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 Shrews shrink in winter and regrow in spring
24.10.2017 | Max-Planck-Institut für Ornithologie

nachricht 'Y' a protein unicorn might matter in glaucoma
23.10.2017 | Georgia Institute of Technology

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Salmonella as a tumour medication

HZI researchers developed a bacterial strain that can be used in cancer therapy

Salmonellae are dangerous pathogens that enter the body via contaminated food and can cause severe infections. But these bacteria are also known to target...

Im Focus: Neutron star merger directly observed for the first time

University of Maryland researchers contribute to historic detection of gravitational waves and light created by event

On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...

Im Focus: Breaking: the first light from two neutron stars merging

Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.

Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....

Im Focus: Smart sensors for efficient processes

Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).

When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...

Im Focus: Cold molecules on collision course

Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.

How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

3rd Symposium on Driving Simulation

23.10.2017 | Event News

ASEAN Member States discuss the future role of renewable energy

17.10.2017 | Event News

World Health Summit 2017: International experts set the course for the future of Global Health

10.10.2017 | Event News

 
Latest News

Shrews shrink in winter and regrow in spring

24.10.2017 | Life Sciences

Microfluidics probe 'cholesterol' of the oil industry

23.10.2017 | Life Sciences

Gamma rays will reach beyond the limits of light

23.10.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>