Leishmaniasis, Visceral

Scientists have discovered the specific enzyme that a species of sandfly uses to produce a pheromone attractant, which could lead to the creation of targeted traps to control them and reduce the spread of the potentially fatal disease, Leishmaniasis. Scientists have discovered the specific enzyme that a species of sandfly uses to produce a pheromone attractant, which could lead to the creation of targeted traps to control them and reduce the spread of the potentially fatal disease, Leishmaniasis. The team from the University of Nottingham's School of Chemistry analysed the genome of the Lutzomyia longipalpis, a species of sandfly native to Brazil and South America that can spread a disease called Leishmaniasis. The study identified the enzyme, called a Terpene Synthase that is responsible for making the terpene pheromone sobralene, that the insect uses to attract others for mating, a discovery that could lead to the development of commercial traps for targeting and controlling this type of sandfly. The research has been published today in PNAS. Over 90 sandfly species are known to transmit Leishmania parasites that are spread to humans through being bitten, but Lutzomyia longipalpis is themajor carrier of the disease in South America. The most common symptoms of the disease are skin ulcers and lesions which can leave life-long scars, in more serious cases people can become very unwell with fever, weight loss, enlargement of the spleen and liver, and anaemia. The most serious form of the disease, known as visceral leishmaniasis, is invariably fatal within 2-years if untreated. Most cases of visceral leishmaniasis occur in Brazil, but the disease can be found in large parts of the tropics and subtropics. Terpenes are widely used in nature for chemical communication, but understanding how these structurally diverse natural products are produced by insects is only now beginning to emerge. Males of the sandfly, Lutzomyia longipalpis, use terpene pheromones to lure females and other males to mating sites. Terpene synthases are responsible for the biosynthesis of many chemicals used by plants and microorganisms for defense and communication. This research identifies the first insect terpene synthase (TPS) from the insect Lutzomyia. It offers the potential for sustainable production of this compound through biocatalysis. Professor Neil Oldham from the University of Nottingham's School of Chemistry led the study, he said: "Finding this enzyme has been very difficult and we have been hunting for it for over 2 years., The Lutzomyia genome contains an unusually high number of candidate terpene synthase genes, but thanks to the persistence of Dr Charlie Ducker, a talented researcher on the team, we were able to find the one that makes the pheromone." "The beauty of the pheromone approach is that it is very specific for this insect and so the next stage of the project will be to engineer microorganisms to make the enzyme in a way that would produce the pheromone. If we can then find a way to scale this up for commercial use this would be a way to control the populations of these insects and hopefully reduce the spread of Leishmaniasis."

For the first time, scientists have begun to figure out why the disfiguring skin lesions caused by cutaneous leishmaniasis don't hurt. For the first time, scientists have begun to figure out why the disfiguring skin lesions caused by cutaneous leishmaniasis don't hurt. Researchers analyzed leishmaniasis lesions on mouse skin to detect metabolic signaling pathways that differed from uninfected mice. Results suggested the parasites that cause the disease change pain perception -- presumably as a way to delay treatment and promote their own survival. "No one knows why these lesions are painless -- but it has been thought that the parasite somehow manipulates the host physiological system," said Abhay Satoskar, senior author of the study and professor of pathology in The Ohio State University College of Medicine. "Based on our data, something the parasites do triggers pathways that suppress pain. How they do that, we're still investigating." Beyond increasing understanding of this parasitic disease afflicting 1 million new patients each year, the research could lead to development of new non-narcotic pain medications. "We hypothesize that any molecules the parasite's presence is producing could be potential painkillers for other health problems," Satoskar said. The study was published recently in the journal iScience. The lack of pain in leishmaniasis lesions has puzzled scientists for years, especially when similar blisters caused by conditions like chicken pox, staphylococcus infections or the herpes virus are itchy, oozy and sore. After giving mice chronic infections with Leishmania mexicana, the species that causes cutaneous leishmaniasis in South, Central and North America, researchers used an unbiased mass spectrometry analysis of the lesions to identify molecules known to be associated with pain suppression. They found numerous metabolites -- products of bio-chemical reactions that break down food to produce energy and perform other essential functions -- that have been linked in previous research to blockage of pain perception. They also found pathways with pain-relief properties tied to the brain's endocannabinoid system, which is involved in a host of physiological processes, including the pain response. Cell-culture experiments in infected macrophages, the immune cells in which Leishmania parasites live, showed an increase in most, but not all, of the same changes as in the lesions. The parasites use these metabolites as nutrition to help them replicate. But finding that certain pain-suppression pathways aren't increased in infected macrophages leaves some questions unanswered, said Satoskar, also a professor of microbiology at Ohio State. "The infection does something in the cell that could be a direct or indirect effect -- we don't know. But the environment that the infection creates leads to production of these metabolites," he said. "The exciting thing is that this is the first time we've begun to understand the cellular basis of why there is no pain in these lesions. "The next key question is, if we know these pathways are responsible, then how are they triggered? By the parasite, or something the parasite is doing to the host cell, or a combination of both? There could be a lot of things happening." Skin test for immunity to Leishmania-caused diseases Satoskar has also co-led an initiative to develop a standardized skin test to check for immunity to Leishmania donovani, the parasite that causes visceral leishmaniasis -- a potentially lethal form of the disease that affects the organs and is fatal if untreated. He and colleagues recently reported in Nature Communications on this work, which is critical for disease surveillance in the most affected regions of the world and will be needed for phase 3 clinical trials of leishmaniasis vaccines the team has developed. The test, using an antigen called leishmanin, is similar to a skin test for tuberculosis -- a positive response means a person has been exposed to the parasite and has cellular immunity that prevents further clinical symptoms. No tests or reagents are available to detect sporadic cases of leishmaniasis reported in the southern United States, so the skin test being developed will facilitate surveillance studies to assess exposure throughout the endemic regions for leishmaniasis -- which include the U.S. "This is a very important test in the field to understand who is exposed to this disease or not," Satoskar said. "For many stakeholders going into a community to conduct surveillance, knowing who is immune and who is not immune is essential so they can deploy their limited resources appropriately for disease control." Leishmanin skin tests have existed and been in use in past years but are no longer available. This research team developed the antigen following Good Laboratory Practice guidelines and tested it in hamsters, a model for human visceral leishmaniasis, to ensure the skin test triggers the expected immune response to both infection and vaccination. "This kind of data can be used for fast-track approval for Leishmania vaccines which are under development. We anticipate fulfilling the need of the entire global community," Satoskar said. Co-lead authors of the Nature Communications paper were Sanjay Singh of Gennova Biopharmaceuticals, Shinjiro Hamano of Nagasaki University, Sreenivas Gannavaram and Hira Nakhasi of the Food and Drug Administration, Greg Matlashewski of McGill University, and Shaden Kamhawi and Jesus Valenzuela of the National Institute of Allergy and Infectious Diseases (NIAID). The Nature Communications work was supported by the Global Health Innovative Technology Fund, the Canadian Institutes of Health Research, the FDA, the National Institutes of Health, NAIAD and the Fonds de recherche du Quebec-Sante. Nakhasi, Gannavaram and Nazli Azodi of the FDA also co-authored the iScience paper along with co-authors Greta Volpedo, Blake Cox, Yulian Mercado, Candice Askwith, and Matthew Bernier of Ohio State and Timur Oljuskin of the U.S. Department of Agriculture. The iScience study was supported by the Metabolomics Workbench/National Metabolomics Data Repository, Common Fund Data Ecosystem and Metabolomics Consortium Coordinating Center.

