Rapid Nipah virus entry into the central nervous system of hamsters via the olfactory route

Vincent J Munster,Emmie De Wit,Rebecca Rosenke,Dan Long,Elizabeth R Fischer,Dana Scott,Heinz Feldmann,Joseph B Prescott,Tina Thomas,Trenton Bushmaker

doi:10.1038/srep00736

Abstract

Encephalitis is a hallmark of Nipah virus (NiV) infection in humans. The exact route of entry of NiV into the central nervous system (CNS) is unknown. Here, we performed a spatio-temporal analysis of NiV entry into the CNS of hamsters. NiV initially predominantly targeted the olfactory epithelium in the nasal turbinates. From there, NiV infected neurons were visible extending through the cribriform plate into the olfactory bulb, providing direct evidence of rapid CNS entry. Subsequently, NiV disseminated to the olfactory tubercle and throughout the ventral cortex. Transmission electron microscopy on brain tissue showed extravasation of plasma cells, neuronal degeneration and nucleocapsid inclusions in affected tissue and axons, providing further evidence for axonal transport of NiV. NiV entry into the CNS coincided with the occurrence of respiratory disease, suggesting that the initial entry of NiV into the CNS occurs simultaneously with, rather than as a result of, systemic virus replication.

Highlights

Encephalitis is a hallmark of Nipah virus (NiV) infection in humans
We followed the progression of Nipah virus upon intranasal inoculation from the nasal epithelium into the central nervous system (CNS) in the Syrian hamster model and showed that transport of virus along neurons in the olfactory epithelium into the brain is one pathway used by Nipah virus to enter the CNS and cause encephalitis
In a previous study we determined that intranasal inoculation of hamsters with 105 TCID50 of Nipah virus, strain Malaysia resulted in an initial respiratory phase of infection after which a www.nature.com/scientificreports demonstrated inflammation and necrosis of either the respiratory epithelium, olfactory epithelium or both

Summary

Introduction

Encephalitis is a hallmark of Nipah virus (NiV) infection in humans. The exact route of entry of NiV into the central nervous system (CNS) is unknown. Follow-up studies have shown that approximately 19% of patients that survived Nipah virus infection still suffered long-term neurological deficits that lasted more than four months after the initial outbreak[4,5]. A member of the closely related genus Morbillivirus in the family Paramyxoviridae, has been shown to travel to the CNS via anterograde transport along olfactory neurons in the nasal cavity, and via the hematogenous pathway, probably through infected lymphocytes[10]. We followed the progression of Nipah virus upon intranasal inoculation from the nasal epithelium into the CNS in the Syrian hamster model and showed that transport of virus along neurons in the olfactory epithelium into the brain is one pathway used by Nipah virus to enter the CNS and cause encephalitis. Entry of Nipah virus into the CNS occurred rapidly, within 4 days of inoculation

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Conclusion