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Fungus

Maurizio Del Poeta. File photo from SBU

By Daniel Dunaief

Maurizio Del Poeta is taking another approach to battling fungal infections that can be deadly, particularly for people who are immunocompromised.

Maurizio Del Poeta. Photo from SBU

A Distinguished Professor at Stony Brook University in the Department of Microbiology and Immunology at the Renaissance School of Medicine at Stony Brook University, Del Poeta has made progress in animal models of various fungal infections in working on treatments and vaccines.

After receiving an additional $3.8 million from the National Institutes of Health for five years, Del Poeta is expanding on some findings that may lead to a greater understanding of the mechanism that makes some fungal infections problematic.

The Stony Brook Distinguished Professor is studying “what makes people susceptible to fungal infections,” he said. “It’s something I’m really passionate about.”

Del Poeta explained that researchers and medical professionals often focus on the people who get sick. Understanding those people who are not developing an infection or battling against a fungus can provide insights into ways to understand what makes one population vulnerable or susceptible and another more resistant.

Expanding such an approach outside the realm of fungal infections could also provide key insights for a range of infections in the future.

Indeed, the awareness of specific signals for other infections could help protect specific populations, beyond those who had general categories like underlying medical conditions, who might be more vulnerable amid any kind of outbreak.

“It’s possible that the study we are doing now with fungi could stimulate interest” in other areas of infectious disease, Del Poeta said.

He suggested that this was “pioneering work” in terms of fungal infections. At this point, his lab has produced “strong preliminary data.”

An important drug treatment side effect as a signal

This investigation arises out of work Del Poeta had done to understand why some people with multiple sclerosis who took a specific drug, called fingolimid, developed fungal infections during their drug treatment.

Del Poeta observed that the drug inhibits a type of immunity that involves the movement of lymphocytes from organs into the bloodstream.

Fingolimid mimics a natural lipid, called a sphingolipid. Del Poeta showed that this sphingolipid is important to contain the fungus Cryptococcus neoformans in the lung. When its level decreases, the fungus can move from the lung to the brain.

Indeed, Fingolimid mimics sphingosin-1-phosphate (S1P) and binds to several S1P receptors.

Del Poeta believes that the pathway between S1P and its receptor regulates the immunity against Cryptococcus. Blocking a specific receptor is detrimental for the host and may lead to reactivation of the fungus.

Putting a team together

Nathália Fidelis Vieira de Sá. Photo by Futura Convites studio

Del Poeta has been working with Iwao Ojima, a Distinguished Professor and the Director of the Institute of Chemical Biology and Drug Discovery in the Department of Chemistry at Stony Brook, to create compounds that energize, instead of block, the target of fingolimid.

Del Poeta has recruited two scientists to join his lab in this effort, each of whom has educational experience in nursing.

Nathália Fidelis Vieira de Sá, who is a registered nurse at the Federal University of Minas Gerais and a chemistry technician at Funec- Contagem City, will join the lab as a technician in the second week of September.

Fidelis Vieira de Sá, who currently lives in her native Brazil, is an “expert on collecting and analyzing organs for mice,” explained Del Poeta in an email.

For her part, Fidelis Vieira de Sá is thrilled to join Del Poeta’s lab at Stony Brook. “I’m very excited,” she said in an email. She is eager to get started because the research is “of such great relevance to public health” and is occurring at such a “renowned institution.”

Fidelis Vieira de Sá believes this is a public health issue that could have a positive impact on people with immunodeficiency conditions who need effective treatment so they live a better, longer life. When she was a peritoneal dialysis nurse, she had a few patients who had fungal infections.

“This is very serious and challenging, detection is difficult, and the life expectancy of these patients drops dramatically with each episode of infection,” she explained. 

Fidelis Vieira de Sá, who has never lived outside Brazil, is eager for new experiences, including visiting Central Park, the Statue of Liberty, Times Square, and the One World Trade Center Memorial.

As for the work, she hopes that, in the near future, Del Poeta will “be able to explain this mechanism deeply and to develop new drugs that will act on this receptor.”

Dr. Marinaldo Pacífico Cavalcanti Neto

Dr. Marinaldo Pacífico Cavalcanti Neto, who is an Assistant Professor at Federal University of Rio de Janeiro, will be arriving at Stony Brook University on August 6. Dr. Neto earned his bachelor of science in nursing and has a PhD in biochemistry from the Medical School of Ribeirão Preto at the University of São Paulo.

Del Poeta described Dr. Neto as an “expert on animal handling and genotyping,”

Dr. Neto recognizes the burden of fungal infections around the world and hoped to work with someone with Del Poeta’s credentials and experience in immunology and infection.

Understanding how cells eliminate infection, how cells might have a lower capacity to control an infection, and looking for how cells respond to treatments such as fingolimid could be a “great strategy to understand why these are so susceptible,” he said.

