Research Article: A Human Lung Xenograft Mouse Model of Nipah Virus Infection

Date Published: April 3, 2014

Publisher: Public Library of Science

Author(s): Gustavo Valbuena, Hailey Halliday, Viktoriya Borisevich, Yenny Goez, Barry Rockx, Andrew Pekosz.

http://doi.org/10.1371/journal.ppat.1004063

Abstract

Nipah virus (NiV) is a member of the genus Henipavirus (family Paramyxoviridae) that causes severe and often lethal respiratory illness and encephalitis in humans with high mortality rates (up to 92%). NiV can cause Acute Lung Injury (ALI) in humans, and human-to-human transmission has been observed in recent outbreaks of NiV. While the exact route of transmission to humans is not known, we have previously shown that NiV can efficiently infect human respiratory epithelial cells. The molecular mechanisms of NiV-associated ALI in the human respiratory tract are unknown. Thus, there is an urgent need for models of henipavirus infection of the human respiratory tract to study the pathogenesis and understand the host responses. Here, we describe a novel human lung xenograft model in mice to study the pathogenesis of NiV. Following transplantation, human fetal lung xenografts rapidly graft and develop mature structures of adult lungs including cartilage, vascular vessels, ciliated pseudostratified columnar epithelium, and primitive “air” spaces filled with mucus and lined by cuboidal to flat epithelium. Following infection, NiV grows to high titers (107 TCID50/gram lung tissue) as early as 3 days post infection (pi). NiV targets both the endothelium as well as respiratory epithelium in the human lung tissues, and results in syncytia formation. NiV infection in the human lung results in the production of several cytokines and chemokines including IL-6, IP-10, eotaxin, G-CSF and GM-CSF on days 5 and 7 pi. In conclusion, this study demonstrates that NiV can replicate to high titers in a novel in vivo model of the human respiratory tract, resulting in a robust inflammatory response, which is known to be associated with ALI. This model will facilitate progress in the fundamental understanding of henipavirus pathogenesis and virus-host interactions; it will also provide biologically relevant models for other respiratory viruses.

Partial Text

Nipah virus (NiV) is a member of the genus Henipavirus (family Paramyxoviridae) that causes severe and often lethal respiratory illness and encephalitis in humans resulting in case fatality rates of up to 92% [1]. The first human cases of NiV infection were identified during an outbreak of severe febrile encephalitis in Malaysia and Singapore in 1998–1999 [2], [3]. More recently, outbreaks have occurred in Bangladesh and India almost yearly since 2001 [1], [4]. NiV can cause Acute Lung Injury (ALI) in humans, and human-to-human transmission has been observed in recent outbreaks of NiV [5], [6], [7]. Data on the histopathology of the lungs of NiV cases is limited to necropsy findings in the respiratory tract of NiV infected cases and include hemorrhage, necrosis and inflammation in the epithelium of the small airways but not in the bronchi [8].

Nipah virus is an emerging zoonotic virus that can cause severe respiratory distress and encephalitis in humans [1]. Despite intensive studies in vitro and in animal models, little is known about the mechanisms governing the development of NiV-related respiratory disease in humans; this is due to difficulties in obtaining human samples where the disease is endemic. To address this important limitation, the goal of the present study was to characterize a novel human lung xenograft model to study the pathogenesis of NiV infection in human lung in vivo.

 

Source:

http://doi.org/10.1371/journal.ppat.1004063

 

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