NORTHAMPTON, MA / ACCESSWIRE / November 7, 2023 / Gilead Sciences / In the late 1980s, people in Dr. Shyam Sundar's homeland in eastern India were dying by the hundreds of thousands of a debilitating parasitic disease known as visceral leishmaniasis (VL). "It was a very, very painful experience," recalls Shyam, Professor of Medicine at Banaras Hindu University in Varanasi, India. "We used to see 40 to 50 patients every week, but we only had a capacity of 20 beds. We had no means to treat them. It was a very difficult situation." The only available treatment was considered highly toxic, requiring multiple applications and a 28-day hospital stay. Shyam resolved to find a better alternative. In the mid-1990s, Shyam met a Gilead scientist and began a long partnership with the company that would ultimately help revolutionize the landscape for the condition, which is the second-deadliest parasitic disease after malaria. The illness is spread by infected sandflies and can cause fever, weight loss, an enlarged spleen and anemia. If left untreated, it's fatal more than 95 percent of the time. Shyam helped conduct research in 2010, showing an innovative approach to the clinical management of VL, which resulted in a New England Journal of Medicine publication. "This was a game-changer," Shyam says. "It really astonished us to find that this innovative approach could potentially help a lot of people." Finding Solutions Against Neglected Tropical Diseases VL is one of 20 conditions identified by the WHO as a Neglected Tropical Disease - a widespread disease that occurs in tropical regions and predominantly in low- and lower middle-income countries. In 2012, the WHO launched a campaign to reduce deaths caused by these diseases in Southeast Asia and the Indian subcontinent by 2030. In response, a coalition of organizations and biopharmaceutical companies, including Gilead, joined together in a pledge to meet those goals. They reaffirmed that pledge in 2022 in what is known as the Kigali Declaration. Since the pledge, Gilead has continued its long history in supporting reducing deaths from VL and controlling other neglected tropical diseases such as cryptococcal meningitis in efforts to advance global health equity. Most recently, the company donated vials of medication and provided financial support for better treatment access and screening in endemic regions such as Bangladesh, Ethiopia, India, Kenya, Nepal and Somalia. "It's in our DNA to do the right thing," says Dennis Israelski, Executive Director and Head of Medical Affairs for Global Patient Solutions at Gilead. "Part of our purpose is to introduce and scale transformative therapies, and help address barriers to care - especially in communities with greatest unmet medical needs." The advanced clinical management approaches and additional community efforts have significantly helped reduce the burden of these tropical diseases. "We went from having hundreds of thousands of people with visceral leishmaniasis to about 800 people," says Shyam. "In my homeland state of Bihar, once an epicenter of the epidemic, physicians have seen only around 14 new patients thus far this year." Addressing Additional Tropical Conditions "What we've learned through our work in visceral leishmaniasis and other diseases can be applied to the medical management of other neglected tropical diseases that are fatal when left untreated," Dennis says. Gilead is partnering with investigators to evaluate the use of these approaches in studying invasive fungal infections in Latin America, Southeast Asia and China. Dennis says these collaborations are a part of Gilead's ongoing efforts to advance global health equity by finding solutions that reach disproportionally impacted communities. "We're dealing with some of the most complex public health problems in low- and lower middle-income countries," Dennis says. "Our work aims to have profound health impacts among people disproportionally affected by diseases across the globe." Originally published by Gilead Sciences View additional multimedia and more ESG storytelling from Gilead Sciences on 3blmedia.com. Contact Info: Spokesperson: Gilead Sciences Website: Email: info@3blmedia.com SOURCE: Gilead Sciences View source version on accesswire.com: