title: Irf8-regulated genomic responses drive pathological inflammation during cerebral malaria.
abstract: Interferon Regulatory Factor 8 (IRF8) is required for development, maturation and expression of anti-microbial defenses of myeloid cells. BXH2 mice harbor a severely hypomorphic allele at Irf8 (Irf8(R294C)) that causes susceptibility to infection with intracellular pathogens including Mycobacterium tuberculosis. We report that BXH2 are completely resistant to the development of cerebral malaria (ECM) following Plasmodium berghei ANKA infection. Comparative transcriptional profiling of brain RNA as well as chromatin immunoprecipitation and high-throughput sequencing (ChIP-seq) was used to identify IRF8-regulated genes whose expression is associated with pathological acute neuroinflammation. Genes increased by infection were strongly enriched for IRF8 binding sites, suggesting that IRF8 acts as a transcriptional activator in inflammatory programs. These lists were enriched for myeloid-specific pathways, including interferon responses, antigen presentation and Th1 polarizing cytokines. We show that inactivation of several of these downstream target genes (including the Irf8 transcription partner Irf1) confers protection against ECM. ECM-resistance in Irf8 and Irf1 mutants is associated with impaired myeloid and lymphoid cells function, including production of IL12p40 and IFNγ. We note strong overlap between genes bound and regulated by IRF8 during ECM and genes regulated in the lungs of M. tuberculosis infected mice. This IRF8-dependent network contains several genes recently identified as risk factors in acute and chronic human inflammatory conditions. We report a common core of IRF8-bound genes forming a critical inflammatory host-response network.
authors.affiliation: Department of Biochemistry and Complex Traits Group, McGill University, Montreal, Quebec, Canada.
authors.forename: Joanne
authors.initials: J
authors.lastname: Berghout
authors.forename: David
authors.initials: D
authors.lastname: Langlais
authors.forename: Irena
authors.initials: I
authors.lastname: Radovanovic
authors.forename: Mifong
authors.initials: M
authors.lastname: Tam
authors.forename: John D
authors.initials: JD
authors.lastname: MacMicking
authors.forename: Mary M
authors.initials: MM
authors.lastname: Stevenson
authors.forename: Philippe
authors.initials: P
authors.lastname: Gros
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D007113:Immunity, Innate; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016779:Malaria, Cerebral / Q000097:blood / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D010962:Plasmodium berghei / Q000276:immunology*; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D000099185:Interferon Regulatory Factor-8
chemical_list: D016207:Cytokines; D050856:Interferon Regulatory Factor-1; D050835:Interferon Regulatory Factors; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D000099185:Interferon Regulatory Factor-8; C494258:Irf1 protein, mouse