Phenotypic plasticity of Nipah virus: An underappreciated driver of spillover risk

Phenotypic plasticity as an underrecognized feature of Nipah virus

Since its identification in Malaysia in 1998, Nipah virus (NiV) has been recognized as a priority zoonotic pathogen by the World Health Organization. Most discussions on NiV have focused on its high case fatality rate, which is commonly reported to range from 40% to 75%.1 Consequently, NiV is primarily regarded as a highly lethal virus, while its marked variability in clinical manifestations and transmission patterns is frequently neglected.

Unlike the influenza or dengue viruses, which typically display relatively stable symptom profiles, NiV exhibits substantial heterogeneity across outbreaks. During the initial outbreak in Malaysia, infection was predominantly neurotropic, with limited human-to-human transmission associated with pig-related spillover. Conversely, outbreaks in Bangladesh and India have been characterized by a respiratory-dominant phenotype, often accompanied by sustained person-to-person transmission.

These observations suggest that epidemic risk is not determined by virulence alone. Instead, the ability of NiV to adapt to diverse hosts and ecological contexts seems to play a pivotal role. Here, phenotypic plasticity refers to the capacity of viral populations to adjust functional behaviors under changing selective pressures and is hypothesized to represent an important facilitator of spillover risk. Conceptually, this short-term functional flexibility is distinct from quasispecies dynamics, which describe underlying genetic diversity,2 and from viral adaptation, which involves longer-term genetic fixation. Rather than replacing existing frameworks, this perspective complements current approaches by linking genomic signals with real-world transmission dynamics.

Clinical heterogeneity and viral adaptation in NiV infection

The diversity of clinical presentations provides an opportunity to examine viral adaptation in real-world settings. In the Malaysian lineage (NiV-M), intensive farming conditions might have favored viral variants adapted to porcine physiology, primarily leading to encephalitic disease in humans. In contrast, the Bangladesh lineage (NiV-B) circumvents intermediate hosts, transmitting directly from Pteropus bats to humans via contaminated date palm sap, where it exhibits a stronger predilection for the respiratory tract.

Importantly, the observed clinical heterogeneity among outbreaks cannot be attributed exclusively to viral phenotypic shifts. These differences are profoundly confounded by ecological and host factors, particularly the route of exposure and infectious dose. For instance, the neurotropic dominance in the Malaysian outbreak may be heavily influenced by close-contact exposure to aerosolized excretions from infected pigs in intensive farming settings.1 Conversely, the ingestion of heavily contaminated raw date palm sap in Bangladesh presents a fundamentally different route of viral entry.1 In this context, phenotypic plasticity may act alongside, rather than override, the effects of ecological and exposure-related determinants.