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Journal of Virology, September 2001, p. 8781-8791, Vol. 75, No. 18
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.18.8781-8791.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Concerted Action of the FasL/Fas and Perforin/Granzyme A and B Pathways Is Mandatory for the Development of Early Viral Hepatitis but Not for Recovery from Viral Infection

Sandra Balkow,1 Astrid Kersten,2 Thi Thanh Thao Tran,1 Thomas Stehle,1 Philipp Grosse,1 Crisan Museteanu,1 Olaf Utermöhlen,3 Hanspeter Pircher,4 Fritz von Weizsäcker,5 Reinhard Wallich,6 Arno Müllbacher,7 and Markus M. Simon1,*

Max-Planck-Institut für Immunbiologie, 79108 Freiburg,1 Institut für Pathologie2 and Institute of Medical Microbiology and Hygiene, Department of Immunology,4 Universität Freiburg, 79104 Freiburg, Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, 50935 Cologne,3 Medizinische Universitätsklinik, Abteilung II, 79106 Freiburg,5 and Institut für Immunologie der Universität Heidelberg, 69120 Heidelberg,6 Germany, and Division of Immunology and Cell Biology, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory 2601, Australia7

Received 22 March 2001/Accepted 11 June 2001

Cytotoxic T lymphocytes (CTL) play a major role in the recovery from primary viral infections and the accompanying tissue injuries. However, it is unclear to what extent the two main cytolytic pathways, perforin-granzyme A and B exocytosis and Fas ligand (FasL)-Fas interaction, contribute to these processes. Here we have employed mouse strains with either spontaneous mutations or targeted gene defects in one or more components of either of the two cytolytic pathways to analyze the molecular basis of viral clearance and induction of hepatitis during lymphocytic choriomeningitis virus infection. Our results reveal that viral clearance is solely dependent on perforin but that virus-induced liver damage only occurs when both the FasL/Fas and the perforin pathways, including granzymes A and B, are simultaneously activated. The finding that development of hepatitis but not viral clearance is dependent on the concomitant activation of FasL-Fas and perforin-granzymes may be helpful in designing novel strategies to prevent hepatic failures during viral infections.

* Corresponding author. Mailing address: Max Plank-Institut für Immunbiologie, Stübeweg 51, 79108 Freiburg, Germany. Phone: 49 761/5108-533. Fax: 49 761/5108-529. E-mail: simon{at}immunbio.mpg.de.

Journal of Virology, September 2001, p. 8781-8791, Vol. 75, No. 18
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.18.8781-8791.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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