Toenail fungus gives up sex to infect human hosts

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PUBLIC RELEASE: 22-FEB-2018
Toenail fungus gives up sex to infect human hosts
Being a clone of itself may make it vulnerable to new treatments
DURHAM, N.C. -- The fungus that causes athlete's foot and other skin and toenail infections may have lost its ability to sexually reproduce as it adapted to grow on its human hosts.

Scientists analyzed samples of this tenacious organism, called Trichophyton rubrum, and found that nearly all belonged to a single mating type. What's more, when they tried to set the fungi up with members of another mating type, they refused to do the deed, even after the scientists enlisted a variety of seduction schemes -- lowering the lights, cloaking the Petri dishes in plastic, flipping them upside down.

If this fungus can't sexually reproduce, it can't diversify, and if it can't diversify, that may mean its days on this planet are numbered, said Joseph Heitman, MD, PhD, senior study author and professor and chair of molecular genetics and microbiology at Duke University School of Medicine.

But don't expect toenail fungus to appear on the endangered species list anytime soon. "It is commonly thought that if an organism becomes asexual, it is doomed to extinction," Heitman said. "While that may be true, the time frame we are talking about here is probably hundreds of thousands to millions of years."

Though that timeline won't be much help to the nearly 2 billion people who currently suffer from fungal infections of the skin and nails, the discovery that this species may be asexual -- and therefore nearly identical at the genetic level -- does highlight potential vulnerabilities that researchers could exploit in designing more effective antifungal medications. The findings appear online in the journal Genetics.

Fungal infections affect approximately 25 percent of the world's population, and Trichophyton rubrum is usually the species to blame. People can pick up this infection by walking barefoot around swimming pools, showers or locker rooms, or by sharing personal items such as towels or nail clippers. Though there are plenty of over-the-counter powders and ointments along with prescription anti-fungal drugs on the market, most keep the infection at bay but don't clear it. The infection is notoriously difficult to cure, and recent evidence suggests it may often be drug-resistant.

In this study, an international team of researchers decided to take a close look at the genetic makeup and sexual predilections of this fungus. They collected 135 different Trichophyton rubrum samples from around the world and determined their mating type by searching the fungal genome for either the alpha or the HMG domain, which is essentially the molecular equivalent of looking between a dog's legs. The researchers were amazed to find that all but one of the samples were from a single mating type.

Though the findings suggested the fungi had become asexual, the scientists wondered if they would mate if given the opportunity. They placed the isolates in petri dishes along with a variety of potentially compatible mating types, under a variety of different conditions, and then waited to see if any magic would happen. After five months, the researchers looked at the petri dishes under a light microscope, scanning for the growth of coiled appendages that might contain spores. They didn't see any.

Curious, the researchers sequenced the genome of the organism. They found that the organism is very clonal, meaning that different isolates (populations) are nearly perfect clones of each other, with little variation from one genome to the next. Any two genomes of Trichophyton rubrum are 99.97 percent identical, which translates to three differences out of every 10,000 genetic letters. Other fungi such as Cryptococcus are only 99.36 percent identical, differing in 64 out of 10,000 letters, making them 21 times more diverse than the toenail fungus.

"Such incredibly high clonality across isolates from around the world is remarkable, and suggests that this organism is very well adapted to humans," said Christina Cuomo, PhD, senior study author and a group leader for the Fungal Genomics Group at the Broad Institute of MIT and Harvard.

But there is a silver lining. Because the fungus is so clonal and could also be asexual, its ability to adapt further may be more limited than some other fungi. Thus, any new strategies that researchers could develop against this species may have a higher chance of success than those targeting sexual species, which are more capable of mutating or amplifying drug-resistance genes.

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CITATION: "Whole Genome Analysis Illustrates Global Clonal Population Structure of the Ubiquitous Dermatophyte Pathogen Trichophyton Rubrum," Gabriela F. Persinoti, Diego A. Martinez, Wenjun Li, Aylin Dö?en, R. Blake Billmyre, Anna Averette, Jonathan M. Goldberg, Terrance Shea, Sarah Young, Qiandong Zeng, Brian G. Oliver, Richard Barton, Banu Metin, Süleyha Hilmio?lu-Polat, Macit Ilkit, Yvonne Gräser, Nilce M. Martinez-Rossi, Theodore C. White, Joseph Heitman, Christina A. Cuomo. Genetics, Early Online Feb. 21, 2018. http://www.genetics.org/content/early/2018/02/21/genetics.117.300573 DOI: 10.1534/genetics.117.300573

 

Whole Genome Analysis Illustrates Global Clonal Population Structure of the Ubiquitous Dermatophyte PathogenTrichophyton rubrum
Gabriela F. Persinoti, Diego A. Martinez, Wenjun Li, Aylin Döğen, R. Blake Billmyre, Anna Averette, Jonathan M. Goldberg, Terrance Shea, Sarah Young, Qiandong Zeng, Brian G. Oliver, Richard Barton, Banu Metin, Süleyha Hilmioğlu-Polat, Macit Ilkit, Yvonne Gräser, Nilce M. Martinez-Rossi, Theodore C. White, Joseph Heitman and Christina A. Cuomo
GENETICS Early online February 21

 

ve been reading about the private life of fungus, in particular the T-Rubrum. It`s fascinating stuff. It has 2 reproductive phases in its life cycle:
1) Anamorph state (imperfect or asexual phase)…or `solo`. After germination, spores produce hyphae (strands of small tubular extensions) and these grow new colonies.
2) Teleomorph state (perfect or sexual phase). Two compatible mating spores produce new fungi. The “male-like” spores seek out the “female-like spores” and when they find them will begin producing their sexual hormones in order to “do the business”. It`s this phase that appears to be less common as the fungus adapts to its host and finds new ways to digest its most-loved food; keratin.

