New research reveals a deadly fungal pathogen's vulnerabilities

The study from the Stowers Institute and the University of Georgia uncovers more than 300 potential targets for drug development for a lethal fungus.
KANSAS CITY, Mo., June 10, 2025 /PRNewswire/ -- Fungal infections, particularly in immunocompromised individuals, are responsible for nearly four million deaths annually—however, current treatments are limited and are frequently ineffective. Now, scientists at the Stowers Institute for Medical Research and the University of Georgia discover how the lethal pathogenic fungus, Cryptococcus neoformans, thrives, allowing them to identify potential novel therapeutic targets for treatment.
Published in PLoS BIOLOGY on June 5, 2025, the study refined a genetic tool to identify which genes in C. neoformans are essential for its survival. Importantly, the research team uncovered more than 1,400 required genes, including more than 300 that share no similarity with human genes, making them promising targets for new antifungal drugs with reduced risks for side effects.
"Cryptococcus neoformans kills around 150,000 people a year. It's the AIDS-defining illness in the majority of HIV patients. Current treatments are limited, and outcomes are often poor," said lead author Blake Billmyre, Ph.D., Assistant Professor at the University of Georgia and former postdoctoral researcher in the lab of Stowers Associate Investigator SaraH Zanders, Ph.D. "There is an urgent need to develop new therapies, and this study provides an atlas."
Although humans and fungi bear little resemblance, genetically, we are surprisingly similar, which has historically made antifungal drug development difficult. Identifying essential genes in fungal pathogens that have no analog to human genes is critical for pinpointing potential antifungal agents that do not harm human cells.
The team uncovered 302 ideal therapeutic targets in C. neoformans—however, because drug development is costly, the researchers also identified a subset of around 30 essential genes conserved across many pathogenic fungi, or 30 potential therapies that could destroy most fungal invaders.
"A big question in biology is which genes are essential for life as well as how they might change over evolutionary time," said Zanders. "Blake's TN-seq project opens the door to genome-wide screens for important traits in pathogenic fungi and will speed the pace of drug discovery."
The team used a genetic technique called transposon mutagenesis sequencing, or TN-seq, where they damaged C. neoformans' genome by bombarding millions of cells with small DNA segments called transposons.
"The analogy we use to explain TN-seq dates back to WWII," said Billmyre. "Fighter planes returning to hangars were mapped for bullet damage to devise ways to strengthen them. However, areas of planes lacking damage were not necessarily better reinforced, but rather were never mapped because they never returned, a phenomenon called survivorship bias."
Transposons landing within essential genes cause the fungal cells to die. By sequencing the DNA of the surviving cells, researchers can map which genes are vital for survival and which are not. Zanders explained: "The TN-seq approach mirrors this survivorship bias with transposon-ridden fungi. When we look genome-wide at all the places with and without damage, we can infer that if you damage a required region of the genome, the organism will die."
TN-seq has been used widely in bacteria and in more established fungal species like baker's yeast. This is the first time the approach was adapted for C. neoformans. It allowed the team to create a mutant library for C. neoformans—with millions of transposon-induced mutations including those in DNA that regulate essential genes. The researchers could then ask even more nuanced questions, such as which genes contribute not only to survival but also to resistance of antifungal drugs.
"Traditional methods involve deleting one gene at a time, but TN-seq lets us make deletions for the entire genome, allowing us to rapidly identify the repertoire of essential genes in Cryptococcus," said Billmyre. "In addition, we were also able to use the tool to test both essential and non-essential genes that confer resistance to the most common antifungal, fluconazole."
Billmyre was recently awarded the prestigious NIH New Innovator Award to examine how fungi evolve to grow at high temperatures, which is key to understanding pathogenicity.
"My lab is now trying to understand the network of genes that enable fungal pathogens to grow at human body temperature," said Billmyre. "This can inform us of what might happen in the future if increases in global temperature cause different species of fungi to acquire pathogenic properties."
Additional authors include Caroline Craig, Joshua Lyon, Claire Reichardt, Amy Kuhn, and Michael Eickbush.
This work was funded by the National Institute of General Medical Sciences of the National Institutes of Health (NIH) (awards: DP2GM132936, R35GM151982), the National Institute of Allergy and Infectious Diseases of the NIH (award: DP2AI184725), and with institutional support from the University of Georgia and the Stowers Institute for Medical Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
About the Stowers Institute for Medical Research
Founded in 1994 through the generosity of Jim Stowers, founder of American Century Investments, and his wife, Virginia, the Stowers Institute for Medical Research is a non-profit, biomedical research organization with a focus on foundational research. Its mission is to expand our understanding of the secrets of life and improve life's quality through innovative approaches to the causes, treatment, and prevention of diseases.
The Institute consists of 20 independent research programs. Of the approximately 500 members, over 370 are scientific staff that include principal investigators, technology center directors, postdoctoral scientists, graduate students, and technical support staff. Learn more about the Institute at www.stowers.org and about its graduate program at www.stowers.org/gradschool.
Media Contact: Joe Chiodo, Head of External Communications and Media Relations 724.462.8529 press@stowers.org
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SOURCE Stowers Institute for Medical Research

