Reciprocal virulence and resistance polymorphism in the relationship between Toxoplasma gondii and the house mouse

Abstract

Virulence in the ubiquitous intracellular protozoon Toxoplasma gondii for its natural intermediate host, the mouse, appears paradoxical from an evolutionary standpoint because death of the mouse before encystment interrupts the parasite life cycle. Virulent T. gondii strains secrete kinases and pseudokinases that inactivate the immunity-related GTPases (IRG proteins) responsible for mouse resistance to avirulent strains. Such considerations stimulated a search for IRG alleles unknown in laboratory mice that might confer resistance to virulent strains of T. gondii. We report that the mouse IRG system shows extraordinary polymorphic complexity in the wild. We describe an IRG haplotype from a wild-derived mouse strain that confers resistance against virulent parasites by interference with the virulent kinase complex. In such hosts virulent strains can encyst, hinting at an explanation for the evolution of virulence polymorphism in T. gondii.DOI: http://dx.doi.org/10.7554/eLife.01298.001

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

“…6D). However, the wild‐derived Indian mouse strain CIM is considerably more resistant to type I T. gondii strains (Lilue et al ., 2013). The median lethal dose of RHΔ hxgprt injected intraperitoneally in these mice was determined to be between 1 × 10 5 and 1 × 10 6 parasites (Fig.…”

“…In addition to Irga6, also Irgb6 and Irgb10 have been shown to be phosphorylated upon infection with T. gondii virulent type I strains in cells of laboratory mice (Fentress et al ., 2010; Steinfeldt et al ., 2010; Behnke et al ., 2012; Lilue et al ., 2013), and inactivation by the ROP5/ROP18/GRA7 kinase complex is accompanied by reduced accumulation at the PVM (e.g. Fig.…”

“…all members of the family of true cats ( Felidae ). Because of their abundant worldwide distribution and sympatry with domestic cats, house mice are probably important intermediate hosts for T. gondii (Lilue et al ., 2013). Nevertheless, some strains of T. gondii are highly virulent for laboratory mice.…”

“…About 20 IRG genes are encoded within the genome of C57BL/6 mice, located in two adjacent clusters on chromosome 11 and one cluster on chromosome 18 (Bekpen et al ., 2005). Four of these genes are transcribed as adjacent pairs, resulting in expression of proteins carrying two IRG domains, the so‐called tandem IRG proteins (Lilue et al ., 2013). Based upon a unique substitution within the first nucleotide binding motif (GX 4 G K / M S), IRG proteins can be classified into two subfamilies.…”

“…Individual sequences of these rop5 paralogues are almost identical within strains but differ considerably between T. gondii types I, II and III strains (Behnke et al ., 2011; Reese et al ., 2011; Niedelman et al ., 2012). In wild‐derived mice, this two‐component ROP5/ROP18 parasite virulence system is counteracted by polymorphic tandem IRG proteins (Lilue et al ., 2013), most likely due to active decoying of ROP5 and ROP18 leaving Irga6 unphosphorylated. Another active rhoptry kinase, ROP17, was demonstrated only recently to phosphorylate Irga6 and Irgb6 in vitro .…”