How to fight fungal infection: the path of yeast resistance

Fungal Disease Awareness Week begins on September 18th. The week is organised by the US Centers for Disease Control and Prevention (CDC), who have chosen this year’s theme of Think Fungus. The campaign aims to highlight the growing challenges, complexities, and the devastating impact of fungal diseases.  

Fungi may not be at the forefront of people’s minds when they think of infectious threats, but disease-causing fungi have the potential to devastate or disrupt human health, wildlife, natural ecosystems, food security, and global trade policies.  

Annually, serious fungal diseases affect over 300 million people across the globe and are more commonly fatal than malaria and tuberculosis. People with weakened immune systems are particularly at risk, and our ability to treat patients is being hampered by increasing levels of drug-resistant strains.  

Fungal infections can also wipe out animal populations and threaten our food security. Take for example the fungal disease chytridiomycosis, which is responsible for the mass extinction of amphibian species over the past few decades, or Magnaporthe oryzae, the fungal pathogen behind the wheat blast outbreak that wiped out harvests in Bangladesh. Worryingly, M. oryzae and other fungal blights of crops continue to spread across the globe.  

To mark the week and the importance of fungal research, the Institute of Infection spoke with Professor Darius Armstrong-James, Professor Mat Fisher, and scientists representing the breadth of fungal research in Imperial College London, to highlight how Imperial is working to address critical fungal challenges, including through Imperial’s Fungal Science Network.  

Professor Darius Armstrong-James is a clinician and scientist who specialises in understanding the mechanisms by which complex pathogens such as fungi that are difficult to diagnose and treat cause such devastating diseases. He leads the Royal Brompton Hospital fungal diseases service, which provides clinical and diagnostic support for patients with fungal disease, and his research programme in the Department of Infectious Disease focuses on aspergillosis and how it interacts with the immune system.   

He leads a UK Cystic Fibrosis (CF) Trust Strategic Research Centre called TrIFIC (Targeting Immunotherapy for Fungal Infections in Cystic Fibrosis) which focuses on investigating whether immunotherapies are useful during Aspergillus infection and which individuals are most likely to benefit from them. Aspergillus fumigatus is found in the phlegm of 50% of people with CF by the time they reach adulthood. One-third of these individuals go on to develop Aspergillus bronchitis, a severe airway infection, and 15% experience allergic broncho-pulmonary aspergillosis. These problems can lead to lung inflammation and a decline in their function and stop patients from being eligible for a lung transplant.  

Some fungal infections are also resistant to anti-fungal medications, which is leading researchers like Professor Armstrong-James to look to immunotherapies as potential treatment options.   

Immunotherapies have the potential to avoid antimicrobial resistance and can be very helpful when the immune system is weak or overactive. They have already been used successfully in patients with CF and Aspergillus infection, and more are being created to target airway inflammation. The investigation will lead to better identification and more personalised treatments for problems arising from A. fumigatus infection in people with CF. 

Professor Mat Fisher (School of Public Health) and colleagues have been working on the emergence of resistance to antifungal drugs both in the clinic and in nature in order to understand the interplay between the environment (e.g., agriculture), amplifiers (e.g., farm or food waste disposal) and exposures (how and where humans, animals and plants encounter resistant drug-resistant fungi).  

The aforementioned A. fumigatus, which can cause the disease aspergillosis in at-risk humans, is a very common mould in soils and air. Emerging resistance to antifungal drugs by this mould is an unfortunate consequence of the prolific use of fungicides to protect crops against disease.   

The health threat is significant. A recent citizen science project by Professor Fisher et al. showed that more than 5% of A. fumigatus spores in the UK air are now resistant to both clinical and agricultural azole antifungals. And as we are all exposed to this mould daily, this is especially serious for people who are immunocompromised, who are at a greater risk of aspergillosis.    

A unique aspect of the treatment of fungi is that the same antifungal agents (e.g., azoles) are used ubiquitously in healthcare (human and animal), agriculture, and even antifungal paints on ships. Such ‘dual use’ accelerates the spread of resistance across the globe and means that we are losing our first line of defence against opportunistic fungal infections in the clinic.  

For patients, it means that the drugs we rely on are no longer working as well as they once did. Moreover, in agriculture, the evolution of resistance to crop-destroying fungi is a perennial threat necessitating the development of new types of fungicides. Resistance therefore threatens our food security, the environment, ecology, and human health. 

We need to find system-level solutions and investments that incorporate new treatment options alongside new diagnostic approaches and clinical practices (see Dr Anand Shah below), stewardship, policy changes and biosecurity.

