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The rapid, global spread and human health impacts of SARS-CoV-2, the agent of COVID-19 disease, demonstrates humanity’s vulnerability to zoonotic disease pandemics. Although anthropogenic land use change is known to be the major driver of zoonotic pathogen spillover from wildlife to human populations, the scientific underpinnings of land use-induced zoonotic spillover have rarely been investigated from the macro-ecology perspective. We call on colleagues to advance our knowledge of land use implications for zoonotic disease emergence. A wide range of disciplinary cosmologies, approaches, and tools are needed to identify the environmental triggers of spillover and inform the decisions needed to protect public health by reducing spillover risk as a biosecurity priority. We call for a mechanistic focus on the zoonotic pathogen “infect-shed-spill-spread” cascade and review the relevant literature, elucidating the current biases and information gaps. We also consider the opportunities for better instituting the necessary scientific collaboration, primary technical challenges, and policy and management issues that warrant particular attention.

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