Nipah Virus (NiV) at the Human-Animal-Environment Interface: Emerging Insights into Spillover Dynamics, Neurotropism, and Future Pandemic Risk

Nipah virus (NiV), a highly pathogenic member of the Henipavirus genus within the Paramyxoviridae family, continues to represent a critical zoonotic threat at the intersection of humans, animals, and the environment. First identified in Malaysia in 1998, NiV has since emerged as a paradigm of viral spillover driven by ecological disruption and anthropogenic activities. This review elucidates contemporary insights into the complex interplay governing NiV transmission dynamics, molecular neurotropism, and its potential to precipitate future pandemics. The spillover of NiV from its natural reservoir, Pteropus fruit bats, to intermediate hosts such as pigs, and ultimately to humans, is profoundly influenced by habitat fragmentation, agricultural intensification, and climate-induced alterations in bat foraging behavior. At the molecular level, NiV exhibits pronounced neurotropism and vasculotropism mediated through its interaction with ephrin-B2 and ephrin-B3 receptors, leading to widespread endothelial infection, microvascular damage, and neuronal dysfunction that culminate in fatal encephalitis. Moreover, the virus demonstrates immune evasion strategies that suppress interferon signaling, thereby facilitating systemic dissemination. Despite its high case fatality rate and recurrent outbreaks in South and Southeast Asia, the absence of licensed antiviral therapies or vaccines underscores the urgency of advancing translational research and cross-sectoral surveillance frameworks. The convergence of ecological perturbations, viral adaptability, and limited healthcare infrastructure in endemic regions amplifies the likelihood of future spillover and sustained human-to-human transmission. A unified One Health approach integrating virological, ecological, and epidemiological disciplines is imperative to mitigate NiV’s pandemic potential and to strengthen global preparedness against emerging zoonoses. Keywords: Neurotropism, Nipah virus (NiV), One Health, Pandemic preparedness, Spillover dynamics, Zoonotic transmission.