A golden hamster model for human acute Nipah virus infection

Abstract

A predominantly pig-to-human zoonotic infection caused by the novel Nipah virus emerged recently to cause severe morbidity and mortality in both animals and man. Human autopsy studies showed the pathogenesis to be related to systemic vasculitis that led to widespread thrombotic occlusion and microinfarction in most major organs especially in the central nervous system. There was also evidence of extravascular parenchymal infection, particularly near damaged vessels (Wong KT, Shieh WJ, Kumar S, Norain K, Abdullah W, Guarner J, Goldsmith CS, Chua KB, Lam SK, Tan CT, Goh KJ, Chong HT, Jusoh R, Rollin PE, Ksiazek TG, Zaki SR, Nipah Virus Pathology Working Group: Nipah virus infection: Pathology and pathogenesis of an emerging paramyxoviral zoonosis. Am J Pathol 2002, 161:2153-2167). We describe here a golden hamster (Mesocricetus auratus) model that appears to reproduce the pathology and pathogenesis of acute human Nipah infection. Hamsters infected by intranasal or intraperitoneal routes died within 9 to 29 days or 5 to 9 days, respectively. Pathological lesions were most severe and extensive in the hamster brain. Vasculitis, thrombosis, and more rarely, multinucleated endothelial syncytia, were found in blood vessels of multiple organs. Viral antigen and RNA were localized in both vascular and extravascular tissues including neurons, lung, kidney, and spleen, as demonstrated by immunohistochemistry and in situ hybridization, respectively. Paramyxoviral-type nucleocapsids were identified in neurons and in vessel walls. At the terminal stage of infection, virus and/or viral RNA could be recovered from most solid organs and urine, but not from serum. The golden hamster is proposed as a suitable model for further studies including pathogenesis studies, anti-viral drug testing, and vaccine development against acute Nipah infection.

Figure 1.

Survival graphs of hamsters infected by NiV via different routes and doses.

Figure 2.

Vascular and parenchymal pathology in acute Nipah infection. A: Large artery in liver showing focal, transmural fibrinoid necrosis with surrounding inflammation. B: Myocardial necrosis (thin arrow) with adjacent inflammation (thick arrow). C: Multiple endothelial multinucleated syncytium (arrows) in pulmonary artery. D: Viral RNA was demonstrated in endothelial syncytia (thin arrows) and vascular smooth muscle (thick arrow) in the same lung. E: Necrosis and karyorrhexis in a cerebral vessel. F: Viral antigen localized to endothelium (thick arrow) and smooth muscle (thin arrows) in a meningeal blood vessel. A–C, E: Hemalin-phloxine-safranin stain; D: in situ hybridization, hematoxylin counterstain; F: IHC, hematoxylin counterstain. Original magnifications: ×20 (A, B); ×40 (D); ×100 (C, E, F).

Figure 3.

Cerebral pathology in acute Nipah infection. A: Small vessel vasculitis (arrow) characterized by mild inflammation in the vicinity of infected neurons. B: Focal areas of parenchymal ischemia, infarction, and edema. C: Neurons with eosinophilic viral inclusions (arrows). D: Immunolocalization of viral antigens to neurons in the nucleus (inset, arrow), cytoplasm, and processes near a vasculitic vessel (arrow). E: Viral antigens localized to ependymal lining (arrow) and neurons. F: Neurons demonstrating viral RNA in the cytoplasm (arrows). A–C: Hemalin-phloxine-safranin stain; D, E: IHC, hematoxylin counterstain; F:in situ hybridization, hematoxylin counterstain. Original magnifications: ×40 (A, B, E, D (inset), ×20 (D); ×100 (C, F).

Figure 4.

A, B: Inflammation in the lung parenchyma associated with vasculitic and thrombotic blood vessels (arrow). C: Glomerulitis characterized by thrombotic plugs, inflammation, and syncytial formation (arrow) at the periphery of the glomerulus. D: Viral antigens were detected in a tubule and glomerulus (arrow). E: Viral antigens found in the epithelium covering the papilla in the kidney (arrow). F: Viral antigens demonstrated in lymphoid cells of the white pulp in the spleen. A–C: Hemalin-phloxine-safranin stain; D-F: IHC, hematoxylin counterstain. Original magnifications: ×5 (A); ×20 (B, F); ×40 (C–E).

Figure 5.

A: Cytoplasmic viral inclusion (arrows) composed of nucleocapsids in a neuron. B: Immunogold-labeled neuronal viral inclusion (arrows) demonstrated by immunoelectron microscopy with specific anti-Nipah antibody. N, nucleus. Scale bars, 0.5 μm.