A. G. Harmsen

Characterization of transmission of Pneumocystis carinii f. sp. muris through immunocompetent BALB/c mice.

ABSTRACT By using mouse models, it has been shown that Pneumocystis carinii f. sp. muris can be transmitted to immunocompetent mice that are exposed to immunosuppressed mice with active P. carinii pneumonia. We sought to determine whether P. carinii f. sp. muris could be transmitted between normal mice. The rationale for these experiments was to demonstrate whether the normal host could serve as the reservoir of organisms that produce Pcp when the organism is acquired by the immunosuppressed host. Under the conditions of these experiments, normal mice are able to be infected by brief cohousing with P. carinii-infected SCID mice. There was active replication of organisms in the normal host such that the organism could be transmitted to other normal mice, again with active replication. Mice that had seroconverted after exposure to P. carinii-infected SCID mice were more resistant to infection when reexposed. Infection in normal mice was well tolerated with minimal effects on dynamic lung compliance. We speculate, based on these results, that transmission from normal host to normal host, as an asymptomatic or minimally symptomatic infection, could be a way to maintain this opportunistic pathogen in the environment.

Pneumocystis carinii Host Origin Defines the Antibody Specificity and Protective Response Induced by Immunization

To determine how the known host species-specific antigenic variation of Pneumocystis carinii would affect immune recognition, mice were immunized with either mouse- or ferret-derived P. carinii, with subsequent analysis of the immune response and the ability of the mice to resist infection after immunosuppression and challenge. Immunization with mouse-derived P. carinii produced a strong immune response to mouse but not ferret P. carinii. These mice were completely protected from P. carinii pneumonia when challenged by intratracheal inoculation with mouse P. carinii. In contrast, immunization with ferret P. carinii produced a limited antibody response to mouse P. carinii and had no protective effect. These results show that P. carinii from different host species are immunologically distinct, and any possible use of immunotherapy for P. carinii pneumonia in humans must take into consideration these biologically significant antigenic differences in P. carinii of animal origin.

Neutralization of interferon-gamma exacerbates pneumocystis-driven interstitial pneumonitis after bone marrow transplantation in mice.

The role of IFNgamma in the development of infection-driven interstitial pneumonitis in a model of murine graft-versus-host disease was investigated. Mice were given either syngeneic or allogeneic bone marrow transplants along with lung Pneumocystis carinii infections and were treated with either control mAb or anti-IFNgamma mAb. At day 21 after transplant, lung weights were elevated nearly twofold in all groups. By day 41, mice in all groups had cleared the P. carinii but only the mice given allogeneic transplants and anti-IFNgamma had increased lung weights. Increased lung weights in the anti-IFNgamma-treated mice corresponded to alveolar infiltration of eosinophils, neutrophils, and multinucleated giant cells and exacerbated interstitial pneumonitis compared with mice treated with control antibody. Intracellular staining indicated that there were 3- to 10-fold more CD4+ cells producing IFNgamma than those producing IL-4 in the lung lavages of mice given either syngeneic or allogeneic transplant. Treatment of transplanted mice with anti-IFNgamma resulted in a significant decrease in IFN-gamma-producing CD4+ and CD8+ cells in the lung lavages but no change in the number of IL-4-producing CD4+ cells. These data indicate that IFNgamma is critical for controlling the development of P. carinii-driven interstitial pneumonia after either syngeneic or allogeneic bone marrow transplant in mice.