Intestinal delta-6-desaturase activity determines host range for Toxoplasma sexual reproduction

Abstract

Many eukaryotic microbes have complex life cycles that include both sexual and asexual phases with strict species specificity. Whereas 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. The molecular determinants that identify cats as the definitive 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 in systemic excess of linoleic acid. 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 their environments as we see increasing evidence for the importance of host lipid metabolism during parasitic lifecycles. 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. 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.

The Riveting Cellular Structures of Apicomplexan Parasites

“…This is also seen in mature female gametes; however it appears to be missing from the male gamete [52,53]. Recently it was shown that increasing the availability of linoleic acid, through supplementation and inhibition of downstream metabolism, allows the generation of T. gondii sexual stages in mice [54]. This may allow the study of these elusive sexual stages, opening the possibility of examining T. gondii metamorphosis for the first time.…”

Somatic cell-derived organoids as prototypes of human epithelial tissues and diseases

“…2 and Table 1). Organoid derivation from other domesticated and laboratory animals, including pigs, dogs, cats and rats, have also been described 24,[37][38][39] , and a similar culture setting further allowed an organoid expansion of snake venom glands 40 , underscoring the cross-species versatility of the organoid culture system. It should be noted that the growth factor combinations are not only tailored to individual tissues but also include unique molecules in some cases, such as gastrin for digestive tissues, neuregulin-1 for mammary organoids 7,18,19 , dihydrotestosterone for prostate organoidsd 6,41 and forskolin for human liver bile duct organoids 25 but not for hepatocyte organoids 26 .…”

“…Toxoplasma gondii is one of the most common parasites in the human population and has two main lifecycle phases: the sexual stage that is restricted to the cat intestinal epithelium and the asexual stage that can occur in any warm-blooded animals. A study using feline small intestinal organoids as a definitive host identified linoleic acid abundance or a deficiency of delta-6-desturase, an enzyme that is essential for linoleic acid metabolism, as a determinant of sexual reproduction of T. gondii 39 , and another study infected bovine and porcine small intestinal organoids with T. gondii tachyzoites as a model of invasion to intermediate hosts 38 .…”

“…For instance, goblet cell and enterocyte differentiation in human colon organoids enabled efficient colonization of enterohemorrhagic E. coli 116 . T. gondii parasites were able to undergo sexual reproduction in small intestinal organoids derived from cats, the only mammal known to lack delta-6-desaturase activity in the intestine 39 . Replication of human influenza virus in human airway organoids dramatically increased in the presence of ciliary cells 123 .…”

A Toxoplasma gondii patatin-like phospholipase contributes to host cell invasion

“…None of the characterized PLP containing genes have shown activity in vitro, which could again indicate a need for additional host factors and further optimized assay buffers for parasite PLPs. Lipid metabolism and signaling is critical during the parasite lifecycle [36], but there is still much to discover about these complex processes. Future work on the remaining T. gondii PLPs and other parasite derived PLPs may reveal novel regulators of parasite replication, infection and virulence.…”