Navigation Links
Researchers uncover molecular pathway through which common yeast becomes fungal pathogen

TORONTO, ONScientists at the University of Toronto have found a molecular mechanism that plays a key role in the transition of Candida albicans yeast into disease-causing fungusone of the leading causes of hospital-acquired infection. The finding highlights the importance of heat in fungal growth, and provides a new target for drug therapies to counter Candida albicans infection.

Candida albicans is a normally harmless yeast that is present in all humans. It becomes infectious in various genetic and environmental conditions, with temperature as a key determinant. It can produce infections that are mildpersistent vaginal or gut infections, for exampleor severe, such as systemic, potentially fatal bloodstream infections in patients with AIDS or those who have undergone chemotherapy (or even a simple round of antibiotics).

The molecular workings of Candida albicans were mapped for the first time in 2009 by Professor Leah Cowen of the University of Toronto's Department of Molecular Genetics, whose lab showed that growth of the fungus is tied to the function of a "molecular chaperone" called heat-shock protein 90 (Hsp90). In a study that will appear in the March 20 edition of the journal Current Biology, Prof. Cowen and her colleagues detail a mechanism that controls response to elevated temperature through a protein named Hms1 in conjunction with a cyclin (another type of protein) and its partner protein called a cyclin-dependent kinase.

"This circuitry fundamentally influences how Candida albicans senses temperature, which is crucial for Candida's ability to cause disease," said Prof. Cowen, who holds the Canada Research Chair in Microbial Genomics and Infectious Diseasea prestigious five-year award for which she was renewed this week.

"We were looking for a transcription factor at the end of a pathway we previously showed was key to the change in shape of the fungus that accompanies elevated temperature or compromise of Hsp90 function, and instead we found an entirely new pathway, with components that haven't been characterized in Candida, so it was very surprising," said Prof. Cowen.

The researchers also showed that deletion of Hms1 inhibits Candida albicans infection, pointing toward a possible clinical therapy. "We observed those weaker disease phenotypes in an insect model system, but the results suggest it may also work in more complicated systems," said Prof. Cowen.

The source of pesky vaginal and gut infections, Candida albicans is a burgeoning problem on implanted medical devicesit's fatal in roughly one-third of device-associated infectionsand is the fourth-leading cause of hospital-acquired infection. The number of acquired fungal bloodstream infections has increased by more than 200% over the last twenty years, owing in part to growing numbers of AIDS and cancer survivors whose treatments have compromised their immune function.

On finding that the Hms1 pathway affects the growth and development of Candida albicans, and knowing of other key regulators through which Hsp90 operates and suspecting many more exist, Prof. Cowen and her lab examined other pathways and proteins that interact with Hsp90 in another study.

In collaboration with Professor Gary Bader at U of T's Donnelly Centre for Cellular and Biomolecular Research, Prof. Cowen's group mapped a much larger portion of the chaperone network with which Hsp90 interacts through a "chemical genomics" approach that had never been applied to Candida albicans. "If we want to have a more global understanding of what Hsp90 is doing during the transition of this fungus between distinct morphological states with different disease causing properties, we need to take global approaches to determine what its interacting with," said Prof. Cowen.

Their results, published online today in the journal PLoS Genetics, showed 226 genetic interactors with Hsp90 in various conditions, such as different temperatures and during exposure to anti-fungal drugs. Of those interactions, 224 were previously unknown. "That's a lot," said Prof. Cowen. "We now have a myriad of new targets through which Hsp90 could be regulating morphogenesis and drug resistance in Candida."

As well, the researchers drew several predictive rules from their study that govern the Hsp90 chaperone network. Some interactors were only important in a small subset of stress conditions, and these are likely to function "downstream" of Hsp90 regulating specialized cellular processes. Other interactors were important in many stress conditions, and so are likely to work "upstream" of Hsp90 regulating its function.

"Hsp90 stabilizes many proteins, but previously nobody could predict what made an Hsp90 client. That we can make such predictions from the chaperone network is pretty cool and unanticipated, so we're further ahead than we expected," said Prof. Cowen.


Contact: Jim Oldfield
University of Toronto

Related biology news :

1. Ottawa researchers to lead world-first clinical trial of stem cell therapy for septic shock
2. UNH researchers find African farmers need better climate change data to improve farming practices
3. Researchers attempt to solve problems of antibiotic resistance and bee deaths in one
4. UC Santa Barbara researchers discover genetic link between visual pathways of hydras and humans
5. Study by UC Santa Barbara researchers suggests that bacteria communicate by touch
6. University of Tennessee researchers invent device to rapidly detect infectious disease
7. Researchers find safer way to use common but potentially dangerous medication
8. SFU researchers help discover new HIV vaccine-related tool
9. Notre Dame researchers are providing insights into elephant behavior and conservation issues
10. Researchers develop worlds first biodegradable joint implant
11. Researchers identify novel pathway responsible for infection of a common STD pathogen
Post Your Comments:
(Date:11/12/2015)... 12, 2015  Arxspan has entered into an ... Harvard for use of its ArxLab cloud-based suite ... The partnership will support the institute,s efforts to ... research information internally and with external collaborators. The ... managing the Institute,s electronic laboratory notebook, compound and ...
(Date:11/10/2015)... About signature verification Signature ... identify and verify the identity of an individual ... secure and accurate method of authentication and is ... because each individual,s signature is highly unique. Signature ... signature of an individual is compared and matched ...
(Date:11/2/2015)... MENLO PARK, Calif. , Nov. 2, 2015 /PRNewswire/ ... to $9 million to provide preclinical development services to ... Under the contract, SRI will provide scientific expertise, modern ... a wide variety of preclinical pharmacology and toxicology studies ... --> --> The PREVENT Cancer Drug ...
Breaking Biology News(10 mins):
(Date:11/27/2015)... , Nov. 27, 2015 /PRNewswire/--  Mallinckrodt plc (NYSE: ... today that it has closed the sale of its ... Guerbet (GBT- NYSE Euronext) in a transaction valued at ... manufacturing facilities and a total of approximately 1,000 employees ... St. Louis area. This entire ...
(Date:11/26/2015)... , November 26, 2015 ... --> Accutest Research Laboratories, a ... Research Organization (CRO), has formed a ... Center - Temple Health for joint ... ,     (Photo: ) , ...
(Date:11/25/2015)... , Nov. 25, 2015  PharmAthene, Inc. (NYSE MKT: ... adopted a stockholder rights plan (Rights Plan) in an ... loss carryforwards (NOLs) under Section 382 of the Internal ... --> PharmAthene,s use of its NOLs could be ... as defined in Section 382 of the Code. In ...
(Date:11/25/2015)... and HOLLISTON, Mass. , Nov. ... (Nasdaq: HART ), a biotechnology company developing bioengineered ... Jim McGorry will present at the LD ... 2015 at 2:30 p.m. PT. The presentation will be ... 30 days. Management will also be available at the ...
Breaking Biology Technology: