Of the estimated millions of fungus species on the planet, only about 150,000 have been described, and just 200 of those cause disease in humans. Bennett, the Charles A. and Helen B. Stuart Professor and chair of molecular microbiology and immunology at Brown, has dedicated his career almost exclusively to just one of them, Candida albicans. 

“There’s enormous diversity within this one species. So how does that happen?” says Bennett, who started working with C. albicans as a postdoc at the University of California, San Francisco. In those pre-genome-sequencing days, “there was next to no knowledge” of what caused the intraspecies differences they observed; Bennett’s lab has spent the last 20 years sussing that out. “We get the best of all these worlds, where we can think about just fundamental mechanisms and how does a cell do what it does. But then we can also go to the other end of the spectrum and say, well, how does this fungus kill us?” he says.

C. albicans lives in and on nearly everyone, kept in check by beneficial bacteria and healthy immune systems. When it can proliferate, it usually causes relatively mild forms of candidiasis like diaper rash, thrush, or vaginal yeast infections. But C. albicans is opportunistic: Given the chance, it will spread from the gut to vital organs or into the bloodstream. Bennett says it can even affect brain function. It’s also developed resistance to antifungals. Mortality rates from invasive candidiasis, including candidemia, which infects the blood, are as high as 40 percent.

 Among other things, Bennett’s lab is trying to understand how C. albicans escapes the gut and causes disease. The fungus has two forms, single celled yeast and multicellular filaments; the former is a better colonizer—but only if the bacteria that normally control C. albicans have been depleted, perhaps by antibiotics. If the fungus switches to its filamentous form, it produces a toxin called candidalysin that attacks the bacteria, so the fungus can flourish. “That was an exciting story for us,” Bennett says of their 2024 paper, which was published in Nature.

“There’s some evidence that the toxin would also help Candida escape the gut by damaging the host tissues,” he adds, but they don’t exactly know how it gets out. They want to better understand how the bacteria and fungi and host cells interact with each other, and for that matter, how candidalysin harms the bacteria. “If you could block the toxin, you could also reduce Candida amounts in your gut,” he says. 

Bennett and his team also found a gene that mutates readily, allowing C. albicans to adapt to different environments and colonize the bloodstream and certain organs. This may help explain its resistance to antifungals, and to rising temperatures. 

“I call it ‘Candida the chameleon’ because it’s always changing its shape, its form, its expression,” Bennett says. “It’ll grow from pH 2 to pH 11. It’ll grow aerobically and anaerobically. … It grows as a yeast at room temperature, but it grows as filaments at 37 [degrees Celsius]—that’s what our body temperature is.” He adds, “And we still don’t really know how Candida undergoes all of this.”

Endothermy usually protects healthy mammals from fungal infections; the pathogen that causes white-nose syndrome in bats can only take hold when their body temperature drops during hibernation. But C. auris is defying conventional wisdom. Though its origins are murky, its adaptation to the warming climate may have enabled its jump to humans. Plus, it arose not in one outbreak but as several different strains, or clades, nearly simultaneously around the world. “It was a bit of a puzzle,” says Christina Cuomo, PhD, the Viatris Professor of Molecular Microbiology and Immunology. “As quickly as it was detected, Candida auris had four separate clades in four different geographic regions.” 

Cuomo came to Brown two years ago from the Broad Institute, where she was the director of fungal genomics. In 2016 her team there worked with the CDC to affirm that contemporaneous emergence; their genomic analysis also showed that C. auris was evolving antifungal resistance as far back as the 1980s. “This may have played a role in expanding the clades,” she says. As cases continue to rise, new treatments might not even help: Cuomo says recent studies found evidence of resistance to a new drug that’s still in development. 

However, this could inform the development of other new drugs. “We don’t completely yet understand how the mechanisms all link together genetically and mechanistically in the cell,” Cuomo says. “If we can map those pathways, we might identify other vulnerabilities that could be targeted.” Meanwhile, other labs are looking for genes related to C. auris’ temperature tolerance, which “may suggest new interventions to fight against it,” she adds.

In a way, C. auris is a one-off; potentially deadly fungi lurk all around us. Cuomo also studies Aspergillus fumigatus and Cryptococcus neoformans, whose spores most healthy people inhale regularly without harm—but are at the top of the WHO’s critical pathogen list for the severe disease and high mortality they can cause in vulnerable populations, and lack of effective treatments. A. fumigatus is a case study of the collateral damage of excessive fungicide use: The mold lives in the soil alongside crops that are sprayed with antifungals, yet it isn’t even their target. Now it’s evolved defenses that complicate medical care. “Genomics has provided a window to map new genes and mutations to more fully describe clinical resistance,” Cuomo says. 

As climate change abets the spread of pathogens, Cuomo suggests researchers be proactive, and study fungi with the potential to adapt and evolve into C. auris-like scourges. “We’d like to understand events like this earlier on and understand risk factors, to think about prioritizing surveillance of environmental sources of pathogen and their evolution to prepare to face fungal threats,” she says.

