SUSCEPTIBILITY TO PNEUMOCYSTIS-CARINII IN MICE IS DEPENDENT ON SIMULTANEOUS DELETION OF IFN-GAMMA AND TYPE-1 AND TYPE-2 TNF RECEPTOR GENES

Pneumocystis carinii pneumonia is an important cause of morbidity and mortality in immunosuppressed patients, particularly HIV-infected indi viduals. An improved understanding of pulmonary host response, includi ng the cytokines required for defense, could suggest novel immunothera peutic approaches to this infection. The cytokines IFN-gamma and TNF h ave contributory roles in host defense against P. carinii, but their c ombined and interactive importance is unclear. To test the roles of th ese cytokines in defense against P. carinii directly, organisms were i noculated intratracheally into wild-type mice and into three groups of gene-deleted mice: those lacking genes for IFN-gamma (IFN-gamma(-/-)) , for TNF receptors 1 and 2 (TNFR-/-), and for both IFN-gamma and TNFR (TNFN-IFN-gamma(-/-)). Four weeks after P. carinii inoculation, lungs of the wild-type, IFN-y(-/-), and TNFR-/- mice demonstrated clearance of P. carinii and only mild inflammation. However, TNFR-IFN-y(-/-) mi ce demonstrated severe P. carinii infection and lung inflammation, Our findings demonstrate conclusively that deletion of either IFN-gamma o r TNF activity alone dogs not block clearance of P. carinii. However, simultaneous deletion of IFN-gamma and TNF receptor genes results in s usceptibility to P. carinii. Rather than focusing exclusively on indiv idual cytokines, our data suggest that immunotherapy targeted at maxim izing both the IFN-gamma and TNF responses to P. carinii may be requir ed to augment host defense against this important opportunistic pathog en.