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Maurizio Del Poeta

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.

Caroline Mota Fernandes Photo by Jonas Nascimento Conde

By Daniel Dunaief

Fungal infections represent a significant health risk for some patients, killing about 1.5 million people globally each year. Doctors struggle to provide medical help for some of these patients, especially those whose weakened immune systems offer insufficient protection against developing pathogens.

Invasive fungal infections, which people typically contract by inhaling them as spores, account for about half of all AIDS-related deaths.

Maurizio del Poeta, Distinguished Professor at the Renaissance School of Medicine at Stony Brook University, has been studying ways to boost the body’s defenses against these potentially deadly infections, even among people with weakened immunities.

Recently, Caroline Mota Fernandes, a postdoctoral researcher in del Poeta’s lab, published research in the journal mBIO, a publication of the American Society for Microbiology, that demonstrated that a heat-killed, mutated version of the fungus Aspergillus conveyed protection in an animal model of an immunocompromised individual.

“The biggest news is that we can simply use the ‘autoclaved’ mutated version,” explained del Poeta in an email. “This version cannot be more dead!”

An autoclave is like a scientific oven: it raises the temperature or pressure. In this case, it can kill the mutated fungus, leaving only the mutated signal that primes the immune system.

The mutated and heat-killed version of the fungus, however, still provided full protection in a condition in a model of a weakened immune system.

“That means this formulation is highly stable and resistant to heat degradation,” del Poeta added.

Del Poeta’s lab had conducted similar research with another fungus called Cryptococcus.

By demonstrating that this approach also works with Aspergillus, del Poeta said the result “validates the cryptococcal vaccine (after all, it uses a mutant of the homolog gene, Sg11 in Crypto and SglA in Aspergillus.”

It also shows that protection exists under an additional type of immunodepression that is different from the one used in the cryptococcal vaccine.

The encouraging results, while in the preliminary stages, are relevant not only for immunocompromised people in general, but also for those who have been battling Covid, as Aspergillus was the cause of death for many patients during the worst of the pandemic.

Homologous genes

Del Poeta’s lab has focused on genes that catalyze the breakdown of steryl glucosides, which scientists have also studied in the context of plants. Crops attacked by various fungi become less productive, which increases the need to understand and disrupt these pathways.

“Folks working with plants started observing that these molecules had some kind of immunomodulatory property,” said Fernandes. “That’s where the idea of this steryl glucosides, which also is medicating fungal virulence, came from.”

The mutation Fernandes studied removed the sterylglucosidase gene sglA. Without the enzyme that breaks up the steryl glucose, the fungus had less hypha, which are necessary for the growth of the fungus. The mutation also changed the cell wall polysaccharides. Mice vaccinated with this heat-killed mutation had a one hundred percent survival rate in response to exposure to the live fungus.

“What was a very great achievement of our work was getting 100 percent protection,” said Fernandes. For immunocompromised people for whom a live attenuated fungus might threaten their health, the effectiveness of the heat-killed mutation proved especially promising.

In the experiment, she administered the vaccine 30 days before exposure, while providing boosters as often as every 10 days.

Fernandes, who started her post doctoral research in del Poeta’s lab in 2018, said several questions remain. “After this study, we are going to try to characterize exactly how this strain induces the immunity and protection to a secondary challenge of Aspergillus,” she said. Dr. Veronica Brauer, another post doctoral researcher in del Poeta’s lab, is conducting this research.

At this point, it’s unclear how long protection against a fungal infection might last.

“For us to estimate the duration of the protection, we have to have a more specific understanding of which immune components are involved in the response,” said Fernandes.

As of now, the mice vaccinated with the mutated and heat-killed fungus had no off target effects for up to 75 days after vaccination.

Fernandes is also working to characterize the mechanism of action of a new class of antifungal drugs previously identified by the lab, called acylhydrazones. She hopes to identify a new virulence protein in Cryptococcus as well.

Collaboration origins

Fernandes, who was born and raised in Rio de Janeiro, Brazil, first worked in del Poeta’s lab in 2013, while she was conducting her PhD research at Federal University of Rio de Janeiro. She was studying antifungal peptides and explained to the Brazilian government why coming to Stony Brook would contribute to her research.

Fernandes started studying fungi when she was in her second year of college at Federal University of Rio de Janeiro.