While Dr. Neto’s background is in immunology, he hopes to learn more about molecular biology.

Unlike Fidelis Vieira de Sá, Dr. Neto, who will live in Centereach, has worked previously in the United States. He has experience at the National Institutes of Health and at the University of California at San Diego and has been attending Del Poeta’s lab meetings from a distance for about a month.

Dr. Neto, whose interest in science increased while he watched the TV show Beakman’s World while he was growing up, is eager to work in an area where he can apply his research.

He appreciates that his work may one day “be used in the generation of protocols in a clinic.

Nivea Pereira de Sa Photo by Rodrigo Carvalho da Silva

By Daniel Dunaief

When people are immunocompromised, exposure to what might ordinarily be a harmless fungus can cause significant health problems.

Researchers in the laboratory of Maurizio del Poeta, Distinguished Professor in the Department of Microbiology and Immunology at the Renaissance School of Medicine at Stony Brook University, have been looking to create new treatments and develop vaccines against these fungi.

Working with a team of scientists at Stony Brook, research scientist Nivea Pereira de Sa, who joined del Poeta’s lab in 2018 as a postdoctoral researcher, recently published research in the journal mBio about potential anti-fungal drugs that target a key enzyme in the fungus Aspergillus fumigatus. 

Without the enzyme, the fungus can’t cause disease and the host defenses have time to eliminate it even if the host is immunodeficient.

Working with Michael Airola, Assistant Professor in the Department of Biochemistry and Cell Biology at SBU, Pereira de Sa started out by trying to find the structure of sterylglucosidase, an enzyme that is a molecular key for the fungus during infection and that aids in its ability to adapt to environmental changes such as low oxygen levels and changes in pH.

Pereira de Sa learned how to do x-ray crystallography from Airola, a process that reveals the structure of compounds.

In an email, Airola described Pereira de Sa as an “expert” in the technique.

Airola called the research “one of the most exciting projects” he’s worked on and hopes the group can translate the results into the clinic. A talented biochemist, Pereira de Sa is also an “expert in so many different scientific areas,” Airola wrote, which he described as “rare.”

Pereira de Sa also determined the structure of the same enzyme for Cryptococcus, another invasive and potentially harmful fungus. The enzymes in both fungi have a high degree of similarity.

Pereira de Sa expressed satisfaction at the application of such work. “Every time I get a crystal structure, it’s so amazing,” she said. “I love doing that.”

Pereira de Sa started screening potential compounds to inhibit sterylglucosidase in Aspergillus,

Del Poeta’s lab coordinated the design and testing of these inhibitors with Iwao Ojima, Distinguished Professor in the Department of Chemistry and Director of the Institute of Chemical Biology and Drug Discovery at Stony Brook.

Refining potential drugs

Ojima’s group is synthesizing derivatives of the hits Pereira de Sa found and she will start tests outside a living organism, or in vitro, soon.

Ojima has synthesized several compounds using computer-assisted drug design. He is currently developing several inhibitors that scored high on his computational molecular docking analysis and will synthesize two to three dozen potential small molecules.

Ojima, who partnered with Pereira de Sa in this study, “greatly appreciates her and her seminal contributions to this project,” he wrote in an email. She made critical contributions to the study that ensured its success and Stony Brook is “very fortunate to have her as a leader in this project.”

Ojima plans to identify highly potent inhibitors individually for Aspergillus and Cryptococcus separately, and then will try to find and develop broad spectrum inhibitors based on those compounds.

The need for a treatment has increased dramatically as the number of immunocompromised patients has increased.

Invasive aspergillosis can have mortality rates above 90 percent. The World Health Organization last October released its first ever list of health threatening fungi, which includes Aspergillus.

Pereira de Sa suggested two possible uses for this inhibitor. It could work as a treatment, knocking down the virulence of the fungus or it could contribute to the development of a vaccine.

In strains with a mutated enzyme, a mouse model has full protection against infection.

Getting a vaccine approved through the Food and Drug Administration for immunocompromised individuals might be challenging, she said. Several studies would be needed to confirm its safety.

Del Poeta added that the vaccine his lab has developed is effective alone when heat killed, reducing the threat a live virus with a defective enzyme might pose to an immunocompromised patient. Del Poeta has been developing a vaccine for cryptococcus and aspergillus and is testing it for other fungal infections as well.

‘A beautiful cause’

Del Poeta described Pereira de Sa as a key contributor to his lab, who is methodical, systematic and hard working.

The program she is developing will take years to go to clinical trials, he added.

Del Poeta met Pereira de Sa in 2017, when he visited Brazil and spoke with her mentor, Daniel de Assis Santos, who gave her an enthusiastic reference.

After meeting with her for only five minutes, del Poeta offered her a job.

“I will never forget her face: surprised, joyful, excited and she could not hold back some tears,” del Poeta described.

