Understanding Fungal Infections at the Molecular Level: New Targets for Antifungal Agents

2023-10-01 22:04:59

02.10.2023

Fungal infections threaten people, animals and plants, sometimes with serious consequences. A research team from Heinrich Heine University Düsseldorf (HHU), together with colleagues from Frankfurt/Main and Aachen, have elucidated an important mechanism of how such infections are regulated at the molecular level.

In the journal Proceedings of the National Academy of Sciences (PNAS) they describe that this can also provide targets for new antifungal agents.

As pathogenic agents, fungi can cause serious diseases in humans, animals and plants. In humans, the skin is often affected, for example with the rather harmless athlete’s foot. Especially with a weakened immune system, internal organs can also be affected; The lung disease aspergillosis, for example, is caused by molds from the Aspergillus family.

Diseases caused by fungi can cause great damage to crops, such as ergot in rye, which is highly toxic to humans, or corn blight, for which the fungus Ustilago maydis is responsible. In order to develop new defense strategies to protect people, animals and plants, it is important to understand how infections are regulated at the molecular level, especially at the DNA and RNA level. However, knowledge of RNA regulation in fungal pathogens in particular is currently still limited.

The working group of Prof. Dr. Michael Feldbrügge from the Institute of Microbiology at HHU, together with research groups from Frankfurt and Aachen, has used a powerful RNA labeling technique for fungi that function in living organisms (“in vivo”). The researchers discovered how an important RNA-binding protein (RBP for short) called Khd4 regulates the growth of infectious hyphae – the thread-like form of the fungi, only these cause an infection.

Membrane transport is important for the growth of infectious hyphae: a recycling process that allows the exchange of materials between the fungus and its environment using vacuoles – special organelles in the cell. Determining the stability of information-carrying mRNAs was an important aspect in the published work. By nature, RNA is not very stable and it is also actively broken down. The amount of protein is regulated via mRNA degradation.

Prof. Feldbrügge: “We have discovered a new regulatory concept for infections for the first time: A single RBP controls the polar growth of infectious hyphae by determining the stability of mRNAs, which in turn regulate membrane traffic. This opens up starting points for the development of new fungicides, “use RBPs as new targets for fungal control.”

The research work was carried out in close collaboration between various institutions both at the HHU and with external partners. The first author and doctoral student Srimeenakshi Sankaranarayanan and Dr. Carl Haag, both of whom are supported by the Manchot Graduate School “Molecules of Infection” (MOI), is primarily concerned with the comparison of plant and human pathogenic fungi. The RNAs were sequenced at the HHU Biological-Medical Research Center (BMFZ). The cooperation partner Dr. Kathi Zarnack from the University of Frankfurt/Main took over the bioinformatic evaluation in the project.

“An important aspect was mathematical modeling, in which theoretical and experimental groups were closely interlinked,” emphasizes Feldbrügge: “This form of cooperation is part of the basic concept of our special research center ‘MibiNet’, which was launched in 2023; this was the contribution of Prof. Dr. Anna Matuszynska from RWTH Aachen contributed significantly to the success of the project.”

» Originalpublikation

Those: University of Düsseldorf