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Bioethicist, sociologist, and executive director of the Institute for Ethics and Emerging Technologies. Yes we should, when it's safe, effective, and voluntary. Calls to permanently ban the creation of genetically modified children often rest on fear, not facts. They mirror past moral panics over interracial marriage, in vitro fertilization, and birth control—all technologies or choices once deemed unnatural or dangerous, and now widely accepted. We should be wary of arguments dressed up as ethics but rooted in anxiety about change. That doesn't mean anything goes. Like any powerful technology, gene editing must be tightly regulated for safety and efficacy. But the agencies we already trust to regulate medicine—the FDA, NIH, and institutional review boards—are largely capable of doing that. We don't need a bioethics priesthood or a new bureaucracy to police reproductive decisions. We need science-based oversight, individual consent, and protection from coercion. One of the loudest objections to genetic editing is the specter of 'eugenics.' But if eugenics means state control over reproduction, then the lesson of the 20th century is to defend reproductive freedom, not curtail it. Governments should not tell parents what kinds of kids to have. Preventing parents from using safe, approved gene therapies to reduce suffering or enhance their children's lives is a strange way to honor that lesson. They should give parents access to all the information and technology for the choices they make. True reproductive liberty includes the right to use the best science available to ensure a child's health. Another objection is that genetic modification could harm people who would rather not participate. But this 'perfection anxiety' ignores how all medical advances shift social norms. We didn't stop improving dental care because it made bad teeth less acceptable. And a healthier society has not led to less compassion for those who remain sick or disabled—if anything, it's strengthened the case for inclusion and support. The goal should be equitable access, not frozen norms. We do need to ensure that parents can access all the gene therapies that actually provide potential benefits for children. Governments with universal healthcare will need to make tough choices about what to cover and what not to cover. For instance, the National Health Service should make gene therapy to remove lethal, painful conditions available for all Britons, but parents may need to pay for medical tourism to some offshore clinic if they want to tweak their embryo's eye color. What about risks we can't foresee? Of course there will be some. All new medical therapies come with uncertainties. That's why we have trials, regulation, and post-market surveillance. There's no reason genetic therapies should be held to an impossibly higher standard. We should start with animal models, and proceed to the most morally defensible gene tweaks, lethal and painful conditions. Over time, as the safety of the techniques are better understood, we can expand the scope of therapeutic choices. Some worry that genetically modified children could disrupt our ideas of family or humanity. But those concepts have already been revolutionized—by urbanization, feminism, economic precarity, and social movements. The family of today would be unrecognizable to most people in 1800. If genetic technologies change our values again, it won't be the first time. Liberal democracies don't freeze culture in place—they ensure people have the freedom to shape it. Ultimately, the question isn't whether we should allow genetically modified children. It's whether we trust parents to make mostly good choices under the oversight of regulators and doctors. We should, because most parents have their children's best interests in mind, as they perceive them. That's why we allow parents to raise their own children in the first place. And we should ensure those choices are equitably available to all, not outlawed out of fear. If we ever find genetic tweaks to reduce suffering, enhance capability, or prevent devastating disease—and we can do so safely and ethically—the real moral failure would be to prohibit it. A Canadian bioethicist and environmentalist currently teaching at the University of Toronto. Well, there's a big difference between genetic enhancement and treatment. And with enhancement, I think we're nowhere near a point where we should be even considering that. But with treatment, the large ethical issue right now is something like single gene mutation. So something like Huntington's disease, muscular dystrophy, or similar diseases, could it be justified to edit the gene for that? The challenge is we don't fully understand all the things. We don't know what we don't know, to put it bluntly. And with germline editing, the changes we would be making are permanent and they run through many generations ahead. So, yes, being able to prevent deadly or debilitating illnesses is absolutely something wonderful. But having said that, you obviously don't have consent of the person who will be born, but you also don't have consent of the generations that come after that. And if there is complications or unexpected problems, you can have an inheritance that just keeps running through generations. But here's the thing with this moratorium; to what end? You can call for a moratorium, but if no one's focusing on anything, if there's no research, no planning, no social discourse, there's just a lot of people with different opinions, and everything gets shelved for 10 years. I'm not sure that's going to be particularly useful. It sounds great if it's going to be 10 concentrated years on building consensus and public engagement and those types of things, but I don't think that's what would actually happen. And also, I'm sure you've noticed, the world's not in good shape, and Western culture is not of one mind these days. And with the ruptures, particularly in the United States, there's a lot of division in Western culture of how people see things. And I'm just not convinced that a moratorium, that people would make use of it in a constructive way. It really needs a coordinated plan, and I'm not sure there is one. So I do see that as quite a problem. The other thing is, we're dealing with high-income countries. So when we look at potential for CRISPR-Cas9 and gene editing, we're dealing with a very small percentage of the world's population. I'm going to guess that it's maybe 15% to 20% of the world's population, because most of the population of the world has no access to things like this and never will. Not never will, but in the foreseeable future, they won't. And I think that's something we miss a lot of the time. And the biggest ethical problem in the world today is not gene editing. It's just access to healthcare. And this doesn't do anything in those domains whatsoever. So from a justice point of view, that is a concern. And I'm going to sound cynical here. Emerging medical technologies are not motivated largely by the social sector. They're motivated by marketing and market forces. So if people can make money on this, somehow, someway, people will proceed. And if gene editing is illegal in Canada and the U.S. and Western Europe and Australia, there's a lot of countries that don't fall into that. And you can set up shop anywhere. Equatorial Guinea or other places are not going to be worried about things like this. They've got enough problems on their hands. And there's a lot of countries out there where this would not be easily called. So I support the essence of it. And I can see why people want to do it. I'm just not convinced it's all that feasible. I think what makes more sense is just not having any germline editing until we have a larger consensus about this technology.

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