Zoonotic diseases present a substantial global health burden. In this Opinion article, Plowrightet al. present an integrative conceptual and quantitative model that reveals that all zoonotic pathogens must overcome a hierarchical series of barriers to cause spillover infections in humans. Zoonotic spillover, which is the transmission of a pathogen from a vertebrate animal to a human, presents a global public health burden but is a poorly understood phenomenon. Zoonotic spillover requires several factors to align, including the ecological, epidemiological and behavioural determinants of pathogen exposure, and the within-human factors that affect susceptibility to infection. In this Opinion article, we propose a synthetic framework for animal-to-human transmission that integrates the relevant mechanisms. This framework reveals that all zoonotic pathogens must overcome a hierarchical series of barriers to cause spillover infections in humans. Understanding how these barriers are functionally and quantitatively linked, and how they interact in space and time, will substantially improve our ability to predict or prevent spillover events. This work provides a foundation for transdisciplinary investigation of spillover and synthetic theory on zoonotic transmission.

The regular cyclic fluctuations in vertebrate numbers have intrigued scientists for more than 70 years, and yet the cause of such cycles has not been clearly demonstrated. Red grouse populations in Britain exhibit cyclic fluctuations in abundance, with periodic crashes. The hypothesis that these fluctuations are caused by the impact of a nematode parasite on host fecundity was tested by experimentally reducing parasite burdens in grouse. Treatment of the grouse population prevented population crashes, demonstrating that parasites were the cause of the cyclic fluctuations.

Zeroing in on Zoonoses: Influenza, plague, and Lyme disease are classic examples of zoonoses—diseases that circulate in livestock and wildlife, as well as in humans. When a pathogen transfers among multiple hosts, the dynamics of circulation, transmission, and outbreak are complex. Lloyd-Smith et al. (p. 1362 ) review the use of analytical mathematical tools, particularly modeling, in the development of control policies and research agendas. Significant gaps are highlighted in analytical efforts during spillover transmission from animals into humans. Moreover, the tendency has been to focus on pathogens with simpler life cycles and of immediate global urgency, such as influenza, whereas insect-transmitted pathogens with complex, multihost life cycles are less well understood.