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.

Infection and immunity ·Vol. 70 ·No. 12 ·2002-12-00 ·Pages 6933-9

Collazo CM, Yap GS, Hieny S, Caspar P, Feng CG, Taylor GA, Sher A

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.

MeSH Terms

Acute Disease Animals Brain/parasitology Cells/parasitology Chronic Disease DNA-Binding Proteins/genetics,metabolism GTP Phosphohydrolases/metabolism Hematopoietic Stem Cells/parasitology Interferon-gamma/pharmacology Mice Mice, Inbred C57BL Nitric Oxide/metabolism STAT1 Transcription Factor Toxoplasma/pathogenicity Toxoplasmosis, Animal/immunology,mortality Trans-Activators/genetics,metabolism

Chemicals

DNA-Binding Proteins STAT1 Transcription Factor Stat1 protein, mouse Trans-Activators Nitric Oxide Interferon-gamma GTP Phosphohydrolases Igtp protein, mouse

Authors & Affiliations

7 authors, click to expand affiliations / ORCID

Collazo Carmen M

Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. CCOLLAZO@niaid.nih.gov

Yap George S

Hieny Sara

Caspar Patricia

Feng Carl G

Taylor Gregory A

Sher Alan

References (37)

37 references, click to expand

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 Nov 1;157(9):4045-54 PMID: 8892638
Interleukin-12 enhances murine survival against acute toxoplasmosis.
Infect Immun. 1994 May;62(5):1639-42 PMID: 7909536
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 Jul 1;90(13):6115-9 PMID: 8100999
Multiple defects of immune cell function in mice with disrupted interferon-gamma genes.
Science. 1993 Mar 19;259(5102):1739-42 PMID: 8456300
Pathophysiology of toxoplasmosis.
Parasitol Today. 1988 Oct;4(10):273-8 PMID: 15463000
Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase.
Cell. 1995 May 19;81(4):641-50 PMID: 7538909
Regulation and function of T-cell-mediated immunity during Toxoplasma gondii infection.
Clin Microbiol Rev. 1998 Oct;11(4):569-88 PMID: 9767056
A dichotomous role for nitric oxide during acute Toxoplasma gondii infection in mice.
Proc Natl Acad Sci U S A. 1997 Dec 9;94(25):13955-60 PMID: 9391134
Studies on the role of interleukin-12 in acute murine toxoplasmosis.
Immunology. 1995 Jan;84(1):16-20 PMID: 7890300
Isolation of a gene encoding a developmentally regulated T cell-specific protein with a guanine nucleotide triphosphate-binding motif.
J Immunol. 1995 Feb 15;154(4):1724-34 PMID: 7836757
The IRG-47 gene is IFN-gamma induced in B cells and encodes a protein with GTP-binding motifs.
J Immunol. 1992 May 15;148(10):3275-81 PMID: 1578148
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 Mar;57(3):477-83 PMID: 7884320
Pathogen-specific loss of host resistance in mice lacking the IFN-gamma-inducible gene IGTP.
Proc Natl Acad Sci U S A. 2000 Jan 18;97(2):751-5 PMID: 10639151
Biologic consequences of Stat1-independent IFN signaling.
Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6680-5 PMID: 11390995
Structures of Toxoplasma gondii tachyzoites, bradyzoites, and sporozoites and biology and development of tissue cysts.
Clin Microbiol Rev. 1998 Apr;11(2):267-99 PMID: 9564564
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 Jul 15;165(2):628-31 PMID: 10878333
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 May;67(5):2233-40 PMID: 10225879
Mechanism of inducible nitric oxide synthase inactivation by aminoguanidine and L-N6-(1-iminoethyl)lysine.
Biochemistry. 1998 Apr 7;37(14):4844-52 PMID: 9538001
Parasite-induced IL-12 stimulates early IFN-gamma synthesis and resistance during acute infection with Toxoplasma gondii.
