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

Overview

Journal Infect Immun

Publisher American Society for Microbiology

Specialty Allergy & Immunology

Date 2002 Nov 20

PMID 12438372

Citations 42

Authors

Carmen M Collazo

George S Yap

Sara Hieny

Patricia Caspar

Carl G Feng

Gregory A Taylor

Alan Sher

Affiliations

Soon will be listed here.

Abstract

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.

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References

Wynn T, Denkers E, Bala S, Grunvald E, Hieny S, Gazzinelli R . In the absence of endogenous IFN-gamma, mice develop unimpaired IL-12 responses to Toxoplasma gondii while failing to control acute infection. J Immunol. 1996; 157(9):4045-54. View

Khan I, Matsuura T, Kasper L . Interleukin-12 enhances murine survival against acute toxoplasmosis. Infect Immun. 1994; 62(5):1639-42. PMC: 186373. DOI: 10.1128/iai.62.5.1639-1642.1994. View

Gazzinelli R, Hieny S, Wynn T, Wolf S, Sher A . Interleukin 12 is required for the T-lymphocyte-independent induction of interferon gamma by an intracellular parasite and induces resistance in T-cell-deficient hosts. Proc Natl Acad Sci U S A. 1993; 90(13):6115-9. PMC: 46878. DOI: 10.1073/pnas.90.13.6115. View

Dalton D, Keshav S, Figari I, Bradley A, Stewart T . Multiple defects of immune cell function in mice with disrupted interferon-gamma genes. Science. 1993; 259(5102):1739-42. DOI: 10.1126/science.8456300. View

FRENKEL J . Pathophysiology of toxoplasmosis. Parasitol Today. 1988; 4(10):273-8. DOI: 10.1016/0169-4758(88)90018-x. View

MacMicking J, Nathan C, Hom G, Chartrain N, Fletcher D, Trumbauer M . Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell. 1995; 81(4):641-50. DOI: 10.1016/0092-8674(95)90085-3. View

Denkers E, Gazzinelli R . Regulation and function of T-cell-mediated immunity during Toxoplasma gondii infection. Clin Microbiol Rev. 1998; 11(4):569-88. PMC: 88897. DOI: 10.1128/CMR.11.4.569. View

Khan I, Schwartzman J, Matsuura T, Kasper L . A dichotomous role for nitric oxide during acute Toxoplasma gondii infection in mice. Proc Natl Acad Sci U S A. 1998; 94(25):13955-60. PMC: 28414. DOI: 10.1073/pnas.94.25.13955. View

Hunter C, Candolfi E, Subauste C, Van Cleave V, Remington J . Studies on the role of interleukin-12 in acute murine toxoplasmosis. Immunology. 1995; 84(1):16-20. PMC: 1415199. View

10.

Carlow D, Marth J, Clark-Lewis I, Teh H . Isolation of a gene encoding a developmentally regulated T cell-specific protein with a guanine nucleotide triphosphate-binding motif. J Immunol. 1995; 154(4):1724-34. View

11.

GILLY M, Wall R . The IRG-47 gene is IFN-gamma induced in B cells and encodes a protein with GTP-binding motifs. J Immunol. 1992; 148(10):3275-81. View

12.

Lafuse W, Brown D, Castle L, Zwilling B . Cloning and characterization of a novel cDNA that is IFN-gamma-induced in mouse peritoneal macrophages and encodes a putative GTP-binding protein. J Leukoc Biol. 1995; 57(3):477-83. DOI: 10.1002/jlb.57.3.477. View

13.

Taylor G, Collazo C, Yap G, Nguyen K, Gregorio T, TAYLOR L . Pathogen-specific loss of host resistance in mice lacking the IFN-gamma-inducible gene IGTP. Proc Natl Acad Sci U S A. 2000; 97(2):751-5. PMC: 15402. DOI: 10.1073/pnas.97.2.751. View

14.

Gil M, Bohn E, OGuin A, Ramana C, Levine B, Stark G . Biologic consequences of Stat1-independent IFN signaling. Proc Natl Acad Sci U S A. 2001; 98(12):6680-5. PMC: 34412. DOI: 10.1073/pnas.111163898. View

15.

Dubey J, Lindsay D, Speer C . Structures of Toxoplasma gondii tachyzoites, bradyzoites, and sporozoites and biology and development of tissue cysts. Clin Microbiol Rev. 1998; 11(2):267-99. PMC: 106833. DOI: 10.1128/CMR.11.2.267. View

16.

Yap G, Pesin M, Sher A . Cutting edge: IL-12 is required for the maintenance of IFN-gamma production in T cells mediating chronic resistance to the intracellular pathogen, Toxoplasma gondii. J Immunol. 2000; 165(2):628-31. DOI: 10.4049/jimmunol.165.2.628. View

17.

Ceravolo I, Chaves A, Bonjardim C, Sibley D, Romanha A, Gazzinelli R . Replication of Toxoplasma gondii, but not Trypanosoma cruzi, is regulated in human fibroblasts activated with gamma interferon: requirement of a functional JAK/STAT pathway. Infect Immun. 1999; 67(5):2233-40. PMC: 115962. DOI: 10.1128/IAI.67.5.2233-2240.1999. View

18.

Bryk R, Wolff D . Mechanism of inducible nitric oxide synthase inactivation by aminoguanidine and L-N6-(1-iminoethyl)lysine. Biochemistry. 1998; 37(14):4844-52. DOI: 10.1021/bi972065t. View

19.

Gazzinelli R, Wysocka M, Hayashi S, Denkers E, Hieny S, Caspar P . Parasite-induced IL-12 stimulates early IFN-gamma synthesis and resistance during acute infection with Toxoplasma gondii. J Immunol. 1994; 153(6):2533-43. View

20.

Ramana C, Gil M, Han Y, Ransohoff R, Schreiber R, Stark G . Stat1-independent regulation of gene expression in response to IFN-gamma. Proc Natl Acad Sci U S A. 2001; 98(12):6674-9. PMC: 34411. DOI: 10.1073/pnas.111164198. View