The daughter of two chemists, Fernandes said she grew up in a house in which she had pH strips, which she used to test the acidity of shampoo, water and anything else she could test. She also entered numerous science fairs.

Fernandes met her husband Jonas Conde, who is a virologist at Stony Brook University and who has studied Covid-19, when they were in nearby labs during their PhD research.

Residents of Port Jefferson, Fernandes and Conde have a four-month-old son named Lucas.

Having a child “motivates me to be better in my work and to set an example for him to be committed in doing some good for other people,” Fernandes said.

Del Poeta described Fernandes as being “extremely effective” in managing her time and has “extraordinary motivation.” He appreciates her commitment to her work, which is evident in the extra papers she reads.

Fernandes appreciates being a part of del Poeta’s lab. She described him as an “amazing” researcher and supervisor and said being a part of his group is “an honor.”

Del Poeta said Fernandes will continue to make mutants for additional fungi, including Mucorales and Rhizopous, for which antifungal therapy is not particularly effective.

Del Poeta added that the urgency of this work remains high. With several other Stony Brook faculty, he has submitted grants to study Sgl1 as a vaccine and antifungal target.

“Imagine [making] a drug that not only can treat the primary infection, but, by doing so, can potentially prevent the recurrence of a secondary infection?” he asked rhetorically. “Exciting!”

Maurizio Del Poeta, right, with his wife, Chiara Luberto, in front of the pizza oven that he built himself at his Mount Sinai home. Photo by TBR News Media

He’s a scientist, dedicated father and husband, businessman, mentor, collaborator, accomplished cook and gracious host. It seems fitting that Dr. Maurizio Del Poeta, a distinguished professor in the Department of Microbiology and Immunology and someone several people described as a Renaissance man, would work at the Renaissance School of Medicine at Stony Brook University.

A fungal researcher who is working to find treatments and vaccines for fungal infections that kill over 1.3 million people annually, Del Poeta turned his talents to the study of COVID-19 this year.

Teaming up with researchers at The University of Arizona and Wake Forest School of Medicine in North Carolina, Del Poeta and his collaborators worked with an enzyme also found in rattlesnake venom that may provide a target for diagnostics and therapeutic intervention for COVID-19.

TBR News Media is pleased to recognize the research efforts of Del Poeta, who represents one of several scientists throughout Long Island and around the world working to find ways to improve human health and reduce the life-altering effects of the pandemic.

In a paper published in the Journal of Clinical Investigation, the research team found that an enzyme called secreted phospholipase A2 group IIA, or sPLA2-IIA, is in higher concentrations in well over half the people with the most severe forms of the disease.

“This is certainly an exciting discovery in terms of a marker [that might] provide a mechanistic understanding of severe cases of COVID,” said David Thanassi, Zhang family endowed professor and chair of the Department of Microbiology and Immunology at the Renaissance School of Medicine. “It’s hard to know exactly how this is going to play out” in terms of a therapy or a cure, he said, but it offers hope in terms of a way to diagnose or treat COVID.

Dr. Yusuf Hannun, director of the SBU Cancer Center who contributed to this research effort, described the work as a “major discovery” that could provide a “novel key player in the development of the COVID-19 illness.”

Hannun, who has known Del Poeta for 25 years, suggested that his colleague’s success stems from his commitment to his work.

Del Poeta’s “energy and passion are very observable in his academic life,” Hannun said. “His research team is energized by his enthusiasm and good instinct for important problems.”

Indeed, the members of his lab appreciate his commitment to making scientific discoveries and to providing considerable personal and professional support for them.

Antonella Rella worked in Del Poeta’s labs from 2010 through 2017. When she arrived in the United States, Rella joined Del Poeta’s lab at the Medical University of South Carolina.

Maurizio Del Poeta. File photo from SBU

While Rella appreciated all the scientific support she received over the years, including after she moved with him to Stony Brook in 2012, she was especially grateful for the first impression he made when she arrived at the airport.

On her trip from Italy, her flight was delayed and she had to stay overnight in Atlanta. When she landed in South Carolina, Del Poeta not only met her at the airport, but he also greeted her with his wife Chiara Luberto and their first child.

“I thought nobody would be at the airport,” said Rella, who is now a senior scientist with Estée Lauder. “When you meet your boss, you are not feeling very comfortable. Instead, I was very happy and relieved and felt welcomed.”

