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 cytokine tumor necrosis factor (TNF) has been proposed as critical for host defense against this pathogen. To investigate the role of this cytokine in PC infection, we treated immunocompetent mice (CD4+) or mice depleted of CD4 lymphocytes (CD4-) with a recombinant adenovirus encoding a TNF inhibitor gene (AdTNF-R). AdTNF-R treated CD4+ animals displayed delayed clearance of PC after intratracheal inoculation, whereas AdTNF-R treated CD4 animals developed more severe chronic infection. Moreover, AdTNF-R treated CD4- animals, in contrast to control CD4- 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 intrapulmonary cytokine cascade in PC infection.