An inside job: hacking into Janus kinase/signal transducer and activator of transcription signaling cascades by the intracellular protozoan Toxoplasma gondii

Abstract

The intracellular protozoan Toxoplasma gondii is well known for its skill at invading and living within host cells. New discoveries are now also revealing the astounding ability of the parasite to inject effector proteins into the cytoplasm to seize control of the host cell. This review summarizes recent advances in our understanding of one such secretory protein called ROP16. This molecule is released from rhoptries into the host cell during invasion. The ROP16 molecule acts as a kinase, directly activating both signal transducer and activator of transcription 3 (STAT3) and STAT6 signaling pathways. In macrophages, an important and preferential target cell of parasite infection, the injection of ROP16 has multiple consequences, including downregulation of proinflammatory cytokine signaling and macrophage deviation to an alternatively activated phenotype.

Fig 1

ROP16 is a multifunctional kinase with diverse effects on the host. (A) ROP16 activates STAT6, resulting in arginase-1 induction. Degradation of arginine limits replication of Toxoplasma, which is auxotrophic for this amino acid. Limiting parasite growth is beneficial for the host. It could also assist in the spread of the parasite, which uses cells such as macrophages and dendritic cells in dissemination during in vivo infection. (B) ROP16 and tyrosine phosphorylate STAT3. This transcription factor can have proinflammatory or anti-inflammatory activity, depending on the context of infection. During Toxoplasma infection, the predominant activity appears to be anti-inflammatory, although the exact nuclear targets of STAT3 are not known. For the parasite, this may be a way to evade antimicrobial immunity. Anti-inflammatory STAT3 function may also be a means to downmodulate harmful proinflammatory pathology. This benefits the host but is also advantageous to Toxoplasma, which seeks to keep its host alive to permit establishment of latent infection that is required for parasite transmission to new hosts. Which of these activities predominates may depend upon host cell type and life cycle stage of the parasite.