Rella said Del Poeta and Luberto, who is research associate professor in the Department of Physiology and Biophysics at Stony Brook, have treated other members of his lab the same way, especially when they come from abroad.

Rella said she and her lab mates were thrilled when Del Poeta and Luberto hosted them at their house in Mount Sinai.

“We were super happy whenever we were invited” to their home, Rella said. “We knew the food would be super amazing” because he cooked pizza at a brick oven he designed and built himself. He also made considerable effort to prepare food like tagliatelle.

“There is heart in everything he does,” Rella said.

That includes his dedication and focus on research. In addition to making scientific discoveries, Del Poeta, who earned his medical degree from the University of Ancona, Italy, is eager to apply those findings to the medical field.

The co-founder of MicroRid Technologies, Del Poeta and MicroRid are working to develop small-molecule anti-fungal drugs. Last year, the company received a five-year, $4 million award administered by the Department of Defense.

As for his COVID research, Del Poeta explained that the use of an existing drug for snake venom would involve a different preparation to treat people battling against the coronavirus.

In addition to the work he does in the lab, Del Poeta contributes to SBU and to the Department of Microbiology and Immunology.

Up until the pandemic, Del Poeta and Luberto hosted prospective graduate students in his department at their house. The gatherings highlighted the camaraderie in the department, Thanassi said.

He appreciates Del Poeta’s commitment to mentoring and training, which helps attract and retain students.

“He brings a really nice recognition to the department” through the results of his research and his funding, Thanassi added.

Hannun is confident in his colleague’s success. He said his first impression of Del Poeta was that he was a capable and committed scientist who was aspiring to go after big questions.

“That was accurate but understated,” Hannun said.

Maurizio Del Poeta in his laboratory at Stony Brook University. Photo by Antonella Rella

By Daniel Dunaief

Researchers at Stony Brook University, the University of Arizona and Wake Forest University School of Medicine in North Carolina may have found an enzyme that drives the worst COVID-19 symptoms. Secreted phospholipase A2 group IIA, or sPLA2-IIA may lead to severe symptoms and death, making this enzyme a potential therapeutic target.

P116, Maurizio DelPoeta, Microbiology

In an examination of plasma samples from 127 patients hospitalized at Stony Brook University Medical Center between January and July 2020 and a mix of 154 patient samples from Stony Brook and Banner University Medical Center in Tucson between January and November 2020, scientists including Distinguished Professor Maurizio Del Poeta of the Renaissance School of Medicine at Stony Brook University found that 63 percent of people with concentrations of the enzyme that were over 10 nanograms/ milliliter generally died. Most healthy people have circulating levels of the enzyme around 0.5 nanograms/ milliliter.

“It is possible that sPLA2 levels represent a tipping point and when it reaches a certain level, it is a point of no return,” said Del Poeta.

The collaborators involved in the study, which was published this week in the Journal of Clinical Investigation, were encouraged by the finding.

“This is exciting as it is leading to really novel connections for COVID-19,” Yusuf Hannun, Director of the Cancer Center at Stony Brook and a contributor to the research who participated in the discussion and data analysis, explained in an email. “It may lead to both diagnostics (for risk prediction) and therapeutics.”

Looking closely at the levels of sPLA2-IIA together with blood urea nitrogen, or BUN, which is a measure of the performance of the kidney, the researchers in this study found that the combination of the two measures predicted mortality with 78 percent accuracy.

“That is an opportunity to stratify patients to those where an inhibitor” to sPLA2-IIA could help patients, said Floyd Chilton, director of the University of Arizona Precision Nutrition and Wellness Initiative and senior author on the paper, said.

While they found a difference in the amount of the enzyme between healthier and sicker patients, the scientists recognize that this could reflect a correlation rather than a causation. The progression of the disease and the threat to people’s lives may come from other contributing factors that also intensify the severity of the illness.

“These studies do not establish causality at the moment, but the strength of the correlation and the known functions of this enzyme raise the possibility of participating in the pathology of the disease,” Del Poeta explained.

Floyd Chilton. Photo from University of Arizona

Indeed, Chilton has studied sPLA2-IIA for over three decades and has described some patterns in other diseases, including sepsis.

