title: 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.
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.
authors.affiliation: 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
authors.forename: Carmen M
authors.initials: CM
authors.lastname: Collazo
authors.forename: George S
authors.initials: GS
authors.lastname: Yap
authors.forename: Sara
authors.initials: S
authors.lastname: Hieny
authors.forename: Patricia
authors.initials: P
authors.lastname: Caspar
authors.forename: Carl G
authors.initials: CG
authors.lastname: Feng
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Taylor
authors.forename: Alan
authors.initials: A
authors.lastname: Sher
mesh_terms: D000208:Acute Disease; D000818:Animals; D001921:Brain / Q000469:parasitology; D002477:Cells / Q000469:parasitology*; D002908:Chronic Disease; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000469:parasitology; D007371:Interferon-gamma / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D050794:STAT1 Transcription Factor; D014122:Toxoplasma / Q000472:pathogenicity*; D014124:Toxoplasmosis, Animal / Q000276:immunology* / Q000401:mortality; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D009569:Nitric Oxide; D007371:Interferon-gamma; D020558:GTP Phosphohydrolases; C101131:Igtp protein, mouse