Toxoplasma's immunogenic balancing act explained

What is it about?

The parasite Toxoplasma gondii is highly successful. It infects up to 95% of people in many regions of the world, and most of them would never know it, due to the parasite’s manipulation of its host’s immune response. Toxoplasma keeps the immune response low enough so that it can thrive, but high enough so that its human hosts generally live healthy lives and can incubate parasites. When a host cell detects a parasite, it sets off a chain reaction. Inside that cell, a series of molecules activate each other until a protein called p38α is activated and moves into the cell’s nucleus. There, it turns on the genes that trigger the inflammatory response. Among other things, the purpose of that response is to eliminate the pathogen. Toxoplasma secretes a protein, GRA24, which activates and controls the inflammatory response. In this paper we show that GRA24 bypasses the cell’s chain reaction, activating p38α directly, and pulling it into the nucleus to turn on inflammatory response genes.

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Why is it important?

This paper demostrates the molecular basis of the control of MAP kinase signalling by GRA24. Using a wide variety of techniques we show that GRA24 is an intrinsically disordered protein that uses an adapted KIM motif to hijack and activate p38α directly, subsequently causing nuclear translocation. Producing a recombinant complex of the toxoplasmosis protein with human p38α has also provided a new way to assess the efficacy of anti-inflammatory drugs, many of which are designed to block p38α. So far it has been difficult to assess how effective they are as producing an active form of p38α is a problem.