Drivers of zoonotic spillover at human–domestic animal–wildlife interfaces: a multi-species model incorporating wildlife chronic stress

Abstract Zoonotic disease emergence at the wildlife–domestic animal–human interface results from a complex interplay of ecological, physiological and anthropogenic factors. Here, we have developed a multi-environment, multi-host compartmental model to identify key drivers of spillover risk across urban, rural and natural environments. The framework incorporates heterogeneous host populations, inter-species contacts and host movement, and includes wildlife chronic stress as one factor influencing susceptibility, transmissibility and recovery. Sensitivity analyses show that domestic animal populations at agricultural interfaces strongly amplify spillover risk through their recovery dynamics and per-contact transmission probabilities, while within-wildlife transmission across environments also shapes system dynamics. Chronic stress effects can further increase spillover risk, and the model indicates that reducing wildlife stress alongside improving domestic animal health and management can markedly lower the likelihood of cross-species transmission. These findings highlight the importance of maintaining ecological conditions that reduce chronic physiological stress in wildlife populations and integrating physiological and ecological data into epidemiological modelling. Such models can inform both bottom-up interventions targeting domestic animals and top-down strategies that sustain resilient wildlife communities and, thereby, mitigate zoonotic spillover.