Keeping parasites from sticking to mosquito guts could block disease transmission - Science Daily
Keeping parasites from sticking to mosquito guts could block disease transmission - Science Daily |
| Keeping parasites from sticking to mosquito guts could block disease transmission - Science Daily Posted: 30 Jul 2019 11:33 AM PDT A group of microorganisms known as kinetoplastids includes the parasites that cause devastating diseases such as African sleeping sickness, Chagas disease, and leishmaniasis. They share an ability to adhere to the insides of their insect hosts, using a specialized protein structure. But what if scientists could prevent the parasite from adhering? Would the parasites pass right through the vectors, unable to be passed on to a human? That's the idea behind a new study led by Michael Povelones of Penn's School of Veterinary Medicine and Megan L. Povelones of Penn State Brandywine. Using a non-disease-causing kinetoplastid species called Crithidia fasciculata, this husband-wife duo and their research team identified a number of genes involved in adherence in its mosquito host. "The parasite has to hold on so it won't pass right through," says Michael Povelones, an assistant professor of pathobiology at Penn Vet. "It needs to get retained in the gut in order to multiply and eventually get transmitted. These mechanisms of adherence seem to be [shared] across kinetoplastid species, so the hope is that our insights about Crithidia will tell us something about adherence in the medically relevant species." The study appears in the journal PLOS Neglected Tropical Diseases. Scientists had long turned to Crithidia fasciculata as a biochemical model to understand features of parasitic disease, as it is easily grown in the lab. Megan Povelones, whose specialty is African trypanosomiasis, was familiar with it from her doctoral studies at Johns Hopkins University, and the subject came up in conversations with her spouse. "We talk shop at home sometimes," says Michael Povelones, whose own research has focused on ways to harness the power of the mosquito's own immune defenses to stop them from transmitting disease. "I was intrigued by the fact that Crithidia infects mosquitoes but isn't a human or animal pathogen, that little was known about its life cycle, and that there had been some electron microscope studies done that show the parasite is actually adhering to the mosquito gut with a very specific type of structure that people had described as a hemidesmosome. I felt like there was some fascinating cell biology there to explore." Together they set out to investigate what happens to enable the parasite to "hold on" to the inside of the mosquito, a trait believed to be critical for disease transmission. In the lab, the researchers were able to replicate what other scientists had found previously: That Crithidia parasites exist in both a swimming form, with a tail-like appendage called a flagellum, and an adhering form, that even sticks to the surface of the plastic dishes in which they were grown in the lab. The swimming form was favored when the culture dishes were placed on a shaker, while the adherent form, which divided to form rosette structures, was more likely to develop when the dishes were kept stationary. Interestingly, they observed that the adherent parasites in the rosettes would occasionally give rise to swimming versions. To focus on the adherent parasites, the researchers would wait to see rosettes appear and would then wash away the swimming parasite. They could then focus on probing the genetics of the two types. "One question we had was really simple," says Michael Povelones, "which was, 'What were the transcriptional differences between the swimming cells versus those allowed to grow as rosettes.'" Remarkably, for two forms of the same species growing in the same medium, the researchers found a significant amount of variation in gene expression between the two. "The process of adhesion transformed their transcriptome in a really dramatic way," says Michael Povelones. When the researchers infected laboratory mosquito strains with Crithidia, they found that the parasites adhering to the mosquitoes, primarily in their hindgut region, resembled the adherent form they were culturing in the lab, giving them confidence that studying their lab strains could reveal important information about what was going on in the parasites' insect hosts. Among the genes with enhanced expression were a group known as GP63s that have been implicated in adhesion to immune cells in the Leishmania parasite. The team is hoping to pursue further investigations of adhesion using Crithidia as a tool, looking specifically at genes involved in the process that are known to be shared across kinetoplastid species and that could perhaps one day serve as a target for blocking transmission of vector-borne diseases. The study was supported by National Science Foundation (Grant 1651517) and National Institutes of Health (grants OD021633-01, AI29646, HG00307907, and AI103858).  |