The enzyme performs an important role in fighting off bacterial infection by destroying microbial cell membranes. When the concentration of sPLA2-IIA rises high enough, however, it can threaten the health of the patient, as it can attack and destroy cells in organs including the kidney.

The enzyme “plays a critical role in host defense,” said Chilton. “These same systems can really turn on the host.”

In order to determine a causative link between sPLA2-IIA and the progression of the disease, Chilton, Del Poeta and others will need to increase their sample size.

“We’ve been very fortunate at getting individuals at some of the top global organizations… who have connected me with medical centers” that have a larger patient population, Chilton said. These executives may be able to expedite the process of expanding this study.

In the 1990’s, scientists studied an inhibitor that had the ability to act on the enzyme. 

That effort had mixed results in phase 2 clinical trials.

“In 2005, the first phase of the phase 2 clinical trials were highly encouraging,” Chilton said. “It really inhibited mortality at 18 hours” by reducing severe sepsis. The second part of those tests, which used a slightly different protocol, failed.

While he’s not a clinical trials expert, Chilton is hopeful that researchers might find success with this same drug to treat COVID-19.

Only clinical trials would reveal whether inhibitors would work with COVID-19, scientists said.

As with many drugs, inhibitors of sPLA2-IIA have side effects.

By blocking the activity of these enzymes, “we do also decrease the production of arachidonic acid, which is a precursor of prostaglandins,” said Del Poeta. “In condition of hyperinflammation, this is a good thing, but prostaglandins are also important in a variety of cellular functions” including blood clots and starting labor.

Chilton pointed out that sPLA2-IIA is similar to the active enzyme in rattlesnake venom. It can bind to receptors at neuromuscular junctions and disable the function of these muscles, he explained.

In nature, some animals have co-evolved with snakes and are no longer susceptible to these toxins. Researchers don’t yet understand those processes.

While copying such evolutionary solutions is intriguing, Chilton said he and his collaborators are “much more interested in the inhibitors” that were taken through clinical trials in 2005 because that might present a quicker solution.

The research collaboration started with Chilton, who partnered with Arizona Assistant Research Professor Justin Snider. The first author on the paper, Snider earned his PhD at Stony Brook, where he knew Del Poeta well.

Snider “knew what a great researcher [Del Poeta] was. I also knew [Hannun] in a former life. We were both working on similar biochemistry 20 to 25 years ago,” Chilton said.

Chilton called the efforts of his Stony Brook collaborators, including Research Assistant Karen You, Research Associate Professor Chiara Luberto and Associate Professor Richard Kew,  “heroic” and explained that he and his colleagues recognize the urgency of this work.

“I’ve been continuously funded by the [National Institute of Health] for 35 years, and I’m very grateful for that,” Chilton said. “There is nothing in my life that has felt this important,” which is why he often works 18 hour days, including on weekends.

After studying the effects of variants on the population, Chilton recognized that building a firewall against COVID-19 through vaccinations may not be enough, especially with the combination of lack of access to the vaccine for some and an unwillingness to take the vaccine from others.

“We may have to go to the other side of the equation,” HE said. “We’ve got to move to specific therapeutics that are agnostic to the variant.”

Maurizio Del Poeta. File photo from SBU

Maurizio Del Poeta, a professor in the Department of Molecular Genetics & Microbiology at Renaissance School of Medicine at Stony Brook University, works to combat potentially deadly fungal infections. Recently, several press reports have highlighted the prevalence in New York and New Jersey of Candida auris, which is resistant to drugs and can cause death. Through an email exchange, Del Poeta shared his perspective on this fungal infection and his efforts to develop a treatment.

Are there multiple drug-resistant strains of numerous types of Candida?

Yes, there are several species of Candida that are resistant to some antifungals. For instance, Candida lusitaniae is normally resistant to amphotericin B. Candida glabrata is normally resistant to fluconazole. There are over 20 species of Candida that can cause infection in humans. Most are sensitive to antifungals. C. auris is normally resistant to all antifungals. They are resistant for mainly two reasons: (1) the target/enzyme is genetically different and, thus, the drug does not recognize the target; thus it does not bind to the target; and thus it does not inhibit it; (2) the drug is pumped out by membrane transporters. C. auris is notorious for having multiple membrane transporters.

I understand the damage from Candida is primarily among people who are immunocompromised. Is there a risk for those people who are also healthy?

