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Murine cytomegalovirus (MCMV) infection in the lungs of T cell-deficient athymic BALB/c (Nu/ Nu) mice and their immunocompetent heterozygous (Nu/+) littermates was examined. Following intranasal inoculation, MCMV replicated in the lungs of both Nu/Nu and Nu/+ mice, but virus titers were significantly higher in T cell-deficient mice. After subcutaneous inoculation, virus disseminated to lung tissue of athymic mice, leading to progressive MCMV replication in lungs that was not seen in the immunocompetent mice. Athymic mice failed to develop an antibody response to MCMV. Histologically, athymic mice uniformly developed focal interstitial cellular aggregates adjacent to blood vessels or airways, which progressively enlarged and coalesced. Pneumonitis was not seen in the lungs of any Nu/+ mice. Thus, MCMV can replicate in the lungs without pneumonitis in immunocompetent mice, but MCMV produces a progressive focal pneumonitis during deficiency of T cell-mediated immunity.

Murine cytomegalovirus was found to replicate in lung and peritoneal macrophages of both CF-1 and BALB/c mice in vitro. Cytopathic changes typical of cytomegalovirus infection, including intranuclear inclusions, developed within the infected cells and eventually resulted in death of infected macrophages. Viral antigens were demonstrable by indirect immunofluorescence microscopy, and morphologically typical herpesvirus particles were observed in both nuclei and cytoplasm of murine cytomegalovirus-infected macrophages. Within 24 h after infection, at which time there was expression of viral antigens but no marcophage death, murine cytomegalovirus-infected macrophages demonstrated marked inhibition of phagocytosis of Staphylococcus aureus. Direct inhibition of macrophage function by cytomegalovirus infection in vivo could impair pulmonary defenses and may account in part for the frequent association of cytomegalovirus infection with other infectious agents.

Using a murine model of murine cytomegalovirus (MCMV) interstitial pneumonitis, we examined the relation between the virus content of the lung and lung disease. While MCMV alone does not cause lung disease, interstitial pneumonitis was present in all mice receiving both MCMV and a single dose of cyclophosphamide. In this case the severity of disease, judged by increases in wet weight of the lung, was proportional to the virus content of the lung. Although both acyclovir (50 mg/kg per day) and passive antibody administration reduced the MCMV titers in lung tissues by greater than 90%, histological evidence of interstitial pneumonitis was present in all animals. However, both virus inhibitors reduced the severity of interstitial pneumonitis in treated mice. While transient alterations in host immunity are necessary to induce interstitial pneumonitis after MCMV infection, the severity of interstitial pneumonitis seems to reflect the burden of virus replication. Reduction of virus growth does not prevent, but may moderate, MCMV interstitial pneumonitis.

Virus replication and interstitial pneumonia were studied in BALB/c mice inoculated intranasally with murine cytomegalovirus (MCMV). In normal mice MCMV replicated in lung tissue but did not produce any consistent histologic abnormalities through day 21. The addition of a single dose of cyclophosphamide (0.20 mg/g) 24 hr after virus inoculation resulted in a slight increase in lung virus titers on day 10. No histologic abnormalities were noted before day 10. However, 22 or 32 virus-infected mice treated with a single dose of cyclophosphamide but only two of 26 simultaneously mock-infected, cyclophosphamide-treated mice developed severe interstitial pneumonia 10-14 days after inoculation. In contrast, animals given cyclophosphamide (0.05 mg/g) every five days after the initial dose developed a 10-fold increase in lung virus titer, but interstitial pneumonia was not observed. These data suggest that the interstitial pneumonitis seen with MCMV pulmonary infection may be immunologically mediated rather than the result of direct viral damage to the lung.