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Journal of Virology, July 1999, p. 5970-5980, Vol. 73, No. 7
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

Laura K. Hanson,1 Jacquelyn S. Slater,1 Zaruhi Karabekian,1 Herbert W. Virgin IV,2 Christine A. Biron,3 Melanie C. Ruzek,3 Nico van Rooijen,4 Richard P. Ciavarra,1 Richard M. Stenberg,1 and Ann E. Campbell1,*

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.

* 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.

Journal of Virology, July 1999, p. 5970-5980, Vol. 73, No. 7
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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