Replication of murine cytomegalovirus in differentiated macrophages as a determinant of viral pathogenesis

Blood monocytes or tissue macrophages play a pivotal role in the pathogenes is of murine cytomegalovirus (MCMV) infection, providing functions benefici al to both the virus and the host. In vitro and in vivo studies have indica ted that differentiated macrophages support MCMV replication, are target ce lls for MCMV infection within tissues, and harbor latent MCMV DNA. However, this cell type presumably initiates early, antiviral immune responses as w ell. In addressing this paradoxical role of macrophages, we provide evidenc e that the proficiency of MCMV replication in macrophages positively correl ates with virulence in vivo. An MCMV mutant from which the open reading fra mes M139, M140, and M141 had been deleted (RV10) was defective in its abili ty to replicate in macrophages in vitro and was highly attenuated for growt h in vivo. However, depletion of splenic macrophages significantly enhanced , rather than deterred, replication of both wild-type (WT) virus and RV10 i n the spleen. The ability of RV10 to replicate in intact or macrophage-depl eted spleens was independent of cytokine production, as this mutant virus w as a poor inducer of cytokines compared to WT virus in both intact organs a nd macrophage-depleted organs. Macrophages were, however, a major contribut or to the production of tumor necrosis factor alpha and gamma interferon in response to WT virus infection. Thus, the data indicate that tissue macrop hages serve a net protective role and may function as "filters" in protecti ng other highly permissive cell types from MCMV infection. The magnitude of virus replication in tissue macrophages may dictate the amount of virus ac cessible to the other cells. Concomitantly, infection of this cell type ini tiates the production of antiviral immune responses to guarantee efficient clearance of acute MCMV infection.