An mRNA therapy research program aims to develop a treatment to counteract inflammation caused by Candida fungal infections. The program is being carried out by a consortium formed by the University of Szeged, the University of Pennsylvania (USA), and King’s College London (UK), which has received a HU-rizont grant. Leading the consortium is Prof. Dr. Attila Gácser, head of the Institute of Biology at the University of Szeged, who has spent 20 years studying pathogenic fungi. The research into mRNA-based therapy began two years ago, prompted by Katalin Karikó’s encouragement.
The research program has integrated insights from professional discussions at the mRNA conference held at the University of Szeged in November 2024. During the event, Dr. Attila Gácser met Prof. Norbert Pardi, whose laboratory was instrumental in bringing the University of Pennsylvania into the consortium. As an expert in mRNA construct design and delivery technologies, Prof. Pardi plays an active role in the research. The consortium’s other international partner is Dr. Julian Naglik, a professor at King’s College London and a globally recognized expert in developing novel therapeutic approaches for fungal infections.
Prof. Dr. Attila Gácser, biologist, head of the Institute of Biology at SZTE’s Faculty of Science and Informatics
Photo: Ádám Kovács-Jerney
In our interview with Dr. Attila Gácser, he explained that the goal of the research program is to develop a treatment that uses mRNA therapy to deactivate inflammation caused by Candida fungi naturally present in the body.
“Our previous research strategy focused on developing a preventive vaccine aimed at activating the immune system against fungal infections. These projects are still ongoing. However, with this new research program, we are shifting toward a therapeutic approach specifically designed to treat fungal infections affecting epithelial tissues, particularly mucous membranes,” Dr. Attila Gácser explained.
“It is important to recognize the fundamental differences in pathology between systemic fungal infections, which affect the entire body, and mucosal infections, such as those occurring in the oral cavity or the female reproductive tract. While systemic infections are considered classic infectious diseases, mucosal infections are primarily inflammatory conditions. Our goal is to integrate this biologically significant distinction into our project, ensuring that our therapeutic approach aligns with these well-documented pathological differences,” Dr. Gácser emphasized.
“Preventive vaccines work by generating an immune response against the fungus, which can be highly effective in combating systemic infections. However, mucosal infections cause symptoms primarily due to inflammation. In these cases, treatments that stimulate a conventional immune response could potentially worsen symptoms by triggering further inflammation. That’s why our strategy for mucosal infections takes the opposite approach: instead of activating the immune system, we aim to reduce inflammation by neutralizing the fungal components responsible for this pathological process,” Dr. Attila Gácser noted.
The antifungal therapy currently used for mucosal infections eliminates the fungus, but in its place, a bacterial infection often emerges. Conversely, the use of antibacterial agents allows the fungus to spread again.
“The first step of any infection is adhesion – when the microbe attaches to the host cell. This is no different for fungi; once attached, the fungus begins to grow and colonize. Under healthy conditions, the immune system regulates this process, preventing the fungal population from exceeding a certain threshold. Yet the presence of fungi also has beneficial effects. Due to their size, fungal cells occupy a significant portion of the mucosal surface, preventing other microbes from settling there. However, when antifungal treatment removes these fungal cells, it creates free space that bacteria can quickly occupy, allowing them to begin colonization and proliferation, potentially leading to a bacterial infection. It’s like a seesaw – when fungi are eliminated, bacteria take over. Maintaining balance is crucial; the immune system is inherently capable of controlling these microbes, but its response must not trigger excessive inflammation. In fact, it is not the fungus itself that causes symptoms, but the body’s response to it,” Dr. Attila Gácser stressed.
Photo: Ádám Kovács-Jerney
Candida fungi naturally inhabit the body surfaces of healthy individuals and can colonize epithelial tissues, such as those in the oral cavity or the vagina. The epithelial cells that form the mucous membrane serve as a crucial part of the immune system’s first line of defense, much like skin epithelial cells, but they are far more vulnerable.
Attila Gácser’s research group is now developing a system to fortify mucosal cells, enhancing their resistance to the harmful effects of the fungus:
“Our strategy involves encoding an mRNA for a chimeric molecule that serves two key functions: ensuring expression within epithelial cells and neutralizing the fungal component responsible for triggering inflammation through its fungus-specific subunit. Another challenge is keeping the mRNA on the surface of epithelial cells long enough to exert its effect. To address this, we use a specialized carrier material developed by Prof. Ildikó Csóka’s research group at the University of Szeged. This allows us to regulate how long the mRNA remains on the mucosal surface and under what conditions it stays active,” explained the biologist.
Lipid nanoparticles (LNPs) are traditionally used to deliver mRNA molecules. However, according to Dr. Attila Gácser, the delivery strategy is also a key element in their new research program:
“In our case, the primary goal is to avoid triggering an immune response. However, lipid nanoparticles have an adjuvant effect, meaning they enhance immune activation. Therefore, our first approach will be to mix the mRNA molecule with the mentioned carrier material and deliver it without LNPs. We will then examine how it behaves,” Dr. Gácser noted.
Photo: Ádám Kovács-Jerney
Importantly, the biologist leading the consortium remarked that Dr. Katalin Karikó is also participating in their research program – as a professor at the University of Szeged:
“We consult regularly, and when we won the HU-rizont grant, I was thrilled to share the news with her. She congratulated me and added that it was time to roll up our sleeves and get to work. Just last week, we talked about the project and our ideas. In fact, during these discussions, she not only gives feedback on our plans but also shares her invaluable experience. These conversations are immensely useful because Professor Karikó doesn’t just provide theoretical knowledge – she also offers practical insights that have never been published, drawn from decades of hands-on research. Sometimes, she can even immediately tell if an idea is worth testing. Other times, based on her lab experience – since she has personally carried out almost every experiment – she firmly advises us to take a different approach, explaining that she has already tried it before, and it didn’t work, so there’s no point in pursuing it further. And sometimes, she responds with a bit of humor, saying she’s not sure it’s a good idea, but we should try it anyway – so at least later, we can say, ‘Karikó didn’t believe in it, and yet it worked.’”
Original Hungarian text by Sándor Panek
Prof. Dr. Attila Gácser, biologist, head of the Institute of Biology at SZTE Faculty of Science and Informatics
Photo: Ádám Kovács-Jerney
