Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
Animal Parasitic Diseases Laboratory, Animal and Natural Resources Institute, United States Department of Agriculture, Agricultural Research Service, Beltsville, Maryland, United States of America.
PLoS Biol. 2019 Aug 20;17(8):e3000364. doi: 10.1371/journal.pbio.3000364. eCollection 2019 Aug.
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.
许多真核微生物的生命周期都很复杂，包括有性和无性两个阶段，且具有严格的物种特异性。虽然原生动物寄生虫弓形虫的无性周期可以在任何温血动物中发生，但有性周期仅限于猫的肠道。将猫鉴定为弓形虫的终末宿主的分子决定因素尚不清楚。在这里，我们定义了弓形虫有性发育的物种特异性机制，并打破了物种障碍，使有性周期能够在老鼠中发生。我们确定，当培养的猫肠道上皮细胞补充亚油酸时，弓形虫就会发生有性发育。猫是唯一在肠道中缺乏 delta-6-脱饱和酶活性的哺乳动物，这种酶是亚油酸代谢所必需的，导致体内亚油酸过量。我们发现，抑制鼠 delta-6-脱饱和酶并在其饮食中补充亚油酸，可使弓形虫在老鼠中发生有性发育。这种物种特异性机制是首次为寄生虫有性周期所定义。这项工作强调了宿主饮食和代谢如何塑造与微生物的共同进化。解锁其他真核微生物物种界限的关键也可能依赖于它们环境中的脂质组成，因为我们越来越多地发现宿主脂质代谢在寄生虫生命周期中的重要性。孕妇被建议不要处理猫砂，因为母体感染弓形虫可能会传染给胎儿，导致潜在的致命后果。了解为弓形虫有性繁殖创造有利环境的分子成分，将有助于开发预防弓形虫寄生虫脱落的治疗方法。最后，鉴于目前依赖伴侣动物来研究弓形虫有性发育，这项工作将使弓形虫领域能够在未来的研究中使用替代模型。
