Nipah virus: an exceptionally virulent emerging zoonotic pathogen

Nipah virus (NiV) is a highly lethal zoonotic paramyxovirus harbored by fruit bats (Pteropodidae). The virus spreads through zoonotic spillover via intermediate animal hosts or contaminated environments, and through human-to-human transmission. Since its emergence in 1998, NiV has triggered recurrent outbreaks across South and Southeast Asia, with case-fatality rates of 40-75%. Two genotypes (NiV-M and NiV-B) differ in transmissibility and pathogenicity. WHO-listed as a priority pathogen, NiV has no approved vaccines or antiviral therapeutics. The virus gains entry into host cells through Ephrin-B2/B3 receptors, and evades innate immunity via non-structural proteins (V, W, C) and structural proteins. These evasion strategies disrupt multiple nodes in type I and II interferon (IFN-I/II) signaling pathways, including suppression of RIG-I/MAVS and inhibition of STAT1/STAT2 nuclear translocation, and dysregulation of NF-κB activation. Finally, these mechanisms facilitate viral replication and systemic dissemination. Infection also elicits adaptive immunity, including neutralizing antibodies against viral glycoproteins (G and F) and durable virus-specific CD4⁺ and CD8⁺ T-cell responses. Fatal outcomes correlate with high early viremia, delayed or insufficient antibody production, and dysregulated innate and adaptive immunity. In affected organs, particularly the brain, persistent cytokine storm driven predominantly by CXCL10 recruits inflammatory infiltrates and amplifies immunopathological damage. Current intervention strategies include vaccine candidates (ChAdOx1 Nipah B, mRNA-1215, HeV-sG) and antiviral approaches such as nucleoside analogs, monoclonal antibodies, and fusion inhibitors. This review comprehensively synthesizes current knowledge on NiV epidemiology, pathogenesis, and countermeasure development, providing a conceptual framework to interpret its exceptional virulence and prioritize targets for effective outbreak control.