Why fungi might increasingly turn into human pathogens

A new study by researchers at Kiel University and MPI-EvolBio describes how more efficient protein production drives the adaptation of fungi to the human body, potentially turning previously harmless species into emerging pathogens.

Joint press release by Kiel University and the Max Planck-Institute for Evolutionary Biology 

To the Point

• Climate change may make fungi better suited to humans: Rising temperatures and shifting environmental conditions favour fungal species that can survive at body temperature, increasing the likelihood of more frequent human infections.

• Not new “killer genes”, but more efficient protein production: Pathogenic and harmless species are genetically surprisingly similar. The crucial difference lies in how efficiently fungi translate genetic information into proteins (translation) — which can dramatically speed up adaptation.

• Lipid metabolism as the key to pathogenicity: Harmful species appear optimised to grow quickly in lipid-rich environments (such as the mammalian body). This optimisation could make the jump from “harmless” to “disease-causing” relatively small — especially concerning in light of rising drug resistance and future climate conditions.

In the wake of global change and the associated rise in temperatures, fungal infections are on the increase worldwide, threatening crops, wildlife and, also, human health. Many fungal species are completely harmless and fulfil important ecological functions, such as decomposing organic matter and releasing nutrients into the soil. As symbionts of multicellular organisms, they perform useful functions for their host. On the other hand, some species are so-called opportunistic human pathogens: particularly in a weakened immune system, such fungi can colonise the body and cause serious and even life-threatening infections.

While fungi are often studied as pathogens of crops at institutions such as Kiel University and the Max Planck Institute for Evolutionary Biology in Plön (MPI-EvolBio), researchers increasingly turn their attention to their harmful effects on humans. A research team led by Professor Eva Stukenbrock, head of the Environmental Genomics group at Kiel University and MPI-EvolBio, has conducted a new study to investigate why certain fungi might become human pathogens in the course of global change. To this end, the researchers analysed various fungal species of the order Trichosporonales, which includes both harmless and dangerous species for humans.

A comparison of genomes in harmless species, usually found in the soil, and harmful species living the in the mammalian body, revealed that they differ less in their genetic makeup and much more in the efficiency with which they transfer genetic information into specific proteins. Harmful fungi have developed an optimisation strategy for their fat metabolism - in contrast to their soil-living relatives that specialize mainly on a carbon-centred lifestyle. This allows the former to adapt more quickly to new living conditions in a fat-rich environment, possibly making the transition to a pathogenic lifestyle easier. Since the genetic makeup of harmless and harmful species is otherwise largely similar, the risk of fungi increasingly turning into human pathogens appears higher than previously assumed. The research team recently published their findings, which are particularly relevant to public health, together with colleagues from Braunschweig, Bochum and Illinois in the scientific journal Nature Communications.

More efficient protein production allows rapid adaptation to new living conditions

The study began with a comparative genome analysis of closely related fungal species in order to identify possible differences. “We assumed that pathogenic fungi feature so-called virulence genes that produce certain harmful proteins to attack human cells, produce toxins or fight the immune system. Contrary to our expectations, however, pathogenic and harmless species were remarkably similar in their genetic makeup,” explains first author Dr Marco Guerreiro, a postdoctoral researcher in Stukenbrock's group.

In fact, the researchers discovered that the crucial difference between harmless and harmful fungi is not which genes they possess, but how efficiently they can use them to optimise the production of certain proteins. “Pathogenic fungi have developed a strategy in which proteins involved in fat metabolism are produced more quickly. This adaptation is extremely important because lipids are abundant in the mammalian body but very rare in the environment. This allows them to rapidly adapt to the human body and flourish in this environment,” says Guerreiro.

This mechanism is based on a late step in gene expression: translation, in which amino acids are assembled into proteins, proceeds faster the better specific signals in the mRNA, known as codons, match the tRNA molecules. “In pathogenic fungi, this match between tRNA and codons is particularly good. Adaptive evolution might have influenced the composition of both to optimise protein production for metabolizing fat and thus achieve adaptation to the human body,” emphasises Guerreiro.

The researchers were able to confirm the effect of this genetic optimisation in the laboratory: Also in their experiments, fungi with genes tuned for fat metabolism showed faster adaptation to living conditions rich in lipids where they grew significantly better. This supports the idea that this strategy indeed helps rapid adaptation to the human body - in contrast to the soil-living fungi in a carbon-rich environment.

Optimised fat metabolism increases the potential for emerging pathogens

The new research thus shows that the step towards the emergence of new fungal pathogens might be very small and in principle can evolve simply through increased efficiency of fat metabolism. “Considering increasing resistance to antifungal drugs, this is particularly worrying, as species thriving at human body temperature but currently considered harmless might easily make this transition,” says Guerreiro, emphasising the importance of the research. Under the climatic conditions predicted for the near future, numerous new and problematic fungal pathogens must be expected.

The researchers therefore aim to identify those fungal species that, based on certain genomic signatures, have the potential to become pathogens before they emerge as a serious health problem. "Overall, our study fundamentally changes the view of fungal pathogenicity and shows that the transformation from harmless environmental organisms to a human health threat may be more rapid and evolutionary accessible than previously imagined. As climate change, increased immunocompromised populations, and global connectivity create new opportunities for fungal diseases, understanding and monitoring these evolutionary dynamics is becoming increasingly important from a medical perspective," summarises Stukenbrock, head of the Kiel Plant Centre (KPC) within Kiel University’s priority research area Kiel Life Science (KLS).