Philippe Gros, Ph.D.
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 Plasmodium (malaria), Mycobacterium (tuberculosis), Salmonella, Legionella 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 Plasmodium berghei. The discovered genes include Ccdc88b, a protein essential for the migratory function of myeloid cells, Themis and Zbtb7b, two proteins that are required for development and pro-inflammatory function of T cells, and Usp15, a de-ubiquitinase that activates type I interferon response in the brain and in immune cells via RIG-I signaling, and IRF1 and 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 Pklr (pyruvate kinase) and Bpgm (Biphosphoglycerate mutase), and the erythroid progenitor factor Trim8. 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.