For a patient to survive an invasive fungal infection, three things have to happen, and fast: a clinician suspects it’s a fungus and orders the right test; the test correctly identifies the pathogen; and a treatment is available and effective. Yet every one of these steps is fraught with problems. 

Infectious disease physician Gerard Nau, MD, PhD, says mycoses are common among his transplant and cancer patients at Rhode Island Hospital. “We always have to keep it in mind, because if the diagnosis is delayed, then you get behind in treatment and it’s harder to eradicate infection,” says Nau, an associate professor of medicine. 

Though bacterial and viral infections remain far more common, Nau says of mycoses, “the numbers are certainly increasing.” Medical advances like immunosuppressants, which leave patients vulnerable to opportunistic fungal infections, are partly to blame; climate change may be, too. And then there’s the “canary in the coal mine,” Nau says—individual case reports “that tell us something is coming,” like, perhaps, a recent inexplicable case of the disfiguring tropical disease chromoblastomycosis in Rhode Island. 

These are teachable moments for medical educators. “We have to keep our minds open to the possibilities,” Nau says. “When infections get hard to diagnose, it’s because people are having too narrow a view.” If infectious disease physicians hear hoofbeats? “We love the zebra,” Mermel says. “We live for that.” But, he adds sympathetically, “it’s dependent on our [ID] brethren to have that expanded knowledge and differential diagnosis to figure it out. You can’t expect the generalist to know all these nuances.” 

Diagnostic tests are the next weak link in the chain. “Fungal diagnostics are way behind the times compared to bacterial diagnostics, or even viral diagnostics,” Nau says. For some molds, lab technicians “literally compare the microscopy to sketched images in an old book.” And the tests are slow—up to two or three days for bacterial cultures, days and even weeks for fungi. “If you’re waiting weeks for a diagnosis, the patient’s not doing well,” says Sean Monaghan RES’14, MD, a trauma, critical care, and acute care surgeon. 

This summer Monaghan, an associate professor of surgery, began testing an in-house molecular diagnostic at Rhode Island Hospital that detects and quantifies RNA in blood samples of patients with infections and identifies a pathogen within five hours. “If we can show that it works just as well as culture, but faster,” he says, “we can really guide what antibiotic a patient should get.” The correct drug could shorten not only hospital stays but the course of treatment: Because Monaghan’s test measures how much pathogen is in the blood, a doctor can see if the drug is working, and stop treatment sooner. 

In these early stages his team is focused on finding the most common sepsis bacteria, but eventually they’ll test for more bacteria as well as fungi. Hospital labs could someday run multiple test panels from one sample, Monaghan says, starting with the most common pathogens for their patient population, then moving on to rarer ones. “Maybe you pick up that fungal infection you typically didn’t think of,” he says, and switch from antibiotics to antifungals. “That would really improve care.” 

Yet even when mycoses are correctly and promptly diagnosed, patients still die due to antifungal resistance and lack of drugs. “We have such a limited number of antifungals that we just do our best,” Nau says. He recalls the “horribly tragic case” of a young chemotherapy patient with an invasive respiratory fungal infection. “We knew what it had to be. We were treating it. And yet there was nothing we could do to stop it,” he says. Proper, effective treatment may also come at a cost, as some antifungals require prolonged use and side effects can be pretty severe, including liver toxicity and kidney damage. 

Getting the right drug to the right place in the body in time to save lives might be a problem best solved by an engineer. Anita Shukla, PhD, who develops antimicrobial biomaterials and drug delivery systems, began her career working with bacteria; a couple of years after arriving at Brown, she started looking at fungal infections too. 

“In the engineering community, there isn’t as much focus on antifungal materials,” says Shukla, the Elaine I. Savage Professor of Engineering. “There’s much less of an appreciation for how important these fungal pathogens are [compared with] bacterial pathogens, and they just get less attention. So it took a little while for us to find the resources to do this work.” 

Shukla’s lab recently devised a method of targeting Candida infections using liposomes—lipid-based nanoparticles—that encapsulate an antifungal drug and specifically target the pathogen. The strategy, which they demonstrated in mice infected with C. albicans, could reduce side effects because it only harms fungal cells. It’s also a significantly more potent delivery system, so doctors could administer lower doses of antifungals. 

“We decorated our liposomes with certain peptides that we found were able to interact with fungal cells more than they interact with mammalian cells,” Shukla says. “It was exciting because nobody had ever used this particular approach.” Her team also has developed hydrogels that could be embedded into materials like wound dressing and degrade on contact with fungal enzymes. Only then would they release the entrapped antifungals—reducing drug exposure and resistance, she says. 

