Abstract
Secretory polymorphic serine/threonine kinases control pathogenesis of Toxoplasma gondii in the mouse. Genetic studies show that the pseudokinase ROP5 is essential for acute virulence, but do not reveal its mechanism of action. Here we demonstrate that ROP5 controls virulence by blocking IFN-γ mediated clearance in activated macrophages. ROP5 was required for the catalytic activity of the active S/T kinase ROP18, which phosphorylates host immunity related GTPases (IRGs) and protects the parasite from clearance. ROP5 directly regulated activity of ROP18 in vitro, and both proteins were necessary to avoid IRG recruitment and clearance in macrophages. Clearance of both the Δrop5 and Δrop18 mutants was reversed in macrophages lacking Irgm3, which is required for IRG function, and the virulence defect was fully restored in Irgm3−/− mice. Our findings establish that the pseudokinase ROP5 controls the activity of ROP18, thereby blocking IRG mediated clearance in macrophages. Additionally, ROP5 has other functions that are also Irgm3 and IFN-γ dependent, indicting it plays a general role in governing virulence factors that block immunity.
Highlights
Toxoplasma gondii is an obligate intracellular parasite that infects a wide range of vertebrate animal hosts and causes zoonotic infection in humans, leading to potentially severe congenital infections and risk of reactivation in immunocompromised patients [1]
Some of these virulence factors are active protein kinases, while other related pseudokinases lack enzymatic activity; it was unclear how they functioned in promoting virulence
In the present work we demonstrate that ROP5, an inactive member of this protein kinase family, regulates the active protein kinase ROP18, which normally prevents clearance of the parasite in interferon-activated macrophages
Summary
Toxoplasma gondii is an obligate intracellular parasite that infects a wide range of vertebrate animal hosts and causes zoonotic infection in humans, leading to potentially severe congenital infections and risk of reactivation in immunocompromised patients [1]. Forward genetic analyses have been used to map the genes responsible for virulence in laboratory mice [4,5]. This complex trait is largely mediated by a few members of a large family of polymorphic serine threonine (S/T) protein kinases secreted from rhoptries (ROP) into the host cell during invasion [6,7]. The ROP kinase family consists of ,20 active members, as well as a similar number of putative pseudokinases that are predicted to lack kinase activity [8]. The structures of several ROP pseudokinases reveal they contain a typical kinase fold and yet they are structurally and phylogenetically diverse [9,10]
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