One Health, "Disease X" & the challenge of "Unknown" Unknowns

The emergence of SARS-CoV-2 and its rapid spread globally emphasizes the ever-present threat of emerging and re-emerging infectious diseases. In this review, the pathogen pyramid framework was utilized to identify the "unknown unknowns" associated with the emergence and rapid transmission of novel infectious disease agents. Given that the evolutionary origin of most of the emerging infectious disease agents can be traced to an animal source, we argue the need to integrate the "One Health" approach as a part of surveillance activities. The need for focusing on undertaking global and regional mapping activities to identify novel pathogens is discussed, given that there are an estimated 1.67 million unknown viruses, of which around 631,000 to 827,000 unknown viruses have the capacity to infect human beings. The emerging risks due to the ever-expanding interface between human, animals, both domestic and wildlife, and the environment are highlighted, these are largely driven by the need for safe habitation, growing food, developing infrastructure to support the increasing human population and desire for economic growth. The One Health approach provides a holistic way to address these cross-sectoral issues, by bridging institutional gaps, enumerating priority risk areas and pathogens, and highlighting putative risk factors for subsequent spillover events involving emerging and re-emerging infectious disease pathogens at the human-animal-environment interface.