Modulation of innate immunity by Toxoplasma gondii virulence effectors

Abstract

Preface Toxoplasma gondii is a common parasite of animals and humans that can cause serious opportunistic infections. However, the majority of infections are asymptomatic possibly because the organism has co-evolved with its many vertebrate hosts and has developed multiple strategies to persist asymptomatically for the lifetime of the host. Over the past two decades, infection studies in the mouse, combined with forward genetic approaches aimed at unraveling the molecular basis of infection, have revealed that T. gondii virulence is mediated, in part, by secretion of effector proteins into the host cell during invasion. Here, we review recent advances that illustrate how these virulence factors disarm innate immunity and promote survival of the parasite.

Toxoplasma gondii Virulence Factor ROP18 Inhibits the Host NF-κB Pathway by Promoting p65 Degradation

“…Toxoplasma gondii is an obligate intracellular parasite and an important opportunistic human pathogen, particularly in patients with primary or acquired defects in T cell-mediated immunity (1,2). The clinical symptoms of T. gondii infections in humans range from mild flu-like symptoms in most people to severe complications in immunocompromised individuals or, after transplacental transmission, to a fetus (3,4).…”

TheToxoplasma gondiirhoptry protein ROP18 is an Irga6‐specific kinase and regulated by the dense granule protein GRA7

“…Virulence of T. gondii in mice is adjusted by dozens of parasite proteins injected into the host cell cytosol at the onset and after host cell invasion (Hunter and Sibley, 2012; Bougdour et al ., 2013; Braun et al ., 2013; Alaganan et al ., 2014; Etheridge et al ., 2014). The rhoptry proteins ROP5 and ROP18 have been shown to inhibit the IRG resistance system by phosphorylation of highly conserved threonine residues in the switch I region of the nucleotide binding site (Fentress et al ., 2010; Steinfeldt et al ., 2010; Behnke et al ., 2012; Fleckenstein et al ., 2012; Niedelman et al ., 2012).…”

Toxoplasma GRA7 effector increases turnover of immunity-related GTPases and contributes to acute virulence in the mouse

“…ROP proteins generated renewed interest when it became evident that some ROPs confer critical strain-specific virulence in mice (8)(9)(10)(11)(12). In particular, the active kinase ROP18 and the pseudokinase ROP5 defend the parasite vacuole by blocking the function of mouse immunity-related GTPases (IRGs) (4). Following up-regulation by IFN-γ, IRGs target susceptible parasites for destruction by relocating to the parasite vacuole and vesiculating the PVM (13).…”

“…ROP proteins are secreted directly into the host cell cytosol at the time of invasion, after which they target to the PVM or other locations within the cell (4). Although many ROP proteins contain a kinase fold, nearly half of these are predicted to be pseudokinases because they lack the critical catalytic residues that are normally required for phosphate transfer (5).…”