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Cell-Mediated Immunity to Toxoplasma gondii Develops Primarily by Local Th1 Host Immune Responses in the Absence of Parasite Replication¹

Jason P. Gigley^*,, Barbara A. Fox^* and David J. Bzik^2,*

^* Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH 03756; and Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington, DC 20037

A single inoculation of mice with the live, attenuated Toxoplasma gondii uracil auxotroph strain cps1-1 induces long-lasting immunity against lethal challenge with hypervirulent strain RH. The mechanism for this robust immunity in the absence of parasite replication has not been addressed. The mechanism of long-lasting immunity, the importance of route of immunization, cellular recruitment to the site of infection, and local and systemic inflammation were evaluated. Our results show that infection with cps1-1 elicits long-lasting CD8⁺ T cell- mediated immunity. We show that immunization with cps1-1-infected dendritic cells elicits long-lasting immunity. Intraperitoneal infection with cps1-1 induced a rapid influx of GR1⁺ neutrophils and two stages of GR1⁺CD68⁺ inflammatory monocyte infiltration into the site of inoculation. CD19⁺ B cells and CD3⁺ T cells steadily increase for 8 days after infection. CD8⁺ T cells were rapidly recruited to the site of infection and increased faster than CD4⁺ T cells. Surprisingly, cps1-1 infection induced high systemic levels of bioactive IL-12p70 and a very low level and transient systemic IFN-. Furthermore, we show significant levels of these inflammatory cytokines were locally produced at the site of cps1-1 inoculation. These findings offer new insight into immunological mechanisms and local host responses to a non-replicating type I parasite infection associated with development of long-lasting immunity to Toxoplasma gondii.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants AI-41930 and J.P.G. was supported by National Institutes of Health Grants T32 AI07363-13 and T32 AI007519.

² Address correspondence and reprint requests to Dr. David J. Bzik, Department of Microbiology and Immunology, Dartmouth Medical School, Room 654, East Borwell Building, 1 Medical Center Drive, Lebanon, NH 03756. E-mail address: David.J.Bzik{at}Dartmouth.edu

³ Abbreviations used in this paper: DC, dendritic cell; PEC, peritoneal exudate cell; WT, wild type.