Understanding and mitigating the impact of emerging antifungal resistance
Is the widespread use of azole antifungal sprays in agricultural crops leading to environmental selection for resistance in Aspergillus fumigatus, thus resulting in decreased patient survival following infection?
A. fumigatus is a globally ubiquitous fungus, being present on decaying vegetation and in soils, where it performs a valuable role in nutrient recycling. The fungus is a minimal health threat to healthy individuals. However, patients who suffer from cystic fibrosis, cancer or who have received organ transplants and are undergoing corticosteroid therapy are at risk from ‘invasive aspergillosis’. Current estimates indicate that over 63,000 patients develop this fungal disease annually across Europe. The current method for controlling infections is by administering azole antifungal drugs, which are also used as fungicides to control crop diseases. However, we and others have shown a sharp increase in the resistance of A. fumigatus to frontline azole antifungals, with unacceptably high mortality rates in these at-risk patient groups. The mutations that confer resistance of A. fumigatus to these drugs appear to have evolved in the environment, rather than the patient.
We use genome sequencing and cutting-edge statistical genetic methods to determine when and where these mutations originated globally, use newly isolates samples to test whether they occur in the UK environment and in patient populations, whether they are spreading to invade new environments here and elsewhere, and whether novel undescribed resistance mutations exist.
We are directly measuring the risk that the use of antifungal compounds has on evolving resistance in non-target fungal species, and also are answering important questions on the distance that these airborne fungi are able to spread and share genes with one another. Our findings will not only be of high relevance to healthcare professionals, directly informing diagnostic protocols and disease management in intensive care settings, but will also inform current debates on the costs of widespread use of antimicrobial compounds in the environment. These goals all feed directly into NERC’s new strategic direction ‘The Business of the Environment’.
Principal Investigator: Professor Matthew C. Fisher, Imperial College London, School of Public Health
Co-Investigator: Dr. Darius Armstrong-James, Imperial College London, National Heart and Lung Institute
Co-Investigator: Professor Elaine Bignell, University of Exeter, Biosciences
Co-Investigator: Dr. Michael Bromley, University of Manchester, Institute of Infection, Inflammation and Repair
Co-Investigator: Professor Paul Dyer, University of Nottingham, Life Sciences
Co-investigator: Professor Paul Verweij, Radboud University Medical Centre, Medical Mycology
Funders: Wellcome Trust
The Global Diversity of Chytrids
A major consequence of the process of globalisation has been the increase of invasive non-native species owing to trade in live animals and plants. An extreme example of this process is a concomitant rise of new emerging infectious diseases (EIDs) as pathogens track human networks of trade to establish in uninfected regions - an example of 'pathogen pollution'. Whilst EIDs affect human populations, their impact has also been broadly detrimental to natural populations f plants and animals, leading to worldwide losses of biodiversity. This dynamic has been most apparent across the class Amphibian, where EIDs leading to population extirpation and species extinctions have contributed to amphibians now being the most endangered class of vertebrates. In particular, the emergence of the parasitic aquatic fungus Batrachochytrium dendrobatidis (Bd) has played a major role in driving amphibian species declines worldwide.
Whilst one lineage of chytrid was originally thought to have caused the ongoing panzootic, we now know that amphibian chytridiomycosis is caused by a much broader swathe of phylogenetic diversity than was originally thought. Through the use of next-generation sequencing and phylogenetic analysis, it is clear that Bd sense stricto is composed of at least six deep genetic lineages, of which five have been shown to be emerging through trade amphibian species. Superimposed upon this background of trade-associated lineages of Bd came the recent discovery of a new species of pathogen chytrid, Batrachochytrium salamandrivorans (B.sal). This pathogen has rapidly extirpated European fire salamanders in the Netherlands and a broad screening of over 5000 amphibians has shown that B.sal occurs naturally in south east Asia.
We are only just recognising the bread of phylogeographic diversity found within the amphibian-parasitising chytridiomycota. Amphibians are over 360 million years old, having diversified into over 7,000 species, and it is possible that their parasitism by aquatic chytrids is equally ancient. Therefore, the lineages of Batrachochytrium that we are describing likely reflect an ancient history of co-speciation that has resulted in a worldwide phylogeographic structuring of chytrids alongside their amphibian hosts - an ancient diversity that is being eroded as wild-collected amphibians vector their chytrid parasites worldwide within trade routes.
Characterising amphiban-chytrid biodiversity and their fitness in competitive interactions is necessary for three reasons:
1) Apart from Bd, and now B.sal, this order of parasites remains entirely unsurveyed and this lack of knowledge is unacceptable as biosecurity measures increasingly fail to stop the expansion of highly pathogenic lineages.
2) Discovering species of amphibian-infecting chytrids in regions where highly pathogenic lineages are still absent holds the key to determining what makes some chytrids lethal, whilst others are relatively avirulent.
3) Avirulent chytrids may have the potential to competitively exclude invasive lineages, offering an entirely new approach to protecting against disease emergence.
Principal Invstigator: Prof. M.C. Fisher, Imperial College London
Funders: NERC, The Leverhulme Trust, The Mohammed Bin Zayed Species Conservation Fund, The Morris Animal Foundation