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,**
* Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
Departments of Biochemistry and Immunology and Pathology, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil;
Laboratorio de Imunorregulacao e Microbiologia, Oswaldo Cruz Foundation, Salvador, Bahia, Brazil;
Biomedical Research Institute, Rockville, MD 20852;
¶ Geriatric Research, Education, and Clinical Center, VA Medical Center, Durham, NC 27705; and
|| Departments of Medicine, Immunology, and Molecular Genetics & Microbiology, and Center for the Study of Aging; Duke University, Durham, NC 27710;
# Department of Immunology, Duke University Medical Center, Durham, NC 27710; and
** Centro de Pesquisas René Rachou, Fundacao Oswaldo Cruz, Belo Horizonte, Brazil
IFN-
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--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- 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--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--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.
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