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

RESEARCH ARTICLE elife.elifesciences.org Reciprocal virulence and resistance polymorphism in the relationship between Toxoplasma gondii and the house mouse Jingtao Lilue1†, Urs Benedikt Müller1†, Tobias Steinfeldt1, Jonathan C Howard1,2* Institute for Genetics, University of Cologne, Cologne, Germany; 2Fundação Calouste Gulbenkian, Instituto Gulbenkian de Ciência, Oeiras, Portugal 1 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: 10.7554/eLife.01298.001 *For correspondence: jhoward@ igc.gulbenkian.pt These authors contributed equally to this work † Competing interests: The authors declare that no competing interests exist. Funding: See page 17 Received: 31 July 2013 Accepted: 13 September 2013 Published: 29 October 2013 Reviewing editor: Detlef Weigel, Max Planck Institute for Developmental Biology, Germany Copyright Lilue et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Introduction A virulent parasite that overcomes the immune system and kills its host may seem to have won the confrontation, but it is a Pyrrhic victory when the early death of the host reduces the probability of parasite transmission. Indeed it is in the interests of all hosts and most parasites to prolong the encounter. In this sense, virulence is a failure of co-adaptation. Haldane’s conjecture (Haldane, 1949) that intense and fluctuating selection imposed by parasites will generate host protein polymorphism is widely accepted (Woolhouse et al., 2002; Clark et al., 2007; Kosiol et al., 2008; Fumagalli et al., 2011). The presence in a population of multiple host resistance alleles confronting multiple parasite virulence alleles may reflect a dynamic equilibrium permissive for the persistence of both parties. However this equilibrium is achieved only at the expense of individual interactions fatal for either the parasite or the host, as a consequence of confrontations of inappropriate alleles. In mammals, however, the ability of the adaptive immune system to respond within the time scale of an individual infection and to remember for a lifetime, buffers individuals against dangerous genetic novelty arising from parasites. As a result, life or death outcomes for common infectious diseases in mammals are not generally determined by single, highly penetrant, polymorphic genes. We here report such a case, involving infection of the house mouse, Mus musculus, with the ubiquitous intracellular protozoan parasite, Toxoplasma gondii. T. gondii has a complex life cycle (Dubey, 1998) (Figure 1). The sexual process occurs in true cats (Felidae) and intermediate hosts become infected by ingesting oocysts spread in cat faeces. A phase of fast intracellular replication and spread (tachyzoite phase) stimulates immunity in the intermediate host, and this in turn induces parasite encystment in brain and muscle cells and lifelong persistence. Predation of the infected host by a cat completes the life cycle. If immunity fails, tachyzoite replication continues uninterrupted, killing the infected host within a few days (Deckert-Schlüter et al., 1996). Thus the probability that T. gondii completes its life cycle, which is roughly linear with duration of infection of the intermediate host, depends on early immune control. Lilue et al. eLife 2013;2:e01298. DOI: 10.7554/eLife.01298 1 of 21 Research article Genomics and evolutionary biology | Microbiology and infectious disease eLife digest The parasite Toxoplasma gondii is one of the most common parasites worldwide and is known for its unusual life cycle. It reproduces sexually inside its primary host—the cat—and produces eggs that are released in faeces. Other animals, most often rodents, can then become infected when they unknowingly eat the eggs while foraging. Once inside its new host, the parasite reproduces asexually until the rodent’s immune system begins to fight back. It then becomes semidormant and forms cysts within the brain and muscle cells of its host. In an added twist, the parasite also causes rodents to lose their fear of cats. This increases their chances of being caught and eaten, thereby helping the parasite to return to its primary host and complete its life cycle. Previous work has shown that virulent strains of T. gondii can evade the host immune system in mice by secreting enzymes that inactivate immune-related proteins called IRG proteins. This prevents the infection being cleared and leads to death of the host within a few days. The existence of these virulent strains is intriguing because parasites that kill their host, and thus prevent their own reproduction, should be eliminated from the population. The fact that they are fairly common suggests that there must be a hitherto unknown mechanism that allows rodents to survive these virulent strains. Lilue et al. now report the existence of such a mechanism in strains of mice found in the wild. In contrast to laboratory mice, wild mice produce IRG proteins that inhibit the enzymes secreted by the virulent strains of T. gondii. Moreover, the IRG genes in wild mice are highly variable, whereas laboratory mice all have virtually identical IRG genes. By uncovering the complexity and variability of IRG genes in wild mice—complexity that has been lost from laboratory strains—Lilue et al. solve the conundrum of how highly virulent T. gondii strains can persist in the mouse population, and offer an explanation for the evolution of parasitic strains with differing levels of virulence. DOI: 10.7554/eLife.01298.002 Mus musculus is probably the evolutionarily most important intermediate host for T. gondii, because it is very abundant worldwide and sympatric with a uniquely abundant felid, the domestic cat. Early immune control of T. gondii in mice depends on a family of IFNγ-inducible cytoplasmic effector proteins, the 47 kDa immunity-related GTPases (IRG proteins; for nomenclature of IRG genes and proteins see Bekpen et al. (2005); Martens and Ho (...truncated)