New insights in the development of azole-resistance related to fatal human lung infections

Published on
June 27, 2019

Researchers at the Laboratory of Genetics at Wageningen University & Research, in collaboration with the Radboudumc and RIVM, investigated a number of factors that may contribute to the development of resistance to azoles in the fungus Aspergillus fumigatus in plant waste. Azoles can cause serious lung infections in patients with a weakened immune system.

Fungicidal agents (chemical pesticides) called azoles are used in the bulb growing industry, as well as in many other applications such as preservation of wood, fruits et cetera. The research team showed that A. fumigatus already develops resistance to these agents at very low concentrations. In addition, the researchers demonstrated that different types of azoles can result in resistance development. The research focussed on accumulating bulb plant waste as in an earlier project it was identified as one of the hotspots of resistance development. Indeed, and for the first time for any site and in such detail, resistant Aspergillus was found to be present throughout the year. The organic waste from the composting industry was also previously found to be a major hotspot.

The research team anticipates that on any site and in any agricultural sector where organic waste accumulates and chemical residues from for instance crop protection are present is a hotspot where microbial resistance and health related accidents are waiting to happen. There is a strong emphasis on circulated agriculture, notably also from the Dutch Ministry of Agriculture. These new research results underscore that the design of circular systems need to take collaterally occurring health risks into account. In other words, circularity needs to be One-Health proof.

Lung infections

A. fumigatus is a fungus that grows on decaying plant material. It produces large amounts of spores, and these spores spread very effectively through the air. Humans inhale these spores on a daily basis. This does not pose a risk to healthy persons, but it can cause serious lung infections in patients with a weakened immune system. The azoles used to combat Aspergillus infections (medicinal azoles) are similar to the azoles that are used in agriculture and industry. The effectiveness of medicinal azoles is diminishing, as increasingly A. fumigatus strains are found that are resistant to these agents.

The resistance develops through adaptation of the fungus in response to azole exposure. The resistance mechanisms found in Aspergillus strains from plant waste were identical to Aspergillus strains cultured from patients. It is therefore considered plausible that patients obtained a resistant infection by inhalation of resistant spores from the environment. Controlling the development and proliferation of resistant Aspergillus strains in plant waste material has the potential to reduce the infection burden of the resistant fungus in patients. We investigated whether the development of resistance could be prevented by disturbing the life cycle of the fungus. The results showed that "disturbance" of the laboratory set-up that mimicking the organic waste heap could not prevent the development of resistance.


Alternative storage and processing methods

The study indicates that storage of decaying plant waste facilitates the selection of azole resistance in A. fumigatus, when residues of azoles are present. A preventive measure can therefore be to avoid the storage of plant waste in the bulb-growing industry and in all other sectors where dead plant material is stored. This however would violate the movement towards a sustainable and circular bulb sector. Therefore, further investigations should focus on proper storage and processing methods of plant waste into compost minimizing the emergence and spread of resistance are needed.