Journal : Severe Acute Respiratory Syndrome Coronavirus Infection Causes Neuronal Death in the Absence of Encephalitis in Mice Transgenic for Human AC

Jason Netland,¹ David K. Meyerholz,² Steven Moore,² Martin Cassell,³ and Stanley Perlman^1,4*

Journal of Virology, August 2008, p. 7251, Vol. 82, No. 15
0022-538X/08/$08.00+0 doi:10.1128/JVI.01175-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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Interdisciplinary Program in Immunology,¹ Departments of Pathology,² Anatomy and Cell Biology,³ Microbiology, University of Iowa, Iowa City, Iowa 52242⁴

Received 3 April 2008/ Accepted 12 May 2008

Infection of humans with the severe acute respiratory syndrome coronavirus (SARS-CoV) results in substantial morbidity and mortality, with death resulting primarily from respiratory failure. While the lungs are the major site of infection, the brain is also infected in some patients. Brain infection may result in long-term neurological sequelae, but little is known about the pathogenesis of SARS-CoV in this organ. We previously showed that the brain was a major target organ for infection in mice that are transgenic for the SARS-CoV receptor (human angiotensin-converting enzyme 2). Herein, we use these mice to show that virus enters the brain primarily via the olfactory bulb, and infection results in rapid, transneuronal spread to connected areas of the brain. This extensive neuronal infection is the main cause of death because intracranial inoculation with low doses of virus results in a uniformly lethal disease even though little infection is detected in the lungs. Death of the animal likely results from dysfunction and/or death of infected neurons, especially those located in cardiorespiratory centers in the medulla. Remarkably, the virus induces minimal cellular infiltration in the brain. Our results show that neurons are a highly susceptible target for SARS-CoV and that only the absence of the host cell receptor prevents severe murine brain disease.

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* Corresponding author. Mailing address: Department of Microbiology, University of Iowa, BSB 3-712, Iowa City, IA 52242. Phone: (319) 335-8549. Fax: (319) 335-9999. E-mail: stanley-perlman@uiowa.edu Published ahead of print on 21 May 2008.