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Journal of Virology, September 2002, p. 8890-8899, Vol. 76, No. 17
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.17.8890-8899.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Hantaan Virus Infection Causes an Acute Neurological Disease That Is Fatal in Adult Laboratory Mice

Dominic Wichmann,1 Hermann-Josef Gröne,2 Michael Frese,3,{dagger} Jovan Pavlovic,4 Bärbel Anheier,1 Otto Haller,3 Hans-Dieter Klenk,1 and Heinz Feldmann5*

Institut für Virologie, Philipps-Universität, Marburg,1 Department of Cellular and Molecular Pathology, Deutsches Krebsforschungszentrum, Heidelberg,2 Institut für Medizinische Mikrobiologie und Hygiene, Universität Freiburg, Freiburg, Germany,3 Institut für Medizinische Virologie, Zürich, Switzerland,4 Canadian Science Centre for Human and Animal Health, National Microbiology Laboratory, Health Canada, Winnipeg, Manitoba, Canada5

Received 26 December 2001/ Accepted 21 May 2002

Hantaan virus, the etiological agent of Korean hemorrhagic fever, is transmitted to humans from persistently infected mice (Apodemus agrarius), which serve as the primary reservoir. Here we demonstrate that several strains of adult Mus musculus domesticus (C57BL/6, BALB/c, AKR/J, and SJL/J) were susceptible to Hantaan virus infection when infected intraperitoneally. First clinical signs were loss of weight, ruffled fur, and reduced activity, which were followed by neurological symptoms, such as paralyses and convulsions. Within 2 days of disease onset, the animals died of acute encephalitis. PCR analysis indicated a systemic infection with viral RNA present in all major organs. Immunohistochemical and in situ hybridization analyses of postmortem material detected viral antigen and RNA in the central nervous system (predominantly brain), liver, and spleen. In the central nervous system, viral antigen and RNA colocalized with perivascular infiltrations, the predominant pathological finding. To investigate the involvement of the interferon system in Hantaan virus pathogenesis, we infected alpha/beta interferon receptor knockout mice. These animals were more susceptible to Hantaan virus infection, indicating an important role of interferon-induced antiviral defense mechanisms in Hantaan virus pathogenesis. The present model may help to overcome shortcomings in the development of therapeutic and prophylactic measurements against hantavirus infections.

* Corresponding author. Mailing address: Canadian Science Centre for Human and Animal Health, 1015 Arlington St., Winnipeg, Manitoba R3E 3R2, Canada. Phone: (204) 789-6019. Fax: (204) 789-2140. E-mail: Heinz_Feldmann{at}hc-sc.gc.ca.

{dagger} Present address: Department of Molecular Virology, University of Heidelberg, Heidelberg, Germany.

Journal of Virology, September 2002, p. 8890-8899, Vol. 76, No. 17
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.17.8890-8899.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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