New research reveals a deadly fungal pathogen's vulnerabilities
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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INDICATION AVTOZMA® (tocilizumab-anoh) is an interleukin-6 (IL-6) receptor antagonist indicated for treatment of: Rheumatoid Arthritis (RA): Adult patients with moderately to severely active RA who have had an inadequate response to one or more Disease-Modifying Anti-Rheumatic Drugs (DMARDs). Giant Cell Arteritis (GCA): Adult patients with GCA. Polyarticular Juvenile Idiopathic Arthritis (pJIA): Patients 2+ years-old with active pJIA. Systemic Juvenile Idiopathic Arthritis (sJIA): Patients 2+ years-old with active sJIA. Cytokine Release Syndrome (CRS): Adults and pediatric patients 2+ years-old with chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome. COVID-19: Hospitalized adult patients with COVID-19 who are receiving systemic corticosteroids and require supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). 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About Celltrion Celltrion is a leading biopharmaceutical company based in Incheon, South Korea that specializes in researching, developing, manufacturing, marketing and sales of innovative therapeutics that improve people's lives worldwide. Celltrion endeavors to offer high-quality, cost-effective solutions through an extensive global network that spans more than 110 countries. Celltrion has seven biosimilars approved by the U.S. FDA: INFLECTRA® (infliximab-dyyb), TRUXIMA® (rituximab-abbs), HERZUMA® (trastuzumab-pkrb), VEGZELMA® (bevacizumab-adcd), YUFLYMA®(adalimumab-aaty), STEQEYMA® (ustekinumab-stba), and AVTOZMA® (tocilizumab-anoh), as well as novel biologic ZYMFENTRA® (infliximab-dyyb). For more information, please visit FORWARD-LOOKING STATEMENT Certain information set forth in this press release contains statements related to our future business and financial performance and future events or developments involving Celltrion Inc. and its subsidiaries that may constitute forward-looking statements, under pertinent securities laws. This press release contains forward looking statements. These statements may be also identified by words such as "prepares", "hopes to", "upcoming", "plans to", "aims to", "to be launched", "is preparing", "once gained", "could", "with the aim of", "may", "once identified", "will", "working towards", "is due", "become available", "has potential to", "anticipates", the negative of these words or such other variations thereon or comparable terminology. In addition, our representatives may make oral forward-looking statements. Such statements are based on the current expectations and certain assumptions of Celltrion Inc. and its subsidiaries' management, of which many are beyond its control. Forward-looking statements are provided to allow potential investors the opportunity to understand management's beliefs and opinions in respect of the future so that they may use such beliefs and opinions as one factor in evaluating an investment. These statements are not guarantees of future performance and undue reliance should not be placed on them. Such forward-looking statements necessarily involve known and unknown risks and uncertainties associated with the company's business, including the risk factors disclosed in its Annual Report and/or Quarterly Reports, which may cause actual performance and financial results in future periods to differ materially from any projections of future performance or results expressed or implied by such statements. Celltrion Inc. and its subsidiaries undertake no obligation to update forward-looking statements if circumstances or management's estimates or opinions should change except as required by applicable securities laws. Trademarks AVTOZMA® is a registered trademark of Celltrion is a registered trademark of Chugai Pharmaceutical Co., Ltd. References [1] AVTOZMA U.S. prescribing information (2025) [2] International Myeloma Foundation. What is Cytokine Release Syndrome (CRS)? Available at: For further information please contact:Andria Arenaaarena@ 516-578-0057 View original content to download multimedia: SOURCE Celltrion Error in retrieving data Sign in to access your portfolio Error in retrieving data Error in retrieving data Error in retrieving data Error in retrieving data