| Posted: 20 Jul 2019 12:00 AM PDT ROBERT KITCHIN/STUFF Malaghan Insitute Professor Graham Le Gros, is seeking healthy volunteers to take part in a clinical trial designed to explore the therapeutic potential of human hookworms. A world-first clinical trial out of Wellington could be a game-changer for those with inflammatory and autoimmune diseases, but first a handful of healthy Kiwis will have to host a colony of worms in their gut. For the past 20 years, Malaghan Institute director Professor Graham Le Gros has been intrigued by the therapeutic potential of parasitic hookworms but human trials had long been off the table, until now. "We think now the time is right to do it here in a proper scientific way. [A] first in the world done here in New Zealand." ISTOCK Each volunteer will play host to dozens of the Necator americanus hookworm during the year-long trial. Funded by the Health Research Council, and in collaboration with the University of Otago Wellington, the trial will see up to 15 healthy Wellingtonians infected with a low, safe dose of Necator americanus larvae, and studied over the course of a year. READ MORE: "Before we start treating people who are sick, we need to understand what worms do to a standard immune system and then we'll be able to give knowledge to the people who actually have a disease," Le Gros said. SUPPLIED Malaghan Institute director Professor Graham Le Gros and head of laboratories Mali Camberis are looking forward to getting human trials underway after about 20 years worth of work. The ultimate aim, he said, was to eventually find better treatment options for a range of diseases, including coeliac, asthma, allergy, multiple sclerosis and inflammatory bowel disease. Hookworms were known masters at dampening down the human immune system to evade detection and expulsion, which could offer "huge therapeutic potential". Part of the reason why the institute had chosen to make the leap to human trials was to help legitimise the treatment which some people have been administering to themselves for years. MALAGHAN INSTITUTE Hookworms have long been of scientific interest due to their ability to alter the immune system of their human host. "Right now, everyone's bootlegging and no one knows what's going on, no decent trial has been done. "There have been cases of people causing harm to themselves because they like their worms and so they dose up and end up in the unhappy situation where they can cause quite severe illness." The institute had put the call out for Wellington-based volunteers aged between 18-65 years and in good health. MALAGHAN INSTITUTE Wellington's Malaghan Institute is seeking healthy volunteers to take part in the clinical trial designed to explore the therapeutic potential of human hookworms. Each participant will have 30 tiny hookworm larvae placed on their skin under a bandage where they would burrow into the skin beginning a journey through blood vessels, the heart and lungs, before travelling up the windpipe to the back of the throat. From there, the worms would be swallowed back down the gullet before making themselves at home in the lower intestine. "It's not painful, more a zingy feeling," Le Gros said. MALAGHAN INSTITUTE Participants would be given "more knowledge than they ever wanted to know about their gut, their blood, their poo and their metabolism", Le Gros said. At any time participants would be able to be given a pill which effectively would rid the body of the worms. Keen to dispel any lingering fear, head of laboratories Mali Camberis said the hookworm could be tolerated by human hosts with few side effects. "They can't multiply inside their host, or be transmitted through physical contact or exchange of bodily fluids. With standard hygiene practices, there is absolutely no risk of participants infecting others." DR KARA FILBEY/MALAGHAN INSTITUTE There are an estimated million species of parasitic worms (helminths) in existence, which infect a wide range of animals including humans. Hookworms can be detrimental to health, however, and Le Gros said it came down to the number of them living inside someone's body. "We think there's a Goldilocks level of worms; too little or none at all is not good; too many and they bleed you dry. Just the right amount is a lovely relationship where you look after each other." Dr Stephen Inns, a gastroenterologist and senior lecturer at the University of Otago Wellington said with the increasing rates of inflammatory disease in the Western world, it was time to look deeper at what had changed. "When we look at improvements in standards of living, hygiene and access to medicine, it seems likely that the loss of gut parasites, such as hookworms, from humans may be partially to blame. There could be a mutually beneficial relationship we're missing out on." Le Gros is excited at getting underway with the human trial. "We've got to get a bit braver. I think there's a lot of people out there who would like to be guinea pigs to try and help other people. * To find out more, or register interest in participating in the trial, email hookworm@malaghan.org.nz Stuff  |
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