Hypermigration of macrophages through the concerted action of GRA effectors on NF-κB/p38 signaling and host chromatin accessibility potentiatesToxoplasmadissemination

Abstract

AbstractMononuclear phagocytes facilitate the dissemination of the obligate intracellular parasiteToxoplasma gondii. Here, we report how a set of secreted parasite effector proteins from dense granule organelles (GRA) orchestrates dendritic cell-like chemotactic and pro-inflammatory activation of parasitized macrophages. These effects enabled efficient dissemination of the type IIT. gondiilineage, a highly prevalent genotype in humans. We identify novel functions for effectors GRA15 and GRA24 in promoting CCR7-mediated macrophage chemotaxis by acting on NF-κB and p38 MAPK signaling pathways, respectively, with contributions of GRA16/18 and counter-regulation by effector TEEGR. Further, GRA28 boosted chromatin accessibility and GRA15/24/NF-κB-dependent transcription at theCcr7gene locus in primary macrophages.In vivo, adoptively transferred macrophages infected with wild-typeT. gondiioutcompeted macrophages infected with a GRA15/24 double mutant in migrating to secondary organs in mice. The data show thatT. gondii, rather than being passively shuttled, actively promotes its dissemination by inducing a finely regulated pro-migratory state in parasitized human and murine phagocytes via co-operating polymorphic GRA effectors.ImportanceIntracellular pathogens can hijack cellular functions of infected host cells to their advantage, for example, for intracellular survival and for dissemination. However, how microbes orchestrate the hijacking of complex cellular processes, such as host cell migration, remains poorly understood. As such, the common parasiteToxoplasma gondiiactively invades immune cells of humans and other vertebrates and modifies their migratory properties. Here, we show that the concerted action of a number of secreted effector proteins from the parasite, principally GRA15 and GRA24, act on host cell signaling pathways to activate chemotaxis. Further, the protein effector GRA28 selectively acted on chromatin accessibility in the host cell nucleus to selectively boost host gene expression. The joint activities of effectors culminated in pro-migratory signaling within the infected phagocyte. We provide a molecular framework delineating howT. gondiican orchestrate a complex biological phenotype, such as the migratory activation of phagocytes to boost dissemination.