Positive interactions with symbionts can provide protection from disease in host organisms. However, these positive interactions often rely on relationships built through shared co-evolutionary history between hosts and symbionts. Invasions by non-native hosts can disrupt or decouple those positive interactions because invasive hosts do not share an evolutionary history with native symbionts, effectively decoupling disease-preventing positive interactions. We demonstrate how such symbiotic decoupling may be occurring in the freshwater cleaning symbiosis between crayfish and their branchiobdellidan symbionts, resulting in an increased intensity of crayfish plague. Recent evidence suggests that this cleaning symbiosis can reduce the effects of plague in host crayfish. However, because non-native crayfish are poor hosts for symbionts, symbiont abundance and diversity decline dramatically as the density of non-native hosts increases relative to native hosts. We combine evidence from field studies, laboratory experiments, and host immune gene expression to show how decoupling in this common cleaning symbiosis may be exacerbating the effects of crayfish plague, and to hypothesize how these effects project at regional and even continental scales.