title: Mice deficient in LRG-47 display enhanced susceptibility to Trypanosoma cruzi infection associated with defective hemopoiesis and intracellular control of parasite growth.
abstract: IFN-gamma is known to be required for host control of intracellular Trypanosoma cruzi infection in mice, although the basis of its protective function is poorly understood. LRG-47 is an IFN-inducible p47GTPase that has been shown to regulate host resistance to intracellular pathogens. To investigate the possible role of LRG-47 in IFN-gamma-dependent control of T. cruzi infection, LRG-47 knockout (KO) and wild-type (WT) mice were infected with the Y strain of this parasite, and host responses were analyzed. When assayed on day 12 after parasite inoculation, LRG-47 KO mice, in contrast to IFN-gamma KO mice, controlled early parasitemia almost as effectively as WT animals. However, the infected LRG-47 KO mice displayed a rebound in parasite growth on day 15, and all succumbed to the infection by day 19. Additional analysis indicated that LRG-47-deficient mice exhibit unimpaired proinflammatory responses throughout the infection. Instead, reactivated disease in the KO animals was associated with severe splenic and thymic atrophy, anemia, and thrombocytopenia not observed in their WT counterparts. In addition, in vitro studies revealed that IFN-gamma-stimulated LRG-47 KO macrophages display defective intracellular killing of amastigotes despite normal expression of TNF and NO synthetase type 2 and that both NO synthetase type 2 and LRG-47 are required for optimum IFN-gamma-dependent restriction of parasite growth. Together, these data establish that LRG-47 can influence pathogen control by simultaneously regulating macrophage-microbicidal activity and hemopoietic function.
authors.affiliation: Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. santiago@icb.ufmg.br
authors.forename: Helton C
authors.initials: HC
authors.lastname: Santiago
authors.forename: Carl G
authors.initials: CG
authors.lastname: Feng
authors.forename: Andre
authors.initials: A
authors.lastname: Bafica
authors.forename: Ester
authors.initials: E
authors.lastname: Roffe
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Arantes
authors.forename: Allen
authors.initials: A
authors.lastname: Cheever
authors.forename: Gregory
authors.initials: G
authors.lastname: Taylor
authors.forename: Leda Q
authors.initials: LQ
authors.lastname: Vieira
authors.forename: Leda Q
authors.initials: LQ
authors.lastname: Vierira
authors.forename: Julio
authors.initials: J
authors.lastname: Aliberti
authors.forename: Ricardo T
authors.initials: RT
authors.lastname: Gazzinelli
authors.forename: Alan
authors.initials: A
authors.lastname: Sher
mesh_terms: D000818:Animals; D014355:Chagas Disease / Q000150:complications / Q000209:etiology / Q000276:immunology*; D004198:Disease Susceptibility / Q000276:immunology / Q000469:parasitology; D019204:GTP-Binding Proteins / Q000172:deficiency / Q000276:immunology*; D006410:Hematopoiesis / Q000276:immunology*; D006790:Host-Parasite Interactions / Q000276:immunology; D007371:Interferon-gamma / Q000172:deficiency / Q000502:physiology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000502:physiology; D018512:Parasitemia / Q000150:complications / Q000209:etiology / Q000276:immunology; D014349:Trypanosoma cruzi / Q000254:growth & development
chemical_list: C096000:Ifi1 protein, mouse; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D019204:GTP-Binding Proteins