Hard ticks interface with diverse microbes while feeding on vertebrate hosts. We previously discovered that ticks horizontally acquired an antimicrobial toxin gene from bacteria known as domesticated amidase effector 2 ( dae2 ). Here we show that this effector from the tick disease vector Ixodes scapularis (Dae2 Is ) is delivered to the host bite site via saliva and that its structural and biochemical divergence from bacterial homologs results in an expanded targeting range to include host skin microbes. Upon disruption of dae2Is , we found higher loads of skin-associated staphylococci within ticks, adversely affecting their fitness. In contrast, Dae2 Is  has no intrinsic lytic activity against Borrelia burgdorferi , the tick-borne pathogen of Lyme disease. Our observations suggest ticks have evolved to preferentially resist opportunistic pathogens, such as host skin commensals, while tolerating their own symbionts. These results highlight a unique interkingdom interface between blood-feeding vectors, hosts, and their associated microbes where incompatible host-microbe interactions lead to disease.### Competing Interest StatementThe authors have declared no competing interest.

Immune factor of bacterial origin protects ticks against host microbial commensals