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Journal of Virology, October 2001, p. 9918-9924, Vol. 75, No. 20
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.20.9918-9924.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Alternative Mechanisms of Respiratory Syncytial Virus Clearance in Perforin Knockout Mice Lead to Enhanced Disease

Sandra Aung,1,dagger John A. Rutigliano,1 and Barney S. Graham2,*

Departments of Microbiology and Immunology1 and Medicine,2 Vanderbilt University School of Medicine, Nashville, Tennessee 37232

Received 15 March 2001/Accepted 29 May 2001

Virus-specific cytotoxic T lymphocytes are key effectors for the clearance of virus-infected cells and are required for the normal clearance of respiratory syncytial virus (RSV) in mice. Although perforin/granzyme-mediated lysis of infected cells is thought to be the major molecular mechanism used by CD8+ cytotoxic T lymphocytes for elimination of virus, its role in RSV has not been reported. Here, we show that viral clearance in perforin knockout (PKO) mice is slightly delayed but that both PKO and wild-type mice clear virus by day 10, suggesting an alternative mechanism of RSV clearance. Effector T cells from the lungs of both groups of mice were shown to lyse Fas (CD95)-overexpressing target cells in greater numbers than target cells expressing low levels of Fas, suggesting that Fas ligand (CD95L)-mediated target cell lysis was occurring in vivo. This cell lysis was associated with a delay in RSV-induced disease in PKO mice compared to the time of disease onset for wild-type controls, which correlated with increased and prolonged production of gamma interferon and tumor necrosis factor alpha levels in PKO mice. We conclude that while perforin is not necessary for the clearance of primary RSV infection, the use of alternative CTL target cell killing mechanisms is less efficient and can lead to enhanced disease.

* Corresponding author. Present address: Vaccine Research Center/National Institutes of Health, Bldg. 40, Room 2502, 40 Convent Dr., Bethesda, MD 20892-3017. Phone: (301) 594-8468. Fax: (301) 480-2771. E-mail: bgraham{at}nih.gov.

dagger Present address: Department of Immunology IMM-15, The Scripps Research Institute, La Jolla, CA 92037.

Journal of Virology, October 2001, p. 9918-9924, Vol. 75, No. 20
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.20.9918-9924.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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