Shukla and other engineers at Brown are now collaborating with Nau’s lab to identify materials that could capture a volatile antifungal compound that he’s been studying. A longtime researcher of innate immunity and bacterial pathogenesis, Nau took an unexpected detour into antifungals a few years ago when an energetic sophomore showed up at his door with a bacterium he and some classmates had dug up in a state park in Cranston. 

“We took the dirt, spun it down, and cultured out the bacteria,” recalls Niko Montaquila ’24 MD’28, who took a course on how to analyze soil samples for potential new antibiotic compounds, and then reached out to Nau to take the research further. The bacteria he identified, Chromobacterium vaccinii, didn’t inhibit the growth of other bacteria, but Montaquila and Nau found studies that showed it did stop environmental molds “very, very well,” Montaquila says. “We weren’t really interested in that. We were interested in these pathogenic, hard-hitting, hard-to-treat fungal infections.” 

They pitted C. vaccinii against several fungal pathogens in culture, including the top four on the WHO’s high-priority list. “It’s our understanding that we’re the first people to analyze this capability in terms of human fungal pathogens,” Montaquila says. “Overall, we’ve tested several different species, many different genuses of fungi, and we found around 90 percent inhibition.” It even performed moderately well against C. auris. They also showed that C. vaccinii isn’t toxic to mammalian cells.

Shukla says depending on how the antifungal compound interacts, on a molecular level, with different biomaterials, it could be loaded in a delivery system, or embedded on a device like a catheter, or even aerosolized—a delivery method that might have saved Nau’s chemo patient whose invasive lung infection they couldn’t treat. 

“While we were delivering antifungals intravenously, if these organisms are … growing into the blood vessels and clotting them off, then we’re not delivering antifungals,” Nau says. “Wouldn’t it be nice if I could have just given her something she could inhale a few times a week, and then actually deliver antifungals right to the space?”

New devices, new drugs, new diagnostics—all exciting developments that will, as Monaghan says, “take years and years and years of work.” But do we have that long? Fungal diseases are so underappreciated that researchers can only guess how many people they kill. 

Last spring, the Medical School held an all-day symposium on climate change and health, which included a presentation, by Bennett, Cuomo, Nau, and Montaquila, on fungal pathogens. Shukla, Bennett, and Nau are co-PIs on a new multidisciplinary collaborative to combat antimicrobial resistance. “Fungal pathogens are one of those potentially catastrophic issues that we are uniquely positioned to address in the Division. You need a distinct array of experts—ecologists, immunologists, biomedical engineers, clinicians—all of which we have,” says Mukesh K. Jain, MD, dean of medicine and biological sciences. “Addressing this problem aligns perfectly with our mission.” 

The chytrid fungus has severely endangered or completely wiped out hundreds of frog and salamander species around the world. White-nose syndrome has killed millions of bats across North America, and over 90 percent of some species. These catastrophic losses endanger the health not only of ecosystems but of humans. Without bats, for example, populations of disease-carrying insects and crop pests are going up. According to a paper in Science last year, in US counties heavily impacted by bat deaths, farmers sprayed 31 percent more insecticides—and infant mortality went up 8 percent, which the author attributed to pesticide exposure.

“I do think of [fungi] as silent assassins,” says Katherine Smith, PhD, the senior associate dean of biology education and co-director of Brown’s Planetary Health Initiative. They’re also, she posits, a sign of bigger problems—Nau’s canary in the coal mine. Is climate change a preexisting condition, making us all more vulnerable? 

“It’s kind of rare for a pathogen to be the sole cause of species extinction. It usually goes hand in hand with other stressors in the environment,” Smith says. She mentions a species of Aspergillus that’s threatening coral reefs off South America. “Corals are dealing with bleaching in a warmer ocean. You throw a pathogen on top of that, you can’t help but expect that it’s going to be a double whammy. I think you can make the same case for amphibians with chytrid, bats with white-nose, and certainly humans with fungal infections,” she says. 

Shukla and others say the complexity of fungal infections calls for a One Health approach, which recognizes that human health is intertwined with that of animals, plants, and the environment. Antifungal resistance in people, for example, can’t be addressed without the collaboration of agricultural, environmental health, and veterinary experts. Those groups could also share knowledge of emerging threats that might someday harm humans. “What’s really important is somehow to get us all together,” Shukla says. “We have to be prepared.” 

Climate change will surely spawn new virulent pathogens like C. auris. There’s a hypothesis that mammals thrived after the extinction of the dinosaurs in part because fungi couldn’t readily infect their warm-blooded bodies. Now, as all life on Earth tries to adapt to rising temperatures, endothermy may no longer save us. Even if The Last of Us isn’t quite our future, it’s not all science f iction, either. 

“Everybody knows about drug-resistant bacteria. Everybody knows about the viruses. But I just don’t think most people understand the importance of fungi or the range of diseases or the numbers of people involved or how serious the infections are or how hard they are to treat. And I do feel they’ve been neglected diseases,” Bennett says. “I wish there were more people working on them.”