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Stony Brook grad student discovers gene in dangerous fungus

Mansa Munshi zeroed in on a gene in a fungus that’s a menace to transplant recipients and people infected with HIV.

Genetics graduate student Mansa Munshi views fungal pathogens

Genetics graduate student Mansa Munshi views fungal pathogens in Dr. Maurizio Del Poeta's laboratory at Stony Brook University. Photo Credit: SBU Communications / John Griffin

The discovery by a Stony Brook University graduate student of a gene in a pathogenic fungus — a noteworthy feat for a scientist in training — is a potential boon for people with suppressed immune systems.

Mansa Munshi, a doctoral student in the molecular genetics and microbiology department, zeroed in on the gene in a fungal species known as Cryptococcus neoformans, a looming menace to organ transplant recipients and people infected with HIV. Her research includes a massive search for a compound capable of quelling the gene’s activity and ultimately serving as a human medication.

Beyond Cryptococcus neoformans, Munshi said the gene additionally is present in a significant number of other fungal species, including Candida auris, a multidrug-resistant superfungus that has alarmingly spread worldwide in less than a decade. It has been particularly prevalent in New York and New Jersey hospitals, with New York reporting the most cases nationwide, according to the Centers for Disease Control and Prevention.

C. auris is defiantly resistant to many potent drugs that should be able to kill it. Any new gene-specific treatment that might emerge from the Stony Brook research may eventually aid the fight against the Candida strain as well.

“When I first began working on this project I pretty much started with a blank slate,” said Munshi, a graduate student in the laboratory of Dr. Maurizio Del Poeta, a Stony Brook physician/scientist. He has garnered an international reputation for his methods of selecting compounds to test as weapons in the war against pathogens.

Both scientists said they have found a few intriguing compounds that warrant further investigation because they may play a role in halting the gene’s activity.

Munshi and her Stony Brook collaborators recently reported the gene discovery and research on C. neoformans in the journal Cell Reports.

She has dubbed the gene, Cer1. It is a tiny snippet of DNA that carries the genetic blueprint for ceramide synthase, a fungus-specific enzyme that triggers the formation of lipid molecules that cells — whether human or fungal — use for a variety of self-sustaining purposes.

C. neoformans, the fungus that Munshi studies, uses lipids as building blocks in a vast array of complex molecules that not only enhance fungal survival in the environment but also in the bodies of people who become infected.

The fungus is harmless to healthy people, but a notorious cause of fungal pneumonia and fungal meningoencephalitis, a brain infection that can be fatal in organ transplant recipients, people infected with HIV, and others with a compromised immune system, Munshi said.

Infection occurs upon inhaling fungal spores, which are in the environment. Worse, current treatments are not always effective. Among immuno-compromised patients the troublesome issue with this organism is not drug resistance by the fungus but its persistence in people who have lost all shields against infection.

“In a lot of patients with lowered immunity, their bodies are not strong enough to control the infection. This pathogen can survive in the blood and spread to the brain,” Munshi said.

About 220,000 new cases of the infection are reported annually worldwide in patients with full-blown AIDS, the disorder that emerges in those with HIV who become vulnerable to a range of invasive fungi, bacteria and viruses.

C. neoformans and the broader family of cryptococcal fungi infections are so burdensome in developing countries that the World Health Organization created guidelines in 2011 stressing rigorous methods of diagnosis, prevention and patient management.

“We are trying to find a drug that can control the activity of this gene, something that will make C. neoformans totally debilitated so that it won’t be able to spread throughout the body,” Munshi said, noting that all fungi pose treatment difficulties — even toenail fungus, which can be persistent.

Fungi, which are yeasts, increasingly are characterized by problems of multi-drug resistance, an emerging health care crisis that affects hospitals globally.

In New Jersey, Dr. David S. Perlin, executive director and professor of the Public Health Research Institute at Rutgers New Jersey Medical School, said he welcomes new approaches to potentially deadly fungal infections, especially C. auris.

“New antifungals with novel mechanisms of action are desperately needed, especially as multidrug resistance to existing drugs is becoming more common,” he said.

Perlin said he hopes the Stony Brook team is on the right track.

“It may well be a viable approach and should be explored with C. auris and other Candida species,” Perlin said of blocking the activity of the Cer1 gene.

“The key is whether Cer1 or its equivalent in C. auris also plays a critical role in ceramide synthesis that cripples or kills the cell,” he said.

Perlin and colleagues are working on a new method to rapidly and accurately identify the deadly C. auris in swabs from patients and hospital surfaces.

C. auris was first identified in Japan in 2009 and has since spread around the world. Of the 215 cases reported in the United States through Jan. 31, the most recent date for complete statistics, 129 have been reported in New York and 52 in New Jersey. The superfungus can spread to patients through medical equipment, such as catheters and ventilator tubing. But there are other modes of transmission, Perlin said.

Most fungi are not passed person to person, but such is not the case when it comes to C. auris.

“Candida auris . . . persists on skin and on environmental surfaces, and it can be easily transmitted from person to person. This is highly unusual, which makes C. auris dangerous to high risk patients in hospitals, especially when strains become multidrug resistant,” Perlin said.

Del Poeta, meanwhile, noted that dozens of compounds are being screened to determine their capacity to block Cer1 gene activity.

A problem with some existing antifungals, Del Poeta said, is their high level of toxicity, something the Stony Brook scientists aim to avoid. He said the thrust of the research is to find a compound that is active against a very specific target.

“We are going after a single lipid pathway,” he said. “We have been using the same antifungals for the past 20 years. It’s time to come up with something new.”

Number and type of confirmed Candida auris cases reported to the CDC, by state.

California:1

Connecticut: 1

Florida: 2

Illinois: 19

Indiana: 1

Maryland: 2

Massachusetts: 7

New Jersey: 52

New York:129

Oklahoma:1

Total: 215

Source: Centers for Disease Control and Prevention

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