Depletion of gamma interferon and tumor necrosis factor alpha in mice with Rickettsia conorii-infected endothelium: impairment of rickettsicidal nitric oxide production resulting in fatal, overwhelming rickettsial disease

Abstract

HeN mice infected intravenously with a dose of Rickettsia conorii (Malish 7 strain) that is sublethal for immunocompetent animals (1.1 x 103 PFU) developed disseminated infection of endothelial cells of the brain, lungs, heart, liver, kidney, testis, and testicular adnexa. In R. conorii-infected mice depleted of gamma interferon (IFN-y) and/or tumor necrosis factor alpha (TNF-ao) by intravenous administration of neutralizing monoclonal antibodies on days 0, 2, and 4, the mortality rate was 100%. Death of the cytokine-depleted animals on days 5 and 6 was associated with overwhelming rickettsial infection documented 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, with rickettsial destruction in phagolysosomes not only in macrophages but also in endothelial cells and hepatocytes. All nondepleted, infected mice recovered and appeared completely healthy by day 9. Assay of liver infiltrated by lymphocytes and macrophages revealed mRNA of IFN-,y and TNF-ft, indicating that the host defenses were activated at the site of infection. Treatment of mice with an analog of L-arginine reduced the synthesis of nitric oxide and impaired rickettsial killing. Nitric oxide production was also impaired in cytokine-depleted infected mice. These observations support the hypothesis that IFN-y secreted by T lymphocytes and natural killer cells and TNF-ct secreted 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. conorii.

Neutralization of bovine Concanavalin‐A T cell supernatant‐mediated anti‐Cowdria ruminantium activity with antibodies specific to Interferon gamma but not to tumor necrosis factor

“…The mechanism by which IFN caused inhibition of C. ruminantium in the studies described here was not through the production of nitric oxide. Nitric oxide has been reported to be the effective anti-intracellular pathogen mediator and inhibits R. prowazekii growth in vitro in L929 cells (Turco & Winkler 1993), and R. conorii infection in vivo in mice (Feng, Popov & Walker 1994). However, since IFN has been reported to have the capacity to directly lyse the rickettsial agents or infected cells (Hanson 1991), this mode of inhibition may be one pathway by which the C. ruminantium growth was inhibited in our studies.…”

A DNA vaccine protects mice against the rickettsial agent Cowdria ruminantium

“…IFN-gamma has been shown to inhibit the growth of C. ruminantium in vitro (Totte et al 1993;Mahan et al 1996) and to play a role in defence against other rickettsial agents (Turco & Winkler 1983a,b, 1989, 1994, Li et al 1987, Manor & Sarov 1990, Gao et al 1993, Feng et al 1994. IFN-gamma therefore could be involved in the protection observed in those mice that survived challenge or experienced a delayed time to death.…”

“…Cell-mediated immunity can be mediated directly through cell cytotoxic effects and indirectly via the production of cytokines that enable the elimination of intracellular infection (Abbas et al 1994). Cytokines in general (Turco & Winkler 1983a, Wisseman & Waddel 1983, Mahan et al 1994 and interferon (IFN)-gamma in particular, have been shown to exert antirickettsial effects in in vitro (Turco & Winkler 1983a,b, 1989, 1994, Wisseman & Waddel 1983, Manor & Sarov 1990, Gao et al 1993, Feng et al 1994, Mahan et al 1994, 1996 and in vivo (Li et al 1987) studies. The inhibitory effects of IFN-gamma (Totte et al 1993, Mahan et al 1996 and IFN-alpha (Totte et al 1993(Totte et al , 1994 on the growth of C. ruminantium have been demonstrated.…”

Immune control of Brucella abortus 2308 infections in BALB/c mice

“…The role of CD8 T cells and TNF-K in vivo was tested by treating BALB/c mice with rat monoclonal antibodies (mAb) reactive with murine TNF-K or CD8 from 24 h prior to infection until 3 weeks post infection by injecting 1.0 mg Ig every 4 days as described by ourselves and others [3,11]. Control mice were given equivalent amounts of normal rat IgG (Sigma, St. Louis, MO, USA).…”