Inactivation of LRG-47 and IRG-47 reveals a family of interferon gamma-inducible genes with essential, pathogen-specific roles in resistance to infection

The cytokine interferon (IFN)-gamma regulates immune clearance of parasitic , bacterial, and viral infections, however, the underlying mechanisms are p oorly understood. Recently, a family of IFN-gamma -induced genes has been i dentified that encode 48-kD GTP-binding proteins that localize to the endop lasmic reticulum of cells. The prototype of this family, IGTP, has been sho wn to be required for host defense against acute infections with the protoz oan parasite Toxoplasma gondii, but not for normal clearance of the bacteri um Lister ia monocytogenes and murine cytomegalovirus (MCMV). To determine whether other members of the gene family also play important roles in immun e defense, we generated mice that lacked expression of the genes LRG-47 and IRG-47, and examined their responses to representative pathogens. After in fection with T, gondii, LRG-47-deficient mice succumbed uniformly and rapid ly during the acute phase of the infection; in contrast, IRG-47-deficient m ice displayed only partially decreased resistance that was not manifested u ntil the chronic phase. After infection with L. monocytogenes, LRG-47-defic ient mice exhibited a profound loss of resistance, whereas IRG-47-deficient mice exhibited completely normal resistance. In addition, both strains dis played normal clearance of MCMV. Thus, LRG-47 and IRG-47 have vital, but di stinct roles in immune defense against protozoan and bacterial infections.