Healthy people should be fine. But who is really “healthy?” Because C. auris is spreading in hospitals and nursing homes, all patients in hospitals and nursing homes are at risk: some more (e.g., cancer patients, patients with an organ transplant, patients in ICU, patients taking corticosteroids) and some patients have less risk because they are more immunocompetent, but certainly those patients could get contaminated.

What makes it so hard to eliminate Candida?

Because (1) we are not used to and (2) because we still do not know which type of disinfectant is efficacious against C. auris … Unlike other Candida infections, which are generally thought to result from autoinfection from host flora, C. auris can be transmitted between patients … C. auris requires implementation of specific infection control measures, such as those used for control of [other infections] (e.g., private room and on contact precautions). Because C. auris can survive in plastic surfaces, floors, and door knobs for weeks, it is essential that infection control measurements be implemented in the health care settings.

Does the work you’re doing offer hope, albeit in the earlier stages, for ways to treat and reduce the virulence of Candida?

Yes, our new compounds are sensitive to C. auris in vitro against the C. auris clinical isolates that are resistant to current antifungals. We are currently testing their efficacy in vivo (animals). We are doing this in collaboration with the National Institutes of Health and the Health Science Center in San Antonio, Texas. Our compounds have different mechanism of action from the current antifungals,

Given that the symptoms of a Candida infection -— fever, weakness and aches — are so prevalent in other types of infections, are there ways to make a clinically differentiated diagnosis of Candida without taking a blood sample or conducting extensive analysis?

Unfortunately, there are not. Diagnosis of C. auris can only be made using sophisticated tests. Normal phenotypic tests are not able to identify C. auris for certain. If we want to stop (or at least control) the epidemic, anyone with a Candida infection in a hospital setting should be treated as C. auris. Hospital trafficking of nurses, doctors, visitors from and to patients with C. auris should be highly restricted. Nurses and doctors should not be allowed in cafeteria without changing gowns, particularly if they are taking care of a patient infected with C. auris and other common sense practices should be implemented; but, unfortunately, they are normally out of the window in the hospital settings … In the case of C. auris “isolating rooms” and “contact precautions” should be implemented.

How does your treatment for Candida work?

The class of compounds are “acylhydrazones.” They target the synthesis of fungal sphingolipids.

Given what you know about the prevalence of Candida, particularly in New York, and the minimal information about the specific locations where hospitals have found Candida, what would you advise anyone who might be “at risk” for Candida to do if they had elective surgery scheduled?

Elderly and immunocompromised people going to the hospital should be treated with “contact precautions.” No need for isolation unless positive for C. auris.

Is C. auris the most virulent or problematic species of Candida confronting public health professionals today?

Not really. C. glabrata is also a nasty Candida strain. What makes C. auris difficult is the resistance to drugs.

Do other species suffer through Candida infections as well?

Although humans are the most known carriers and hosts for Candida infection, other animals can also get infected such as dogs, horses and cattle. Certain Candida species are used in food production. Candida utilis extracts are used in Asia as a “salt” instead of salt because these extracts are salty and do not cause hypertension. We actually have a collaboration with the Japanese company that makes these extracts. Candida krusei is used to ferment cacao during chocolate production. Whereas C. utilis is not a human pathogen, C. krusei actually is.

How do you protect yourself, your office and your staff from the spread of the infection?

We use biosafety label 2. My lab is certified to handle BSL2 organisms, such as C. auris. We use all sorts of protective gears and standard protective procedures to make sure lab personnel are protected and to make sure we keep the microbes inside the lab. Entrance to my lab is strictly prohibited to anyone that did not receive appropriate training.

Maurizio Del Poeta. File photo from SBU

By Daniel Dunaief

Sometimes, fixing one problem creates another.

People with multiple sclerosis have been taking a medication called fingolimod for a few years. The medicine calms immune systems that attack the myelin around nerve cells. Fingolimid decreases the lymphocyte number in the bloodstream by trapping them in the lymph nodes.

In a few cases, however, the drug can reduce the immune system enough that it allows opportunistic infections to develop. Cryptococcosis, which is a fungal infection often spread through the inhalation of bird droppings or from specific trees such as eucalyptus, is one of these infections, and it can be fatal if it’s not caught or treated properly, especially for people who have weakened immune systems.