J Immunol. 1994 Sep 15;153(6):2533-43 PMID: 7915739
Stat1-independent regulation of gene expression in response to IFN-gamma.
Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6674-9 PMID: 11390994
Effector cells of both nonhemopoietic and hemopoietic origin are required for interferon (IFN)-gamma- and tumor necrosis factor (TNF)-alpha-dependent host resistance to the intracellular pathogen, Toxoplasma gondii.
J Exp Med. 1999 Apr 5;189(7):1083-92 PMID: 10190899
The Stat family in cytokine signaling.
Curr Opin Cell Biol. 2001 Apr;13(2):211-7 PMID: 11248555
Identification of a novel GTPase, the inducibly expressed GTPase, that accumulates in response to interferon gamma.
J Biol Chem. 1996 Aug 23;271(34):20399-405 PMID: 8702776
The inducibly expressed GTPase localizes to the endoplasmic reticulum, independently of GTP binding.
J Biol Chem. 1997 Apr 18;272(16):10639-45 PMID: 9099712
A sensitive immunochemical assay for biologically active MuIFN-gamma.
J Immunol Methods. 1987 Nov 23;104(1-2):137-42 PMID: 3119723
Identification of an endotoxin and IFN-inducible cDNA: possible identification of a novel protein family.
J Leukoc Biol. 1995 Oct;58(4):477-84 PMID: 7561525
Inducible nitric oxide is essential for host control of persistent but not acute infection with the intracellular pathogen Toxoplasma gondii.
J Exp Med. 1997 Apr 7;185(7):1261-73 PMID: 9104813
Regulation of c-myc expression by IFN-gamma through Stat1-dependent and -independent pathways.
EMBO J. 2000 Jan 17;19(2):263-72 PMID: 10637230
Two families of GTPases dominate the complex cellular response to IFN-gamma.
J Immunol. 1998 Dec 15;161(12):6715-23 PMID: 9862701
Interferon gamma blocks the growth of Toxoplasma gondii in human fibroblasts by inducing the host cells to degrade tryptophan.
Proc Natl Acad Sci U S A. 1984 Feb;81(3):908-12 PMID: 6422465
Cell-mediated immunity to Toxoplasma gondii: initiation, regulation and effector function.
Immunobiology. 1999 Dec;201(2):240-7 PMID: 10631573
Immune response in mice that lack the interferon-gamma receptor.
Science. 1993 Mar 19;259(5102):1742-5 PMID: 8456301
In vivo blockage of nitric oxide with aminoguanidine inhibits immunosuppression induced by an attenuated strain of Salmonella typhimurium, potentiates Salmonella infection, and inhibits macrophage and polymorphonuclear leukocyte influx into the spleen.
Infect Immun. 1999 Feb;67(2):891-8 PMID: 9916105
Gamma interferon-induced inhibition of Toxoplasma gondii in astrocytes is mediated by IGTP.
Infect Immun. 2001 Sep;69(9):5573-6 PMID: 11500431
Inactivation of LRG-47 and IRG-47 reveals a family of interferon gamma-inducible genes with essential, pathogen-specific roles in resistance to infection.
J Exp Med. 2001 Jul 16;194(2):181-8 PMID: 11457893
Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway.
Cell. 1996 Feb 9;84(3):431-42 PMID: 8608597
Interferon-gamma: the major mediator of resistance against Toxoplasma gondii.
Science. 1988 Apr 22;240(4851):516-8 PMID: 3128869

Article Info

Journal

Infection and immunity

Abbr.

Infect Immun

ISSN

0019-9567

DOI

10.1128/IAI.70.12.6933-6939.2002

ccollazo@niaid.nih.gov

Published

2002-12-00

Pages

6933-9

Language

English

Region

United States

NLM ID

0246127

PMCID

PMC132942

Subset

External Links

PubMed source DOI: 10.1128/IAI.70.12.6933-6939.2002 PMC Full Text View journal details

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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.

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