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Infection and Immunity, September 2002, p. 5216-5224, Vol. 70, No. 9
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.9.5216-5224.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Mechanism of Entry Determines the Ability of Toxoplasma gondii To Inhibit Macrophage Proinflammatory Cytokine Production

Barbara A. Butcher and Eric Y. Denkers*

Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853-6401

Received 1 April 2002/ Returned for modification 23 May 2002/ Accepted 10 June 2002

Macrophages (M{phi}) infected with tachyzoites of the opportunistic protozoan Toxoplasma gondii are blocked in production of the proinflammatory cytokines tumor necrosis factor alpha (TNF-{alpha}) and interleukin-12 (IL-12) in response to lipopolysaccharide (LPS) triggering, and this is associated with parasite-induced inhibition of NF{kappa}B translocation. Here, we demonstrate a requirement for active invasion in the ability of the parasite to mediate suppression. Neither soluble tachyzoite antigen nor secreted products were suppressive, and heat-inactivated, antibody-coated tachyzoites, which efficiently entered the cell through receptor-mediated uptake, failed to inhibit LPS responses. Cytochalasin D, a drug blocking tachyzoite invasion of, but not adherence to, M{phi}, severely curtailed Toxoplasma-induced suppression. In addition, parasite-induced nonresponsiveness, as measured by TNF-{alpha} production, was reversed by treating infected cells with the toxoplasmastatic drugs pyrimethamine and 6-thioxanthine prior to LPS stimulation. A divergence in IL-12 and TNF-{alpha} responses was found during extended incubation of tachyzoites and M{phi} in that 24 h of incubation of infected M{phi} resulted in IL-12, but not TNF-{alpha}, secretion, and production of the latter cytokine remained suppressed when these cells were subjected to LPS triggering. Our results demonstrate that active invasion and survival of the parasite within the parasitophorous vacuole are required to induce and maintain M{phi} cytokine-specific nonresponsiveness to LPS. They also show that the effects of Toxoplasma on IL-12 and TNF-{alpha} production are nonidentical, with the parasite exerting a longer-lasting suppression of the latter.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853-6401. Phone: (607) 253-4022. Fax: (607) 253-3384. E-mail: eyd1{at}cornell.edu.

Editor: J. M. Mansfield

Infection and Immunity, September 2002, p. 5216-5224, Vol. 70, No. 9
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.9.5216-5224.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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