Swiss pharmaceutical giant Novartis contacted Stony Brook University fungal expert Maurizio Del Poeta, a professor in the Department of Molecular Genetics & Microbiology, to understand how this drug opens the door to this opportunistic and problematic infection. He is also exploring other forms of this drug to determine if tweaking it can allow the benefits without opening the door to problematic infections.

Most of the human population has been exposed to this fungus. In a study in the Bronx, over 75 percent of children older than 2 years of age had developed an antibody against Cryptococcus neoformans, which means they have been exposed to it. It is unknown whether these people harbor the fungus or if they have just mounted an immune reaction. Exposure may be continuous, but infections may only occur if a person is immunocompromised.

Fingolimid “inhibits a type of immunity” that involves the movement of lymphocytes from organs into the bloodstream,” Del Poeta said. “Because of this, there are certain infections that can develop.”

Through a spokeswoman, Novartis explained that the company was “happy to have started a scientific collaboration” with Del Poeta to understand the role of a specific pathway in cryptococcus infections.

Cryptococcal meningitis is one of several infections that can develop. Others include herpes meningitis and disseminated varicella zoster. Before starting fingolimid, patients need to receive immunization for varicella zoster virus. At this point, doctors do not have a vaccine for cryptococcosis.

To study the way this drug and its derivatives work, Del Poeta recently received a $2.5 million grant over a five-year period from the National Institutes of Health.

Yusuf Hannun, the director of the Cancer Center at SBU, was confident Del Poeta would continue to be successful in his ongoing research.

Del Poeta “does very important and innovative work on fungal pathogenesis and he is a leader in the field,” Hannun wrote in an email. “His work will enhance our understanding of the molecular mechanisms.”

Fingolimid mimics a natural lipid. Years ago, Del Poeta showed that this sphingolipid, which is on the external surface of the membrane, is important to contain cryptococcosis in the lung. If its level decreases, the fungus can move from the lung to the brain.

While people with multiple sclerosis have developed signs of this infection, it is also prevalent in areas like sub-Saharan Africa, where people with AIDS battle cryptococcosis. About 40 percent of this HIV population develops this fungal infection, Del Poeta said. About 500,000 people die of cryptococcosis every year.

In certain areas of the United States, such as the Pacific Northwest, this fungus is also endemic. On Vancouver Island, about 19 people died from Cryptococcus gattii infections between 1999 and 2007. Most of those patients were immunocompromised.

When the fungus migrates from the lung to the brain, it is “very difficult, if not impossible in most cases, to eradicate,” Del Poeta explained in an email. If the diagnosis is made early enough before the infection spreads to the brain, the recovery rate is high, he suggested. In people whose immune systems are not compromised by drugs or disease, “death is rare.” 

Del Poeta plans to study the interaction between the drug and the fungal infection through a mouse model of the disease. The mouse model mimics the human disease and will provide insights on how to control the infection, particularly when the fungus reaches the brain.

Some of the derivatives Novartis has developed do not cause a fungal infection. Del Poeta is working with Novartis to study other forms of fingolimid that do not reactivate cryptococcosis. Del Poeta said Novartis is currently in Phase III clinical trials for another drug for multiple sclerosis. The new drug acts on a different receptor.

“We think the reason the fingolimid reactivates cryptococcosis is that it is blocking one receptor, which is important for the containment” of the fungus. The other drug doesn’t allow the disease-bearing agent to escape.

“This is a hypothesis,” Del Poeta said. He is waiting to corroborate the cell culture data in animal models.

Del Poeta has been working with Novartis for over three years. The Stony Brook scientist used some preliminary studies on the way fingolimid analogs behave as part of the research grant application to the NIH that led to the current grant.

Del Poeta said he is excited about the possibility of contributing to this area.

“Not only will this work contribute to the field of MS, but it will also have a contribution to the field of cryptococcosis,” he said. “This will have important implications for MS patients [and] for the entire HIV population.” He said he believes patients may have some other defect. If he is able to discover what that is, he may be able to protect them from a cryptococcosis infection.

Ultimately, Del Poeta hopes this work leads to a broader understanding of fungal infections that could apply to other pathogens as well.

Mycobacterium tuberculosis causes a granuloma very similar to the one caused by the cryptococcosis and we could potentially study whether the same molecular mechanisms involved in the control of the infection in the lung are similar between the two infections,” he explained in an email.