In vitro investigation of host resistance to Toxoplasma gondii infection in microglia of BALB/c and CBA/Ca mice

Toxoplasmic encephalitis (TE) is a life-threatening disease of immunocompro mised individuals and has increased in prevalence as a consequence of AIDS. TE has been modeled in inbred mice, with CBA/Ca mice being susceptible and BALB/c mice resistant to the development of TE, To better understand the i nnate mechanisms in the brain that play a role in resistance to TE, nitric oxide (NO)-dependent and NO-independent mechanisms were examined in microgl ia from BALB/c and CBA/Ca mice and correlated with the ability of these cel ls to Inhibit Toxoplasma gondii replication. These parameters were measured 48 h after stimulation with lipopolysaccharide (LPS) gamma interferon (IFN -gamma), tumor necrosis factor alpha (TNF-alpha), or combinations of these inducers in T. gondii-infected microglia Isolated from newborn mice. CBA/Ca microglia consistently produced less NO than did BALB/c microglia after st imulation with LPS or with IFN-gamma plus TNF-alpha, and they inhibited T,g ondii replication significantly less than did BALB/c microglia. Cells of bo th strains treated with IFN-gamma alone significantly inhibited uracil inco rporation by T. gondii, and N-G-monomethyl-L-arginine (NMMA) treatment did not reverse this effect In cells treated with IFN-gamma in combination with other inducers, NMMA treatment resulted in only partial recovery of T. gon dii replication. This IFN-gamma -dependent inhibition of replication was no t due to generation of reactive oxygen species or to increased tryptophan d egradation. These data suggest that NO production and an IFN-gamma -depende nt mechanism contribute to the inhibition of T. gondii replication after in vitro stimulation with IFN-gamma plus TNF-alpha or with LPS. Differences i n NO production but not in IFN-gamma -dependent inhibition of T. gondii rep lication were observed between CBA/Ca and BALB/c microglia.