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Journal of Virology, October 2001, p. 9918-9924, Vol. 75, No. 20
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.
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

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