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* Department of Biochemistry,
Centre for the Study of Host Resistance,
Department of Medicine, and
Department of Human Genetics, McGill University, Montreal, Quebec, Canada
The chronic myeloid leukemia syndrome of the BXH-2 mouse strain (Mus musculus) is caused by a recessive mutation (R294C) in the transcriptional regulator Icsbp1/IRF-8. In trans activation assays using an IL-12p40 gene reporter construct introduced in RAW 264.7 mouse macrophages, we show that the Icsbp1C294 isoform behaves as a partial loss-of-function. The Icsbp1C294 hypomorph allele appears to have a threshold effect on IL-12 production, with pleiotropic consequences on resistance to different types of infections in vivo. Despite the presence of a resistance Nramp1G169 allele, BXH-2 mice (Icsbp1C294) show impaired control of Mycobacterium bovis (bacille Calmette-Guérin) multiplication both early and late during infection, with uncontrolled replication linked to inability to form granulomas in infected liver and spleen. Studies in informative (BXH-2 x BALB/cJ)F2 mice show that homozygosity for Icsbp1C294 causes susceptibility to Salmonella enterica serovar Typhimurium to a level comparable to that seen for mice lacking functional Nramp1 or TLR4. Finally, impaired Icsbp1C294 function is associated with the following: 1) increased replication of the Plasmodium chabaudi AS malarial parasite during the first burst of blood parasitemia, and 2) recurring waves of high blood parasitemia late during infection. These results show that Icsbp1 is required for orchestrating early innate responses and also long-term immune protection against unrelated intracellular pathogens.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by research grants to P.G. from Canadian Genetic Diseases Network and the Cancer Research Society. P.G. is a James McGill Professor of Biochemistry. K.T. was supported by studentships from the Canadian Institutes of Health Research and the Ruth and Alex Dworkin Scholarship from the McGill Faculty of Medicine. D.M. is a McGill William Dawson Scholar of Human Genetics.
2 Address correspondence and reprint requests to Dr. Philippe Gros, Department of Biochemistry, 3655 Sir William Osler Promenade, Room 907, Montreal, Quebec, Canada, H3G-1Y6. E-mail address: philippe.gros{at}mcgill.ca
3 Abbreviations used in this paper: BCG, bacille Calmette-Guérin; HA, hemagglutinin; IAD, IRF association domain; IRF, IFN regulatory factor; ISRE, IFN-stimulated response element; MSMD, Mendelian susceptibility to mycobacterial diseases; PRBC, parasitized RBC.
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