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Journal of Virology, July 1999, p. 5970-5980, Vol. 73, No. 7
Department of Microbiology and Molecular Cell
Biology, Eastern Virginia Medical School, Norfolk, Virginia
235071; Department of Pathology,
Washington University School of Medicine, St. Louis, Missouri
631102; Department of Molecular
Microbiology and Immunology, Brown University, Providence, Rhode Island
029123; and Department of Cell
Biology and Immunology, Free University, Amsterdam, The
Netherlands4
Received 30 November 1998/Accepted 16 April 1999
Blood monocytes or tissue macrophages play a pivotal role in the
pathogenesis of murine cytomegalovirus (MCMV) infection, providing
functions beneficial to both the virus and the host. In vitro and in
vivo studies have indicated that differentiated macrophages support
MCMV replication, are target cells for MCMV infection within tissues,
and harbor latent MCMV DNA. However, this cell type presumably
initiates early, antiviral immune responses as well. In addressing this
paradoxical role of macrophages, we provide evidence that the
proficiency of MCMV replication in macrophages positively correlates
with virulence in vivo. An MCMV mutant from which the open reading
frames M139, M140, and M141 had been deleted (RV10) was defective in
its ability to replicate in macrophages in vitro and was highly
attenuated for growth in vivo. However, depletion of splenic
macrophages significantly enhanced, rather than deterred, replication
of both wild-type (WT) virus and RV10 in the spleen. The ability of
RV10 to replicate in intact or macrophage-depleted spleens was
independent of cytokine production, as this mutant virus was a poor
inducer of cytokines compared to WT virus in both intact organs and
macrophage-depleted organs. Macrophages were, however, a major
contributor to the production of tumor necrosis factor alpha and gamma
interferon in response to WT virus infection. Thus, the data indicate
that tissue macrophages serve a net protective role and may function as
"filters" in protecting other highly permissive cell types from
MCMV infection. The magnitude of virus replication in tissue
macrophages may dictate the amount of virus accessible to the other
cells. Concomitantly, infection of this cell type initiates the
production of antiviral immune responses to guarantee efficient
clearance of acute MCMV infection.
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Replication of Murine Cytomegalovirus in
Differentiated Macrophages as a Determinant of Viral
Pathogenesis
*
Corresponding author. Mailing address: Department of
Microbiology and Molecular Cell Biology, Eastern Virginia Medical
School, P.O. Box 1980, 700 W. Olney Rd., Norfolk, VA 23507. Phone:
(757) 446-5667. Fax: (757) 624-2255. E-mail:
campbeae{at}evms.edu.
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