsic ability to killBorrelia burgdorferi, the tick-borne bacterium of Lyme disease. Our observations suggest that ticks have evolved to tolerate their own symbionts while resisting host skin commensals, which we discover are natural opportunistic pathogens of ticks. This work moves our understanding of vector biology beyond a human-centric view: just as tick commensals are pathogenic to humans, so too do our commensals pose a threat to ticks. These observations illuminate how a complex and mirrored set of interkingdom interactions between blood-feeding vectors, their hosts, and associated microbes can ultimately lead to disease.