Discussion

Barbara Clough, Ashleigh Johnston, Daniel Fisch, Joseph Wright and Eva-Maria Frickel Host-Toxoplasma Interaction Laboratory, The Francis Crick Institute, London
Certain intracellular pathogens avoid host cytosolic cellular defence mechanisms by residing inside pathogen vacuoles (PVs). The Frickel Lab studies human host defence against the protozoan parasite Toxoplasma gondii. Toxoplasma always leads to chronic infection and has a seroprevalence in man of 30 percent. Infection with Toxoplasma leads to the rapid production of IFNγ, a proinflammatory cytokine that upregulates host defence mechanisms that target the pathogens. We study how IFNγ-mediated ubiquitin- and guanylate binding protein (GBP)-driven mechanisms target Toxoplasma. These mechanisms remodel pathogen vacuoles (PVs) within host cells to limit Toxoplasma replication and mediate parasite killing. For example, human primary endothelial cells target Toxoplasma PVs with ubiquitin to cause parasite death by acidification in the cell’s endo-lysosomal system. In epithelial cells and macrophages, GBPs are responsible for Toxoplasma replication restriction. In order to classify the host response to Toxoplasma in an unbiased and high content fashion we have recently developed an artificial intelligence-driven image analysis pipeline. Using this tool, we are now in the position to rapidly classify host defence mechanisms to Toxoplasma in a variety of human cell types.