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Infection and Immunity, December 2002, p. 6933-6939, Vol. 70, No. 12
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.12.6933-6939.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

The Function of Gamma Interferon-Inducible GTP-Binding Protein IGTP in Host Resistance to Toxoplasma gondii Is Stat1 Dependent and Requires Expression in Both Hematopoietic and Nonhematopoietic Cellular Compartments

Carmen M. Collazo,1* George S. Yap,2 Sara Hieny,1 Patricia Caspar,1 Carl G. Feng,1 Gregory A. Taylor,3 and Alan Sher1

Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892,1 Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, Rhode Island 02912,2 Departments of Medicine and Immunology, Duke University Medical Center, and Geriatric Research, Education, and Clinical Center, Durham Veterans Affairs Medical Center, Durham, North Carolina 277053

Received 24 January 2002/ Returned for modification 16 April 2002/ Accepted 11 September 2002

IGTP is a member of the 47-kDa family of gamma interferon (IFN-{gamma})-induced GTPases. We have previously shown that IGTP is critical for host resistance to Toxoplasma gondii infection. In the present study, we demonstrate that T. gondii-induced IGTP expression in vivo and IFN-{gamma}-driven synthesis of the protein in vitro are dependent on Stat1. Consistent with this observation, Stat1-deficient animals succumbed to T. gondii infection with the same rapid kinetics as IGTP-/- mice. To ascertain the cellular levels at which IGTP functions in host control of acute infection, we constructed reciprocal bone marrow chimeras between IGTP-deficient and wild-type mice. Resistance to infection was observed only when IGTP was present in both hematopoietic and nonhematopoietic compartments. To assess the possible contribution of IGTP to the maintenance of parasite latency, partial chemotherapy was used to allow the establishment of chronic infection in IGTP-deficient animals. Upon cessation of drug treatment, these animals showed delayed mortality compared with similarly infected and treated IFN-{gamma}-deficient or inducible nitric oxide synthase-deficient mice, which succumbed rapidly. Parallel experiments performed with drug-treated bone marrow chimeras supported a role for the hematopoietic compartment in this NO-dependent, IGTP-independent control of chronic infection. Taken together, our findings demonstrate that host resistance mediated by IGTP is a Stat1-induced function which in the case of T. gondii acts predominantly to restrict acute as opposed to chronic infection. This effector mechanism requires expression of IGTP in cells of both hematopoietic and nonhematopoietic origin. In contrast, in latent infection, hematopoietically derived cells mediate resistance by means of a largely NO-dependent pathway.

* Corresponding author. Mailing address: Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 50, Room 6144, 50 South Dr., MSC 8003, Bethesda, MD 20892. Phone: (301) 594-2874. Fax: (301) 402-0890. E-mail: CCOLLAZO{at}niaid.nih.gov.

Editor: S. H. E. Kaufmann

Infection and Immunity, December 2002, p. 6933-6939, Vol. 70, No. 12
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.12.6933-6939.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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