Intestinal Delta-6-desaturase Activity Determines Host Range For Toxoplasma Sexual Reproduction

Discussion in 'Articles & Scientific Studies' started by HumanLife, Jul 15, 2019.

  1. HumanLife

    HumanLife Member

    Mar 4, 2019
    Hey guys, this is the study Haidut mentioned in Danny Roddy's 6th bioenergetic news and Q&A about linoleic acid being what Toxoplasma gondii depends on.

    "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. 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."

    The Atlantic article:

    "Toxo infects more than a third of the world’s people, spreading through undercooked meat or food or water contaminated by infected cat waste (but not through direct contact with cats). In most cases, the parasite is harmless, and much-hyped claims that it affects human behavior are weak. But it can also pass from mother to fetus, causing blindness, developmental problems, hydrocephalus, and other disabilities. There is no vaccine or cure, and research has been generally slow and difficult, which Toxo’s cat-dependent life cycle doesn’t help.

    The study is available online and is set to be published in a scientific journal after three reviewers described it as “truly remarkable,” “transformative,” and “a key breakthrough.”

    At first, Knoll’s colleagues Bruno Di Genova and Sarah Wilson tried rearing Toxo on cat organoids—lab-grown balls of feline intestinal tissue. It didn’t work: The parasites grew, but never reached the sexual stage. The team wondered whether it had missed an important nutrient; perhaps a fatty acid, which Toxo is known to scavenge from its hosts. And sure enough, when the team added linoleic acid, “we had sex all over the place,” Knoll says.

    Our guts convert linoleic acid into other substances that regulate our immune systems, control blood pressure, and more. This transformation depends on an enzyme called delta-6-desaturase, or D6D for short. And cats, it turns out, are the only mammals that don’t make D6D in their guts. They can still produce the enzyme in other organs, but they shut it off in their intestines. Knoll suspects that they did so because they evolved in desert environments, and adapted by preserving their fatty acids. Indeed, linoleic acid makes up 25 to 46 percent of fatty acids in a cat’s blood, but just 3 to 10 percent of those in a mouse’s.

    Cat-food manufacturers and other researchers figured these details out in the 1970s, Knoll says, but the Toxo community was largely unaware of them. And yet, they perfectly explain the parasite’s life cycle. Toxo only has sex in cats because it depends on linoleic acid, and cats are the only mammals that build up enough of the stuff. “Whenever I give talks, I often get the question: Why the cats? What’s special about the cats?” Knoll says. “Now we have an answer.”

    Once the team figured out that linoleic acid was the key, it set about trying to figure out how to shut down D6D in mice. Fortunately, a drug that blocks the enzyme was commercially available. The team fed it to mice, along with a linoleic-rich diet and some Toxo. After a week, it saw signs that the parasites had reached the sexual stage, and were making oocysts, the sporelike structures that spread Toxo infections to new hosts. “The first experiment we did, we could see oocysts being pooped out in the mouse feces,” Knoll says. “That was super cool.”

    Isabelle Coppens of the Johns Hopkins Bloomberg School of Public Health. Toxo researchers still don’t have enough techniques for conclusively identifying sexual-stage parasites, she says, and the oocyst images in Knoll’s paper are a little blurry. Still, “I believe that there is something hot in this piece of work,” she says, “and the implications will be huge.”

    Science journalists are often mocked for describing preliminary discoveries in mice that may or may not translate to humans. There’s even a Twitter account—@justsaysinmice—that retweets overhyped news stories with “IN MICE” appended overhead. It’s delightful, then, to write about a study in which doing something in mice is the entire point.

    Knoll is now trying to delete the gene for D6D in mice, to create a strain of lab rodents that can host Toxo without the need for any drug. Her success would greatly accelerate the pace of Toxo research, because scientists could study the parasite using a common lab animal that’s more familiar and easier to work with. “It is extremely important for the field,” says John Boothroyd of the Stanford University School of Medicine. “We probably know over 100 times more about the mouse and have far more than 100 times more reagents for its study than we do for felines.”

    Many important techniques in modern biology rely on cross-breeding different strains of a given organism—and that’s hard when said organism only has sex in cats. For the past three decades, in order to cross-breed Toxo, “you’d have to infect mice with your strains, wait 30 days, and send their brains to the USDA in Maryland, where they would feed [the organs] to cats and send you back cat ***t,” Knoll says. If that process becomes simpler, it may be quicker to find treatments and vaccines—for cats, as well as humans.