Defense mechanisms used by the fungus Cryptococcus neoformans enable it to lead to fatal meningitis, which is one of the opportunistic infections often associated with death in HIV/AIDS patients, organ transplant recipients, diabetics and other immunosuppressed patients. In describing the complex process of how C. neoformans averts destruction in the lungs of mice, the Duke researchers have opened new options for drug development.
"Very few antifungal drugs are effective, so we need to identify the Achilles' heel of these fungal pathogens," said Dennis J. Thiele, PhD, the George Barth Geller Professor of Pharmacology and Cancer Biology at Duke University. Thiele is senior author of a study published March 13, 2013, in the journal Cell Host & Microbe. "With this research we may be closer to understanding how this fungal pathogen evades death in its host, and hopefully be closer to finding effective treatments."
Found in the environment, C. neoformans spores can be inhaled and cause infection, particularly when people have weakened immune systems. The Centers for Disease Control and Prevention estimates that worldwide, C. neoformans causes 1 million cases of meningitis a year among HIV/AIDS patients, with nearly 625,000 deaths.
Thiele and colleagues focused on the interplay between C. neoformans in the lungs of mice and the host's immune system, which mount an immediate attack against the pathogen.
The immune response is led by macrophages, which circulate in the blood stream and engulf invading microbes to destroy them. The macrophages are essentially tiny torture chambers for pathogens, using hostile conditions and toxic substances to kill invaders.
Among the substances inside the macrophages is copper, a mineral the body needs for normal cognitive function and development, but also known to have antifungal properties. In the face of a pathogenic invasion of fungal spores, the macrophages begin concentrating more copper within their torture chamber as one of the body's antifungal weapons.
The Duke researchers found that lethal strains of C. neoformans have two ways of battling against the toxicity of the copper. First, the pathogen turns on genes that make proteins to protect it from copper toxicity, so even when exposed to the hostile copper environment in the macrophages, it survives.
But a second defense mechanism is also deployed. The fungus, sensing the copper-rich environment, triggers a response that shuts down the host's ability to pump more copper into the macrophages – defusing this weapon in the immune system's arsenal.
"With these two mechanisms, C. neoformans can defend itself by sequestering the copper, and somehow communicate to the host macrophage, commanding that it shut down the copper pumps," Thiele said.
Thiele said studies are now focusing on how antifungal agents might thwart the pathogen's two defense systems. "The detoxification machinery might represent an effective drug target," Thiele said.
In addition to Thiele, study authors include Chen Ding, Richard A. Festa, Ying-Lien Chen and Joseph Heitman from Duke; Anna Espart and Sílvia Atrian from Universitat de Barcelona, Spain; Òscar Palacios, Jordi Espín and Mercè Capdevila from Universitat Autònoma de Barcelona, Spain.
The work was supported in part by the National Institutes of Health (GM48140-24, 2P30 AI064518-06, AI50438).
Sarah Avery | EurekAlert!
Don't Give the Slightest Chance to Toxic Elements in Medicinal Products
23.03.2018 | Physikalisch-Technische Bundesanstalt (PTB)
North and South Cooperation to Combat Tuberculosis
22.03.2018 | Universität Zürich
Satellites in near-Earth orbit are at risk due to the steady increase in space debris. But their mission in the areas of telecommunications, navigation or weather forecasts is essential for society. Fraunhofer FHR therefore develops radar-based systems which allow the detection, tracking and cataloging of even the smallest particles of debris. Satellite operators who have access to our data are in a better position to plan evasive maneuvers and prevent destructive collisions. From April, 25-29 2018, Fraunhofer FHR and its partners will exhibit the complementary radar systems TIRA and GESTRA as well as the latest radar techniques for space observation across three stands at the ILA Berlin.
The "traffic situation" in space is very tense: the Earth is currently being orbited not only by countless satellites but also by a large volume of space...
An international team of researchers has discovered a new anti-cancer protein. The protein, called LHPP, prevents the uncontrolled proliferation of cancer cells in the liver. The researchers led by Prof. Michael N. Hall from the Biozentrum, University of Basel, report in “Nature” that LHPP can also serve as a biomarker for the diagnosis and prognosis of liver cancer.
The incidence of liver cancer, also known as hepatocellular carcinoma, is steadily increasing. In the last twenty years, the number of cases has almost doubled...
In just a few weeks from now, the Chinese space station Tiangong-1 will re-enter the Earth's atmosphere where it will to a large extent burn up. It is possible that some debris will reach the Earth's surface. Tiangong-1 is orbiting the Earth uncontrolled at a speed of approx. 29,000 km/h.Currently the prognosis relating to the time of impact currently lies within a window of several days. The scientists at Fraunhofer FHR have already been monitoring Tiangong-1 for a number of weeks with their TIRA system, one of the most powerful space observation radars in the world, with a view to supporting the German Space Situational Awareness Center and the ESA with their re-entry forecasts.
Following the loss of radio contact with Tiangong-1 in 2016 and due to the low orbital height, it is now inevitable that the Chinese space station will...
Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP, provider of research and development services for OLED lighting solutions, announces the founding of the “OLED Licht Forum” and presents latest OLED design and lighting solutions during light+building, from March 18th – 23rd, 2018 in Frankfurt a.M./Germany, at booth no. F91 in Hall 4.0.
They are united in their passion for OLED (organic light emitting diodes) lighting with all of its unique facets and application possibilities. Thus experts in...
A new scenario seeking to explain how Mars' putative oceans came and went over the last 4 billion years implies that the oceans formed several hundred million...
23.03.2018 | Event News
19.03.2018 | Event News
16.03.2018 | Event News
23.03.2018 | Materials Sciences
23.03.2018 | Agricultural and Forestry Science
23.03.2018 | Physics and Astronomy