Toxoplasma Polymorphic Effectors Determine Macrophage Polarization and Intestinal Inflammation

SummaryEuropean and North American strains of the parasite Toxoplasma gondii belong to three distinct clonal lineages, type I, type II, and type III, which differ in virulence. Understanding the basis of Toxoplasma strain differences and how secreted effectors work to achieve chronic infection is a major goal of current research. Here we show that type I and III infected macrophages, a cell type required for host immunity to Toxoplasma, are alternatively activated, while type II infected macrophages are classically activated. The Toxoplasma rhoptry kinase ROP16, which activates STAT6, is responsible for alternative activation. The Toxoplasma dense granule protein GRA15, which activates NF-κB, promotes classical activation by type II parasites. These effectors antagonistically regulate many of the same genes, and mice infected with type II parasites expressing type I ROP16 are protected against Toxoplasma-induced ileitis. Thus, polymorphisms in determinants that modulate macrophage activation influence the ability of Toxoplasma to establish a chronic infection.

► Toxoplasma strains induce either classical (M1) or alternative (M2) macrophage activation
► Rhoptry kinase ROP16 from strain types I or III induces M2 activation
► Toxoplasma dense granule protein GRA15 from type II strains induces M1 activation
► Type I ROP16 protects mice from type II Toxoplasma-induced ileitis