Role of gamma interferon in the host immune and inflammatory responses to Pneumocystis carinii infection

The role of gamma interferon (IFN-γ) in host defense to Pneumocystis carinii was investigated by use of three different murine models of infection. C57BL/6 scid/scid (severe combined immunodeficient [SCID]) mice were given intratracheal inoculations of P. carinii and reconstituted with splenocytes from either mice with disrupted IFN-γ genes (IFN-γ(-/-) mice) or homozygous wild-type (IFN-(+/+)) mice. Unreconstituted SCID mice had log₁₀ 7.08 ± 0.13 P. carinii nuclei in their lungs at day 22 postinfection, whereas SCID mice reconstituted with splenocytes from either wild-type or IFN-γ(-/-) mice had cleared the infection. However, there was a prolonged and exacerbated inflammatory response in the lungs of SCID mice reconstituted with IFN-γ(-/-) splenocytes which was characterized by interstitial pneumonia, eosinophilia, and multinucleated giant cell formation. Similar results were found in C.B17 SCID mice reconstituted with CD4⁺ cells from P. carinii-immunized donors treated with neutralizing anti- IFN-γ monoclonal antibody (MAb). These mice resolved their P. carinii infections; however, they also exhibited exacerbated lung pathology compared with mice treated with a control MAb. Finally, IFN-γ(-/-) mice challenged intratracheally with P. carinii resolved their infection within 56 days as did IFN-γ(+/-) mice. Furthermore, depletion of T cells in vivo with a MAb resulted in IFN-γ(-/-) mice becoming susceptible to P. carinii infection. Together, these data indicate that IFN-γ is not required for resolution of P. carinii infection; however, in the absence of IFN-γ, there is a prolonged and exacerbated P. carinii-driven interstitial pneumonia characterized by eosinophilia and formation of multinucleated giant cells.