Intestinal delta-6-desaturase activity determines host range forToxoplasmasexual reproduction

Abstract

Many eukaryotic microbes have complex lifecycles that include both sexual and asexual phases with strict species-specificity. While the asexual cycle of the protistan parasite Toxoplasma gondii can occur in any warm-blooded mammal, the sexual cycle is restricted to the feline intestine 1 . The molecular determinants that identify cats as the definitive 5 host for T. gondii are unknown. Here, we defined the mechanism of species specificity for T.gondii sexual development and break the species barrier to allow the sexual cycle to occur in mice. We determined that T. gondii sexual development occurs when cultured feline intestinal epithelial cells are supplemented with linoleic acid. Felines are the only mammals that lack delta-6-desaturase activity in their intestines, which is required for linoleic acid metabolism, resulting 10 in systemic excess of linoleic acid 2, 3 . We found that inhibition of murine delta-6-desaturase and supplementation of their diet with linoleic acid allowed T. gondii sexual development in mice.This mechanism of species specificity is the first defined for a parasite sexual cycle. This work highlights how host diet and metabolism shape coevolution with microbes. The key to unlocking the species boundaries for other eukaryotic microbes may also rely on the lipid composition of 15 their environments as we see increasing evidence for the importance of host lipid metabolism during parasitic lifecycles 4, 5 . Pregnant women are advised against handling cat litter as maternal infection with T. gondii can be transmitted to the fetus with potentially lethal outcomes. Knowing the molecular components that create a conducive environment for T.gondii sexual reproduction will allow for development of therapeutics that prevent shedding of T. 20 gondii parasites. Finally, given the current reliance on companion animals to study T. gondii sexual development, this work will allow the T. gondii field to use of alternative models in future studies.3 Main: The apicomplexan parasite Toxoplasma gondii causes a chronic infection in nearly one third of the human population and is well-known for causing congenital infections leading to blindness, mental retardation, and hydrocephaly of the developing fetus. T. gondii has a complex lifecycle containing both sexual and asexual phases. The T. gondii asexual cycle can occur in any 5 warm-blooded animal when contaminated food or water is consumed and T. gondii disseminates throughout the host, converting to an encysted form in muscle and brain tissue. In contrast, the T.gondii sexual cycle is restricted to the feline intestinal epithelium, culminating in the excretion of environmentally resistant oocysts 1 . The molecular basis for this species specificity is unknown. 10To determine the molecular mechanisms that define the species specificity of T. gondii sexual development, we generated cat intestinal organoids ( Fig. 1a), then seeded these epithelial cells onto glass coverslips. These monolayers displayed intestinal epithelial properties, including polarization and ...

Fussing About Fission: Defining Variety Among Mainstream and Exotic Apicomplexan Cell Division Modes

“…Reports on T. gondii endopolygeny suggest geometric expansion of nuclei: 8-16 progeny per endopolygeny replication cycle in the cat gut have been observed (Ferguson et al, 1974). Historically, the sexual cycle of T. gondii has been poorly experimentally accessible, but in vitro completion of the sexual cycle in cat intestinal organoids was recently reported, which is expected to provide experimental accessibility (Martorelli Di Genova et al, 2019). To date, T. gondii endopolygeny studies have not been so comprehensive to support a strong conclusion in this matter.…”

Supply and demand—heme synthesis, salvage and utilization by Apicomplexa

“…Demand for heme in sexual stages will depend on how these stages generate energy as well as on the availability of heme in the cat gut environment. Recent, elegant studies suggest that these stages may become more tractable in the future [42,43], opening the possibility for these questions to be addressed.…”

The Structural and Molecular Underpinnings of Gametogenesis in Toxoplasma gondii

“…Breakthrough work by Martorelli Di Genova and colleagues, approached a long-standing mystery in the field: what is the biochemical footprint that makes felines the selected definitive host? Briefly, the authors identified that host-specificity to felines in the sexual stage is owed to the accumulation of linoleic acid, given by the lack of delta-6-desaturase activity in their intestines, ( Di Genova et al., 2019 ). Felines are the only mammals that lack this enzyme activity in their intestines.…”

“…Felines are the only mammals that lack this enzyme activity in their intestines. Remarkably, inhibiting this enzyme’s activity alone, and supplementing mice diet with an excess of linoleic acid, allowed them to now become T. gondii infectious oocyst spreaders ( Di Genova et al., 2019 ).…”