Zoonotic Viral Spillover: From Reservoir Ecology and Viral Evolution to Pandemic Prevention.

Zoonotic viral spillover represents a major global health challenge arising from complex interactions among viral evolution, reservoir ecology, host biology, environmental disruption, and human activities. Successful emergence requires viruses to overcome successive ecological, cellular, and immunological barriers, including receptor compatibility, cellular tropism, replication efficiency, and innate immune restriction. Reservoir hosts such as bats, rodents, birds, and livestock contribute to viral maintenance and diversification through distinct ecological and physiological characteristics, while deforestation, agricultural expansion, wildlife trade, intensive farming, urbanization, and climate variability can increase opportunities for cross-species transmission. Following spillover, viral adaptation and host susceptibility determine whether infections remain sporadic or progress to sustained human transmission. This review integrates ecological, molecular, immunological, and anthropogenic determinants of zoonotic emergence and examines major historical spillover events involving coronaviruses, influenza viruses, filoviruses, henipaviruses, and arboviruses. We further evaluate genomic and metagenomic surveillance, wastewater monitoring, artificial intelligence, ecological modeling, and integrated One Health approaches for early risk assessment and pandemic preparedness. Major knowledge gaps include limited characterization of global viral diversity, surveillance bias, inadequate functional validation of newly identified viruses, fragmented data systems, and limited predictive capacity. Future prevention requires integration of technological innovation with ecological conservation, equitable surveillance capacity, responsible biotechnology governance, and sustainable One Health Planetary Health strategies.