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Infection and Immunity, February 2001, p. 765-772, Vol. 69, No. 2
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.2.765-772.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

In Vitro Investigation of Host Resistance to Toxoplasma gondii Infection in Microglia of BALB/c and CBA/Ca Mice

Yvonne R. Freund,1,* Naunihal T. Zaveri,1 and Harold S. Javitz2

Immunology Program, Pharmaceutical Discovery Division,1 and Center for Health Sciences,2 SRI International, Menlo Park, California 94025

Received 5 May 2000/Returned for modification 14 June 2000/Accepted 9 November 2000

Toxoplasmic encephalitis (TE) is a life-threatening disease of immunocompromised 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 innate mechanisms in the brain that play a role in resistance to TE, nitric oxide (NO)-dependent and NO-independent mechanisms were examined in microglia from BALB/c and CBA/Ca mice and correlated with the ability of these cells 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 stimulation with LPS or with IFN-gamma plus TNF-alpha , and they inhibited T. gondii replication significantly less than did BALB/c microglia. Cells of both strains treated with IFN-gamma alone significantly inhibited uracil incorporation by T. gondii, and NG-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. gondii replication. This IFN-gamma -dependent inhibition of replication was not due to generation of reactive oxygen species or to increased tryptophan degradation. These data suggest that NO production and an IFN-gamma -dependent mechanism contribute to the inhibition of T. gondii replication after in vitro stimulation with IFN-gamma plus TNF-alpha or with LPS. Differences in NO production but not in IFN-gamma -dependent inhibition of T. gondii replication were observed between CBA/Ca and BALB/c microglia.

* Corresponding author. Mailing address: SRI International, 333 Ravenswood Ave., Menlo Park, CA 94025. Phone: (650) 859-6550. Fax: (650) 859-3153. E-mail: yvonne.freund{at}sri.com.

Infection and Immunity, February 2001, p. 765-772, Vol. 69, No. 2
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.2.765-772.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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