As shown by the examples above, fungal scientists are demonstrating the critical need for major policy changes, including concerning border control, antifungal stewardship, and global trade. Government and policymakers must be made aware of the science and weigh up the health, food security, and ecological impacts against the cost and the impacts on global trade. Moreover, these are things that countries cannot do on their own: it must be a global effort, with ambitions on a global scale: see for example the global surveillance system or trade agreements described by Dr Rhodes below. 

It is, therefore, no wonder that fungal experts are increasingly being included in national and international policy discussions. For example, Professor Armstrong-James’s expertise was recently sought by the Department of Health towards their five-year action AMR plan.  “It’s good to see fungi on the agenda,” he said.  

Dr Claire Stanley (Department of Bioengineering) develops novel microfluidic technologies to probe the interplay between microbes at the single cell level. Her devices consist of tiny microorganism-holding wells on either end of a ‘chip’ with connecting microscopic channels. The technology allows researchers to gain insights into biological events that could not be achieved from traditional plate methods, including imaging the movement of hyphae in real-time and the heterogeneity between individual cells.  

In collaboration with microbiologists and other scientists, Dr Stanley’s devices have been adapted to answer questions about how fungi interact with bacteria, other fungi, plants, and nematode worms, giving critical insights in microbiology, environmental science, and agriculture. Dr Stanley is an ardent believer that her technology should be usable by the researchers asking the biological questions rather than specialist technologists. “Simplicity is important,” she said. 

In recalling a time when she was most inspired, Dr Stanley described how an exploratory collaboration with a colleague studying microscopic nematode worms became the penny-drop moment when she realised the potential power of the technology. When the researchers combined the microbiologist’s expertise with Dr Stanley’s technology, they discovered new insights into the ways by which fungi defend themselves against nematode attack, and captured images of the fungi communicating the threat via their hyphae. The story was picked up by the New York Times.

Another collaborative project - this time with a PhD student studying agricultural biocontrol - focused on fungal-fungal interactions. Stunning real-time images (below) showed how a pathogenic fungus (Fusarium graminearum) responded when placed in proximity to a fungal biocontrol agent used on crops (Clonostachys rosea). This was another example of researchers gaining astonishing insight beyond their expectations.  

Dr Stanley’s microfluidic device is also helping the study of arbuscular mycorrhizal fungi, which form important symbiotic relationships with 70-80% of land plants. It gives the researchers a tool to explore how the soil microbiome helps plants take up nutrients, how hyphae search physical space to allow the fungus to find plant roots, and how the environment (soil microbiome, pesticides, and antibiotics) influences fungal behaviour.  

With recent advances in rapid sequencing capabilities, researching human fungal pathogens using genomic epidemiological techniques can be applied to real-time outbreaks of fungal infections. Dr Johanna Rhodes (School of Public Health) uses omics technologies to generate sequence data, which can be mined to understand drug resistance mechanisms, transmission events, and how these pathogens spread through time and space.  

Over the last few years, she has become interested in where drug-resistant fungi are coming from in the environment, how resistance is evolving in a changing climate, and what impact that has on humans. She also worked with a team at the Big Data Institute at Oxford to create the first genomic surveillance platform for the fungal pathogen, Candida auris, which causes severe illness and spreads easily in healthcare facilities. She said: “We hope this surveillance platform will help clinicians determine drug resistance profiles quickly (it can analyse sequence data in just a few minutes)”. 

Dr Rhodes emphasised how the ‘one health’ approach is highly relevant to fungal science because “fungi are everywhere”. It is an approach that she embraces: 

• One project looks at samples from patients and the environment and uses genomics to understand how patients acquire their infections from the environment.   
• Related to healthcare systems, her work has helped to implement infection control measures in hospitals (e.g. updating disinfectants) which have successfully prevented recent outbreaks of C. auris.  
• Looking to food security, Dr Rhodes noted: “Fortunately, there are ways to protect crops… one way is to set up a global surveillance network using genomics (part of the WHO strategy 2022-2032) so that the movements of pathogens can be tracked. We can also improve biosecurity in traded seeds and non-sterile goods to slow the spread of fungal infections."
• Referring to the agricultural industry, for the rise in drug-resistant Aspergillus, she believes the best way to combat this is to “stop using the same drug classes clinically and agriculturally…This would require a globally agreed policy where every country accepts this.” 
• And, looking to ocean science, one of her PhD students has recently partnered with Ocean Cleanup to sample ocean water to identify which drug-resistant fungi are present.