DEPLETION OF GAMMA-INTERFERON AND TUMOR-NECROSIS-FACTOR-ALPHA IN MICEWITH RICKETTSIA CONORII-INFECTED ENDOTHELIUM - IMPAIRMENT OF RICKETTSICIDAL NITRIC-OXIDE PRODUCTION RESULTING IN FATAL, OVERWHELMING RICKETTSIAL DISEASE

C3H/HeN mice infected intravenously with a dose of Rickettsia conorii (Malish 7 strain) that is sublethal for immunocompetent animals (1.1 x 10(3) PFU) developed disseminated infection of endothelial cells of t he brain, lungs, heart, liver, kidney, testis, and testicular adnexa. In R. conorii-infected mice depleted of gamma interferon (IFN-gamma) a nd/or tumor necrosis factor alpha (TNF-alpha) by intravenous administr ation of neutralizing monoclonal antibodies on days 0, 2, and 4, the m ortality rate was 100%. Death of the cytokine-depleted animals on days 5 and 6 was associated with overwhelming rickettsial infection docume nted by titration of rickettsial content in the brain and liver and by immunohistologic demonstration of massive quantities of R. conorii in endothelial cells of all organs examined, in macrophages of the liver and spleen, and in hepatocytes. Nondepleted, immunocompetent animals showed markedly reduced rickettsial content in the tissues on day 6, w ith rickettsial destruction in phagolysosomes not only in macrophages but also in endothelial cells and hepatocytes. All nondepleted, infect ed mice recovered and appeared completely healthy by day 9. Assay of l iver infiltrated by lymphocytes and macrophages revealed mRNA of IFN-g amma and TNF-alpha, indicating that the host defenses were activated a t the site of infection. Treatment of mice with an analog of L-arginin e reduced the synthesis of nitric oxide and impaired rickettsial killi ng. Nitric oxide production was also impaired in cytokine-depleted inf ected mice. These observations support the hypothesis that IFN-gamma s ecreted by T lymphocytes and natural killer cells and TNF-alpha secret ed by macrophages act in a synergistic, paracrine fashion on adjacent rickettsia-infected endothelial cells, hepatocytes, and macrophages to stimulate synthesis of nitric oxide, which kills intracellular R. con orii.