Del Poeta is thrilled with his choice, as she has gone above and beyond his expectations.

Born and raised in Belo Horizonte, Brazil, Pereira de Sa lives in East Setauket with her husband Rodrigo Carvalho da Silva, who is an airplane mechanic.

She enjoys Long Island, particularly during the summer, when she goes hiking, visits parks, kayaks and goes paddle boarding.

Pereira de Sa is encouraged by the progress in her work and is hoping her research contributes to future treatments.

“We are developing tools to help people,” she said. “It’s a beautiful cause I’m fighting for.”

She said the mortality rate from these fungal infections is “very high,” especially because a fungus like Aspergillus is ubiquitous.

“The fungus is present everywhere,” she said. “We are inhaling the spores of it every day.”

The invasive fungal disease starts in the lungs and spreads to the rest of the body, including in the brain, which can cause seizures.

Pereira de Sa recognizes the urgency of developing an effective treatment.

“We need some solutions and we need it now,” she said. “We are not prepared to fight fungal infections” on a large scale.

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Fungus on dead tree stumps helps to break down the dead wood, returning the nutrients to the soil. Photo by Ellen Barcel

By Ellen Barcel

One of the things that a gardener needs to do is to identify fungi on plants and take appropriate steps to control the fungi (if possible) if it is detrimental to the plant. But not all fungi will kill plants. Some just make the plant look bad. And some actually are beneficial.

In the past, I’ve had several trees which didn’t survive because of fungus. My beautiful mimosa trees died due to a fungus (mimosa wilt) which could not be stopped at the time. Leaves turned yellow in midsummer and dropped. The tree never sprouted the following growing season. The trees literally died within a few weeks.

A rust killed a mountain ash I had. I was really disappointed, and missed the beautiful orange berries the tree bore and which persisted on the tree well into winter. Mountain ash is a native of North America and has white flowers in spring.

Cedar apple rust can also be found on trees on Long Island. It particularly attacks cedar, apple and crabapple trees. The fruiting body develops as a brownish growth on the tree. Then orange tentacles emerge from the growth. The rust is not fatal to the tree but definitely unsightly, almost looking like something out of a sci-fi movie. Remove the growth making sure to sterilize gardening tools afterwards, so as not to spread the pathogen to other trees.

Orange ‘tentacles’ emerge from the cedar apple rust fungus. Photo courtesy of the Missouri Botanical Garden
Orange ‘tentacles’ emerge from the cedar apple rust fungus. Photo courtesy of the Missouri Botanical Garden

Now for some generalities on fungal diseases and their prevention:

First of all, weak plants are more prone to getting a fungal disease than strong ones. So, make sure you feed and water your plants appropriately.

Plants that are crowded with no air circulation are also more prone to fungal diseases.

It’s better to water plants at ground level, especially in the evening, so leaves don’t stay wet overnight. A drip irrigation system works well sending water to the roots and not the leaves.

Look for fungus-resistant plants such as rust resistant apple and crabapple trees, tomatoes which are resistant to tomato blight, roses resistant to black spot, etc. The tomato blight, for example, will prevent you from getting a decent crop of tomatoes. So this one definitely falls in the bad category.

Know that some trees are prone to the fungal disease anthracnose, but generally it is more unsightly, than dangerous. Maples and catalpas in particular develop it in humid weather. The leaves look like they are covered with a white power. Unless the tree is very old and weak it will usually survive with no treatment at all. So, this is a case of ugly, but not really dangerous. When anthracnose develops on the native dogwood (Cornus florida), however, it is much more serious. This is why some recommend planting other varieties of dogwood.

Replace plants that are prone to fungal diseases with those with similar attributes but which don’t contract certain diseases. For example, impatiens in recent years have been attacked by a fungus. They are annuals that do well and bring color to shady areas. Instead, plant coleus which are also annuals that do well and bring color to shady areas but are not prone to fungal diseases.

If you see a fungus growing on a live tree, check out that tree carefully. Usually large fungi only grow on dead or dying trees. I missed this important sign a number of years ago. An enormous section of one of my maple trees broke off the tree and landed across the street. An arborist gave me the bad news that my tree was dying and needed to be removed. I now check periodically to see if any large fungi are growing on my trees.

Now for the good: Some edible fungi, such as chicken fungi (Chicken of the Woods, Laetiporus sulphureus), grow on dead or dying trees or tree stumps. Be very careful here, as most fungi are not safe to eat. Make sure you check this out with an expert. Also, fungi with large, visible fruiting bodies help to break down dead wood, i.e., the cycle of nature, returning nutrients to the soil. Toad stools growing in the grass help to break down organic matter as well.

Ellen Barcel is a freelance writer and master gardener. Send your gardening questions to [email protected]. To reach Cornell Cooperative Extension and its Master Gardener program, call 631-727-7850.