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Nipah virus is a zoonotic pathogen that causes severe disease in humans. The mechanisms of pathogenesis are not well described. The first Nipah virus outbreak occurred in Malaysia, where human disease had a strong neurological component. Subsequent outbreaks have occurred in Bangladesh and India and transmission and disease processes in these outbreaks appear to be different from those of the Malaysian outbreak. Until this point, virtually all Nipah virus studies in vitro and in vivo, including vaccine and pathogenesis studies, have utilized a virus isolate from the original Malaysian outbreak (NiV-M). To investigate potential differences between NiV-M and a Nipah virus isolate from Bangladesh (NiV-B), we compared NiV-M and NiV-B infection in vitro and in vivo. In hamster kidney cells, NiV-M-infection resulted in extensive syncytia formation and cytopathic effects, whereas NiV-B-infection resulted in little to no morphological changes. In vivo, NiV-M-infected Syrian hamsters had accelerated virus replication, pathology and death when compared to NiV-B-infected animals. NiV-M infection also resulted in the activation of host immune response genes at an earlier time point. Pathogenicity was not only a result of direct effects of virus replication, but likely also had an immunopathogenic component. The differences observed between NiV-M and NiV-B pathogeneis in hamsters may relate to differences observed in human cases. Characterization of the hamster model for NiV-B infection allows for further research of the strain of Nipah virus responsible for the more recent outbreaks in humans. This model can be used to study NiV-B pathogenesis, transmission, and countermeasures that could be used to control outbreaks. Author Summary: Nipah virus causes severe disease in humans and outbreaks have occurred in two geographic regions, Malaysia and Bangladesh, and viruses have been isolated during outbreaks from both of these regions (NiV-M and NiV-B, respectively). The original outbreak of Nipah virus occurred in Malaysia and caused severe encephalitis in humans. All subsequent outbreaks of Nipah virus have occurred in Bangladesh or India and disease has been characterized as having a strong respiratory component. Nipah virus is a public health concern that can cause up to 100% lethality in humans and there is no approved treatment or vaccine. Current research should focus on understanding disease progression and pathogenicity. We compared NiV-M and NiV-B infection and disease progression using the Syrian hamster model. We found that NiV-M is more destructive in cultured hamster cells and has faster onset of cytopathogenicity compared to NiV-B. This is also true in hamsters, where although both viruses are pathogenic and cause a similar disease, pathology caused by NiV-M infection is accelerated. These data show that there is a difference in disease progression between the two strains of Nipah virus and will allow for a more detailed understanding of the events leading to disease caused by these viruses. [ABSTRACT FROM AUTHOR]