Sudy unravel mechanism critical for fungal virulence

Apr 05, 2013
Unravelled a mechanism critical for fungal virulence
The smallest MTs known up to now, also induced by cooper, were previously found from other fungi, such as Neurospora crassa i Agaricus bisporus, fungi used in molecular biology studies.

Metallothioneins, proteins able to capture metal ions, play a major role in the virulence of Cryptococcus neoformans, a fungal pathogen which causes severe infections in immunodeficient and immunocompetent individuals (AIDS patients, transplant receivers, etc.) This is one of the main conclusions of the research published on the journal Cell, Host & Microbe, and developed by the researchers Sílvia Atrian and Anna Espart, from the Department of Genetics and the Institute of Biomedicine of the University of Barcelona (IBUB), affiliated with the campus of international excellence BKC.

Proteins which bind metal ions

Discovered in 1957 by the experts Marghoses and Vallee, metallothioneins (MT) are low molecular weight, cysteine-rich proteins. Thanks to their structure, they can bind and act as chelating agents —compounds which capture metals— to capture and distribute biologically interesting metals (copper, zinc, cadmium, quicksilver, etc.). MTs are very heterogeneous and polymorphic, and can be found in any type of organism (prokaryotes, fungi, plants, vertebrates, etc.), in which they facilitate metal detoxification processes and help to modulate the of the organism's physiological response against a lack or excess of metals.

The fight against an opportunistic fungus

Cooper has a long history as an antimicrobial agent. To capture and eliminate cooper excess is a major step forward in the progress of infections.

Previous studies identified some proteins produced by C. neoformans in response to high cooper concentrations. "This new research states for the first time that these proteins are metallothioneins; they play a critical role in virulence and colonization of the pathogen", explain Professor Sílvia Atrian, head of the Consolidated Research Group on Metallothioneins, Metallomics and Networks of Response to Metals (METMET), composed by experts from the UB and the UAB and recognised by the Government of Catalonia. The experts on bioinorganic chemistry Jordi Espín i Òscar Palacios, from the collaborating group headed by Mercé Capdevilla (UAB) and members of METMET, also participate in the study, led by Dennis J. Thiele (Duke University, USA).

The study proves that the genetic expression of C. neoformans metallothioneins is active in pulmonary infection. According to researcher Anna Espart, "when the fungus can infect lungs, macrophage cells —and other defence strategies—increase cooper concentrations to combat the infection. In a high cooper environment, the synthesis of C. neoformans metallothioneins is activated; they can capture cooper enabling then the infection to advance in a hostile environment".

In tandem repetitions: a successful evolutive strategy

The smallest MTs, also induced by cooper, were previously found from other fungi, such as Neurospora crassa and Agaricus bisporus, fungi used in molecular biology studies. According to the experts, one of the most surprising findings is that C. neoformans MT sequences are originated by in tandem repetitions of a unit which is very similar to the one of Neurospora and Agaricus, which can bind six cooper atoms.

"MTs which show a similar modular structure to the one of Cryptococcus have been also identified in other fungal pathogens", highlights Professor Atrian. "Data points out that —she adds— C. neoformans MTs are longer and have an exceptionally high cooper binding capacity compared to other MT proteins, perhaps due to evolutionary pressure to evolve by tandem amplification. So, it is not an isolated characteristic, but an evolutive strategy of certain pathogens to successfully infect different hosts, ranging from plants to people". The expert ensures that this evolutive strategy is different from MTs' one in most multicellular organisms, "which is based on making several copies of a certain gene to synthetize proteins specialised in specific biological functions". For example, this happens in mammals, as they have four metallothionein isoforms (MT1, MT2, MT3 and MT4).

The new research, carried out with mice, shows that when MTs have been modified and are not able to bind metals, the pathogen is unable to infect host cells. "From a therapeutic point of view, results prove that any element which interferes in MT synthesis can avoid the infection development", explains the researcher Anna Espart. A better knowledge of the molecular mechanism that inhibits synthesis and inactivates pathogen opens up new horizons in the international research on new pharmacological and therapeutic tools against cryptococcosis.

Explore further: Genomes of malaria-carrying mosquitoes sequenced

More information: www.sciencedirect.com/science/… ii/S1931312813000681

add to favorites email to friend print save as pdf

Related Stories

Berkeley chemists pioneer low-cost water testing devices

Dec 23, 2008

(PhysOrg.com) -- Because of both population growth and the impact of climate change, safe drinking water will become one of the planet's most precious commodities. But public health workers lack simple, low-cost ...

Cryptococcus infections misdiagnosed in many AIDS patients

Sep 01, 2011

Most AIDS patients, when diagnosed with a fungal infection known simply as cryptococcosis, are assumed to have an infection with Cryptococcus neoformans, but a recent study from Duke University Medical Center suggests that a ...

Predicting fatal fungal infections

Jun 16, 2009

In a study published in The Journal of Infectious Diseases, researchers from Albert Einstein College of Medicine of Yeshiva University have identified cells in blood that predict which HIV-positive indivi ...

Recommended for you

Genomes of malaria-carrying mosquitoes sequenced

Nov 27, 2014

Nora Besansky, O'Hara Professor of Biological Sciences at the University of Notre Dame and a member of the University's Eck Institute for Global Health, has led an international team of scientists in sequencing ...

How calcium regulates mitochondrial carrier proteins

Nov 26, 2014

Mitochondrial carriers are a family of proteins that play the key role of transporting a chemically diverse range of molecules across the inner mitochondrial membrane. Mitochondrial aspartate/glutamate carriers are part of ...

Team conducts unprecedented analysis of microbial ecosystem

Nov 26, 2014

An international team of scientists from the Translational Genomics Research Institute (TGen) and The Luxembourg Centre for Systems Biomedicine (LCSB) have completed a first-of-its-kind microbial analysis of a biological ...

Students create microbe to weaken superbug

Nov 25, 2014

A team of undergraduate students from the University of Waterloo have designed a synthetic organism that may one day help doctors treat MRSA, an antibiotic-resistant superbug.

User comments : 0

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.