Secretory kinases in parasites block innate immunity (99.2)

Abstract

Toxoplasma gondii is a widespread parasite of animals that is transmitted between cats and rodents, although it also infects a wide range of vertebrates including humans. Genetic mapping studies have identified a family of polymorphic serine threonine (S/T) kinases that control acute virulence in the mouse. These kinases are released from organelles called the rhoptries (ROP) and they target different host pathways. One of the key virulence determinants is ROP18, which phosphorylates switch region I in the GTPase domain of a family of immunity related GTPases, which are important in pathogen control. Phosphorylation in this key region prevents oligomerization and blocks GTPase function, thus protecting the parasite within the host cell. Recent studies have revealed that ROP18, and other active ROP kinases, are control by the pseudokinase ROP5, which lacks catalytic activity, but is required for acute virulence. ROP5 regulates the activity of ROP18, as well as binding to its substrates to facilitate their phosphorylation. Collectively, these studies reveal a complex network of S/T kinases in the parasite that control acute virulence of T. gondii by blocking innate immunity in the mouse.