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Infection and Immunity, March 2004, p. 1257-1264, Vol. 72, No. 3
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.3.1257-1264.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

STAT1 Is Essential for Antimicrobial Effector Function but Dispensable for Gamma Interferon Production during Toxoplasma gondii Infection

L. Cristina Gavrilescu,1 Barbara A. Butcher,1 Laura Del Rio,1 Gregory A. Taylor,2,3 and Eric Y. Denkers1*

Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853,1 Departments of Medicine and Immunology, Duke University Medical Center, Durham, North Carolina 27710,2 Geriatric Research, Education, and Clinical Center, Durham Veterans Affairs Medical Center, Durham, North Carolina 277053

Received 2 October 2003/ Returned for modification 16 November 2003/ Accepted 19 November 2003

The opportunistic protozoan Toxoplasma gondii is a prototypic Th1-inducing pathogen inducing strong gamma interferon (IFN-{gamma}) cytokine responses that are required to survive infection. Intracellular signaling intermediate STAT1 mediates many effects of IFN-{gamma} and is implicated in activation of T-bet, a master regulator of Th1 differentiation. Here, we show that T. gondii-infected STAT1-null mice fail to upregulate the IFN-{gamma}-dependent effector molecules inducible nitric oxide synthase (iNOS), IGTP, and LRG-47, which are required for mice to survive infection. Both T-bet and interleukin-12 receptor ß2 (IL-12Rß2) failed to undergo normal upregulation in response to T. gondii. Development of IFN-{gamma}-producing CD4+ and CD8+ T lymphocytes was severely curtailed in the absence of STAT1, but a substantial level of STAT1-independent non-T-cell-derived IFN-{gamma} was induced. Absence of STAT1 also resulted in increased IL-4, Arg1, Ym1, and Fizz1, markers of Th2 differentiation and alternative macrophage activation. Together, the results show that T. gondii induces STAT1-dependent T-lymphocyte and STAT1-independent non-T-cell IFN-{gamma} production, but that effector functions of this type 1 cytokine cannot operate in the absence of STAT1, resulting in extreme susceptibility to acute infection.

* 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: W. A. Petri, Jr.

Infection and Immunity, March 2004, p. 1257-1264, Vol. 72, No. 3
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.3.1257-1264.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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