Icsbp1/IRF-8 is required for innate and adaptive immune responses against intracellular pathogens.
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 Icsbp1(C294) isoform behaves as a partial loss-of-function. The Icsbp1(C294) 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 Nramp1(G169) allele, BXH-2 mice (Icsbp1(C294)) 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)F(2) mice show that homozygosity for Icsbp1(C294) causes susceptibility to Salmonella enterica serovar Typhimurium to a level comparable to that seen for mice lacking functional Nramp1 or TLR4. Finally, impaired Icsbp1(C294) 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.
Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
Karine
K
Turcotte
Susan
S
Gauthier
Danielle
D
Malo
Mifong
M
Tam
Mary M
MM
Stevenson
Philippe
P
Gros
D019943:Amino Acid Substitution; D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D005808:Genes, Recessive; D007113:Immunity, Innate / Q000235:genetics; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000276:immunology*; D053762:Interleukin-12 Subunit p40 / Q000276:immunology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology / Q000469:parasitology; D008288:Malaria / Q000235:genetics / Q000276:immunology* / Q000662:veterinary; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D020125:Mutation, Missense; D009163:Mycobacterium bovis / Q000276:immunology*; D018512:Parasitemia / Q000235:genetics / Q000276:immunology; D016788:Plasmodium chabaudi / Q000276:immunology; D012480:Salmonella Infections / Q000235:genetics / Q000276:immunology*; D012486:Salmonella typhimurium / Q000276:immunology; D013577:Syndrome; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology; D014376:Tuberculosis / Q000235:genetics / Q000276:immunology* / Q000662:veterinary; D000099185:Interferon Regulatory Factor-8; D000099173:Natural Resistance-associated Macrophage Protein 1
D027682:Cation Transport Proteins; D050835:Interferon Regulatory Factors; D053762:Interleukin-12 Subunit p40; D051197:Toll-Like Receptor 4; D000099185:Interferon Regulatory Factor-8; D000099173:Natural Resistance-associated Macrophage Protein 1; C493487:Tlr4 protein, mouse