 

PUBLIC RELEASE: 28-JUN-2018
Study investigates the reproductive habits of the fungus that causes athlete's foot
Genomic analysis suggests that asexual reproduction is the rule among individuals of the species Trichophyton rubrum. The authors believe that this factor should be considered in drug development

The sexual habits of Trichophyton rubrum, the fungus that causes athlete's foot and other kinds of skin and nail infections, were the focus of a study published by Brazilian scientists and international collaborators in the journal Genetics.

The researchers' findings suggest that asexual reproduction is the rule for this species. Mating between individuals is not common and requires highly specific conditions if it does occur. As a result, the genetic variability in the population is low even when comparing isolates from different parts of the world.

"We found the population to be clonal. There's practically no mating between individuals, and few variations in the genome are created," said Gabriela Felix Persinoti, lead author of the study, which was performed during her postdoctorate with support from the São Paulo Research Foundation - FAPESP.

According to the principal investigator of the project, Nilce Martinez-Rossi, a professor at the University of São Paulo's Ribeirão Preto Medical School (FMRP-USP) in Brazil, understanding how the fungus reproduces is basic science, but progress in applied research is impossible without it.

"Genetic variability is a factor to be considered in drug development, for example, as it may point to the risk that the pathogen will adapt and develop resistance to treatment," she said.

Scientists have discovered that the greater the genetic variability among individuals of a given species is, the likelier these individuals are to adapt to adverse conditions and survive.

Persinoti's work is part of one of two research lines coordinated by Martinez-Rossi at FMRP-USP. This line's goal is to investigate how dermatophytes - fungi that cause skin, hair and nail infections - interact with their hosts. The other line aims to understand the mechanisms of drug resistance in this same group of microorganisms.

T. rubrum is a dermatophyte species that infects only humans, Martinez-Rossi explained. Infections are typically chronic and superficial since the fungus feeds on the keratin in skin and nails. These infections cause discomfort, itching, and structural damage to nails, impairing the infected individual's quality of life. In rare cases, generally associated with low immunity, the infection may spread through the patient and become life-threatening.

"We want to unpack the molecular mechanisms of pathogenicity in these dermatophytes - in other words, to understand how they cause infection. Revealing the 'weapons' these fungi use during the infectious process will contribute to the development of drugs to combat them," Martinez-Rossi said.

Persinoti conducted her study in Christina Cuomo's laboratory at the Broad Institute of MIT and Harvard in the United States during a research internship abroad funded by FAPESP.

Genomic analysis

As the authors of the article explain, the species Trichophyton rubrum is actually a complex that can be subdivided into several different morphotypes. These morphotypes are highly similar fungi with small variations in color or structure or in the compounds they produce.

In the first stage of the research, Persinoti and collaborators analyzed the genetic variability in 100 morphotypes isolated in several parts of the world. To do this, they used multilocus sequence typing (MLST), a method that sequences key fragments (or loci) of DNA rather than the whole genome.

"To complement this analysis, 12 isolates were submitted to whole-genome sequencing," said the FAPESP-funded researcher.

This more deeply analyzed sample comprised ten morphotypes of T. rubrum and two isolates of T. interdigitale, which also infects humans; none of the genomes of these isolates have been described hitherto.

After sequencing, the group focused on analyzing a genomic region known as the mating type (MAT). Individuals cannot mate unless they have complementary MATs - one must have MAT 1 and the other MAT 2, for example.

Mating has been observed in some dermatophytes in studies by other groups, but so far, mating has never been observed in T. rubrum.

"When we analyzed this genomic region, we found MAT 1 in almost all morphotypes of T. rubrum and MAT 2 in only one morphotype," Persinoti said.

The scientists conducted laboratory experiments designed to induce sexual reproduction between the MAT 2 isolate and MAT 1 individuals, but the fungi failed to mate.

"This led us to the conclusion that sexual reproduction in this species probably doesn't happen or requires a very specific condition in order to take place," Persinoti said.

The conclusion was reinforced by other experiments performed during the FAPESP-supported research, which showed that similarity in the genomes of the individuals analyzed exceeded 99%.

According to Persinoti, however, the genes required for sexual reproduction found in other dermatophytes are still present in T. rubrum. This suggests that the transition to asexual reproduction is a recent event in the species and could be associated with its specialization in infecting humans.

"We performed a series of phylogenetic comparisons between the different morphotypes, and the results enabled us to delineate the species more correctly. One of the morphotypes, known as soudanense, proved to be divergent from the rest and could come to be considered a separate species," Persinoti said.