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Focus

My laboratory uses genetic analysis in experimental mouse models to identify genes and pathways that are required for the function of lymphoid and myeloid immune cells and ultimately for protection against infections with intracellular pathogens such as听Plasmodium听(尘补濒补谤颈补),听Mycobacterium听(迟耻产别谤肠耻濒辞蝉颈蝉),听Salmonella,听Legionella听and several others. This is accomplished using phenotype-driven forward genetic screen in mutant mice that carry naturally occurring or chemically induced mutations. Recently, we have focused on genes which inactivation protects mice against acute neuroinflammation, a pathological feature of cerebral malaria caused by听Plasmodium berghei. The discovered genes include听Ccdc88b, a protein essential for the migratory function of myeloid cells,听Themis听补苍诲听Zbtb7b, two proteins that are required for development and pro-inflammatory function of T cells, and听Usp15, a de-ubiquitinase that activates type I interferon response in the brain and in immune cells via RIG-I signaling, and听IRF1听补苍诲听IRF8, 2 transcription factors that are necessary for the development and pro-inflammatory function of dendritic cells, and NK cells. Using a similar approach, we have also detected genes that affect the intracellular milieu of the erythrocytes and that modulate susceptibility to blood stage malaria (P chabaudi), including the erythrocytes enzymes听Pklr听(pyruvate kinase) and听Bpgm听(Biphosphoglycerate mutase), and the erythroid progenitor factor听Trim8.听 We also use genomic and epigenetic approaches to identify the pathways regulated by IRF1 and IRF8 (IRF1/IRF8 regulome) in myeloid cells. We have determined that several of the genes in the IRF1/IRF8 regulome are mutated in patients suffering from primary immunodeficiencies, and /or are associated with susceptibility to chronic inflammatory conditions in humans, such as Inflammatory Bowel Disease, Multiple Sclerosis, Rheumatoid Arthritis and Lupus. Several of these genes are now being investigated in our lab as potential targets for drug development and therapeutic intervention in these common human diseases. In a long standing collaboration with the laboratory of Jean-Laurent Casanova, we conduct detailed genetic, biochemical and immunological studies in engineered mouse mutants that correspond to genes found mutated in patients suffering from Mendelian Susceptibility to Mycobacterial Diseases; Over the past 10 years, these genes include IRF8, ISG15, SPPL2A, OX40, and more recently T-BET, PD-1, CD28, cREL and IRF1.

Keywords

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Selected Publications

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