EXACERBATION OF MURINE PNEUMOCYSTIS-CARINII INFECTION BY ADENOVIRAL-MEDIATED GENE-TRANSFER OF A TNF INHIBITOR

The role of mononuclear phagocytes and their cytokine products in host defense against Pneumocystis carinii (PC) remains unclear. The cytoki ne tumor necrosis factor (TNF) has been proposed as critical for host defense against this pathogen. To investigate the role of this cytokin e in PC infection, we treated immunocompetent mice (CD4(+)) or mice de pleted of CD4 lymphocytes (CD4(-)) with a recombinant adenovirus encod ing a TNF inhibitor gene (AdTNF-R). AdTNF-R treated CD4(+) animals dis played delayed clearance of PC after intratracheal inoculation, wherea s AdTNF-R treated CD4(-) animals developed more severe chronic infecti on. Moreover, AdTNF-R treated CD4(-) animals, in contrast to control C D4(-) mice, failed to show any interleukin-6 (IL-6) gene induction in the lung after PC challenge. The results firmly implicate TNF in host defense against PC, and support a role for TNF in orchestrating the in trapulmonary cytokine cascade in PC infection.