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Although pneumonia virus of mice (PVM) is ubiquitous among rodent colonies in the United States, it has not been reported to cause clinically apparent disease in euthymic mice. However, PVM has been reported to cause respiratory disease and death in experimentally infected euthymic and athymic mice. A group of nu/nu mice, housed in quarantine in a Trexler-type isolator, had weight loss and dyspnea. Gross necropsy findings included cachexia and diffuse pulmonary edema or lobar consolidation. Histologically there was diffuse interstitial pneumonia. Electron microscopy revealed filamentous virions budding from plasma membranes, and immunohistochemical staining of lung tissue was positive for PVM antigen. PVM was isolated from affected lung tissue in BHK 21 cells and mouse antibody production tests resulted in seroconversion to PVM. Experimental inoculation of athymic mice with lung homogenate from spontaneously infected mice resulted in clinically apparent respiratory disease and histologic lung changes similar to those in naturally infected mice. Inoculation of athymic mice with infected BHK 21 cell culture fluid resulted in pneumonia which was qualitatively similar to, but less severe than, that observed in mice with spontaneous disease. These findings indicate that naturally occurring PVM infection in athymic mice may cause respiratory disease and wasting.