Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Enzyme Revealed That is Key to Fungus’s Ability to Breach Immune System

11.11.2003


A newly discovered mechanism by which an infectious fungus evades the immune system could lead to novel methods to fight the fungus and other disease-causing microbes, according to Howard Hughes Medical Institute investigators at Duke University Medical Center.


Joseph Heitman, M.D., Ph.D.



Disruption of a key enzyme in the fungus Cryptococcus neoformans -- a common cause of infection of the central nervous system in patients such as organ transplant recipients who lack a functioning immune system -- led to a significant loss of fungal virulence in mice, the team found. That loss of virulence stemmed from the fungus’s inability to launch a counterattack against components of the innate immune system, the body’s first line of defense against infection, the study showed.

The Duke-based team -- led by HHMI geneticist Joseph Heitman, M.D., director of Duke’s Center for Microbial Pathogenesis, and HHMI biochemist Jonathan Stamler, M.D. -- reported their findings in the Nov. 11, 2003, issue of Current Biology. The work was funded by the National Institutes of Allergy and Infectious Diseases and the Burroughs Wellcome Fund.


The "fungal defense" enzyme, called flavohemoglobin, is prevalent among many bacterial and fungal pathogens, Heitman said, which suggests that the findings in Cryptococcus are likely relevant to other infectious microbes. New drugs that target these enzymes might therefore represent effective treatments for a wide range of infectious diseases, he said.

The human immune system uses a two-pronged mechanism to fight infection: a rapid innate response and a slower adaptive response that depends on the production of antibodies. Key components of the innate immune system are "search-and-destroy" cells called macrophages that engulf and kill invading pathogens. Macrophages kill infectious microbes using a combination of oxidants, including hydrogen peroxide, nitric oxide and related molecules.

"The body must rely on macrophages of the innate immune system to protect itself before the adaptive immune system can respond to invasion," Heitman said. "While much is known about how pathogens defend themselves against hydrogen peroxide produced by the macrophages, this study is the first biologically relevant test of what microbes do to counteract nitric oxide and promote infection."

The researchers found that a mutant C. neoformans strain lacking the flavohemoglobin enzyme failed to break down nitric oxide in laboratory cultures. Fungus with the enzyme deficiency also ceased to grow when in the presence of nitric oxide, whereas ordinary fungus survived normally.

Mice infected with the flavohemoglobin-deficient C. neoformans survived for five days longer than those infected with the normally virulent strain. In contrast, the normal and mutant fungal strains were equally virulent in mice whose immune cells could not produce nitric oxide, the team reported.

The mutant fungus also failed to grow normally in laboratory dishes containing macrophage cells, further implicating the innate immune system in the loss of virulence exhibited by fungi lacking flavohemoglobin.

The team discovered a second enzyme, known as GSNO reductase, which also plays a role in defending the fungus against nitric oxide-related molecules produced by macrophages. Mutant fungal strains deficient in both enzymes were more severely impaired than those lacking flavohemoglobin only.

"By disabling either the fungal nitric oxide defense system or the immune system’s ability to produce nitric oxide, we were able to tip the balance one way or the other -- in favor of the fungal infection or the host," Heitman said. "That raises the possibility that we could treat infectious disease with drugs that either inhibit fungal defense enzymes or increase the innate immune system’s ability to mount a nitrosative attack."

Collaborators on the study include Marisol de Jesus-Berrios, Ph.D., Gary Cox, M.D., Limin Liu, Ph.D., and Jesse Nussbaum, all of Duke.

Kendall Morgan | dukemed news
Further information:
http://www.dukemednews.org/news/article.php?id=7186

More articles from Life Sciences:

nachricht Tag it EASI – a new method for accurate protein analysis
19.06.2018 | Max-Planck-Institut für Biochemie

nachricht How to track and trace a protein: Nanosensors monitor intracellular deliveries
19.06.2018 | Universität Basel

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Overdosing on Calcium

Nano crystals impact stem cell fate during bone formation

Scientists from the University of Freiburg and the University of Basel identified a master regulator for bone regeneration. Prasad Shastri, Professor of...

Im Focus: AchemAsia 2019 will take place in Shanghai

Moving into its fourth decade, AchemAsia is setting out for new horizons: The International Expo and Innovation Forum for Sustainable Chemical Production will take place from 21-23 May 2019 in Shanghai, China. With an updated event profile, the eleventh edition focusses on topics that are especially relevant for the Chinese process industry, putting a strong emphasis on sustainability and innovation.

Founded in 1989 as a spin-off of ACHEMA to cater to the needs of China’s then developing industry, AchemAsia has since grown into a platform where the latest...

Im Focus: First real-time test of Li-Fi utilization for the industrial Internet of Things

The BMBF-funded OWICELLS project was successfully completed with a final presentation at the BMW plant in Munich. The presentation demonstrated a Li-Fi communication with a mobile robot, while the robot carried out usual production processes (welding, moving and testing parts) in a 5x5m² production cell. The robust, optical wireless transmission is based on spatial diversity; in other words, data is sent and received simultaneously by several LEDs and several photodiodes. The system can transmit data at more than 100 Mbit/s and five milliseconds latency.

Modern production technologies in the automobile industry must become more flexible in order to fulfil individual customer requirements.

Im Focus: Sharp images with flexible fibers

An international team of scientists has discovered a new way to transfer image information through multimodal fibers with almost no distortion - even if the fiber is bent. The results of the study, to which scientist from the Leibniz-Institute of Photonic Technology Jena (Leibniz IPHT) contributed, were published on 6thJune in the highly-cited journal Physical Review Letters.

Endoscopes allow doctors to see into a patient’s body like through a keyhole. Typically, the images are transmitted via a bundle of several hundreds of optical...

Im Focus: Photoexcited graphene puzzle solved

A boost for graphene-based light detectors

Light detection and control lies at the heart of many modern device applications, such as smartphone cameras. Using graphene as a light-sensitive material for...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Munich conference on asteroid detection, tracking and defense

13.06.2018 | Event News

2nd International Baltic Earth Conference in Denmark: “The Baltic Sea region in Transition”

08.06.2018 | Event News

ISEKI_Food 2018: Conference with Holistic View of Food Production

05.06.2018 | Event News

 
Latest News

Carbon nanotube optics provide optical-based quantum cryptography and quantum computing

19.06.2018 | Physics and Astronomy

How to track and trace a protein: Nanosensors monitor intracellular deliveries

19.06.2018 | Life Sciences

New material for splitting water

19.06.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>