Tackling emerging fungal threats to animal health, food security and ecosystem resilience

The Kingdom Fungi is a biodiverse and essential component of our habitable planet. However, the last 100 years have witnessed an increasing number of virulent emerging pathogenic fungi across ecosystems, with these infections causing the greatest disease-driven losses of biodiversity ever documented. Fungal life-history characteristics, namely high virulence, environmental persistence, broad host-ranges and flexible genomic architecture, predispose this kingdom to emergence as terminal pathogens across susceptible populations of hosts. Anthropogenic activity is a key factor that perturbs natural cycles of infection by increasing long-distance dispersal of inocula and through environmental forcing of infection dynamics. I demonstrate these concepts by analysing patterns and processes across the backdrop of globally-emerging amphibian-parasitising chytrid fungi. Genome sequencing defines ancient amphibian/chytrid associations that are being widely eroded as lineages of these fungi spread. Where divergent lineages of chytrids forge new contacts in nature, hybrids can form with potentially new epidemiologically-relevant traits, or outcompeted chytrids are themselves driven to extinction. Across newly infected regions where outbreaks are occurring, we see varied host population responses ranging from extirpation through to recovery that illustrate complex ecological-modifiers of the host/pathogen interaction. Long term field studies show that climate forces infection dynamics, with regional warming projected to heighten the severity of future outbreaks. These studies argue that ongoing 'fungal pollution' will increasingly cause the attrition of biodiversity unless steps are taken to tighten global biosecurity for this rapidly emerging class of pathogens.

Forest ecosystems are put under stress from adverse biotic and abiotic conditions. Over evolutionary time, host trees and pathogens are believed to enter a terror balance when occurring in proximity to each other. However, this balance is upset by introductions of potential pathogens from distant continents. The history of forest pathology is full of such introductions causing devastating outbreaks of disease. Predictions of unbalanced outcomes of host-pathogen interaction would be helped by classifying pathosystems based on the co-evolutionary history, but this is not always straightforward.  Genetic evidence such as signs of recent population expansions or genetic bottleneck effects, or patterns of ecological adaptation as well as tracing trade routes can help to elucidate disease history. Environmental factors can strongly influence tree disease. It is predicted that biotrophic, necrotrophic and vascular wilt pathogens, respectively, will create different patterns of host response to environmental stress. This is mediated by differential pathways of the various pathogens to interact with fundamental processes in the tree. Key components are the levels and distribution of non structural carbon hydrates allowing for above and below ground growth, reproduction, repair and defence. Environmental stresses, that are likely to increase in the light of climate change, can set novel limits to energy budgets for trees and climatic changes can open up new windows of opportunity for infection. Both these aspects can lead to emerging disease syndromes.  Also, multiple infections over time and space can act synergistically to create new challenges to forest ecosystems.

Emerging infectious diseases pose a key threat to wildlife populations. White-nose syndrome is an emerging fungal disease caused by the pathogen Pseudogymnoascus destructans. The disease has caused widespread declines in bat populations across eastern North America, and several species appear to be at risk of extinction. For white-nose syndrome, and other emerging fungal wildlife diseases, determining which species will persist and which will go extinct is critical for targeting disease management efforts. We find that mortality from white-nose syndrome appears to be driven primarily by infection intensity, with infection prevalence approaching 75% or greater across 6 bat species, and the highest loads in the most impacted species. We also find that some populations in regions where the disease has been present the longest have lower fungal loads, suggesting that some hosts may be developing mechanisms to persist with infection. In contrast, one species has been nearly extirpated from eastern North America, experiences uniformly high fungal loads, suggesting extinction may be imminent. These results provide key information needed to mitigate the causes and consequences of this devastating disease.

In 2008, a disease affecting wild snake populations was reported from isolated locations in the Northeastern and Midwestern United States. The disease was characterised by grossly visible skin lesions and disfiguration of the head. Microscopically, fungal hyphae could be seen invading the skin, and the syndrome became known as snake fungal disease (SFD). In both geographic areas, infections were associated with the novel species of fungus, Ophidiomyces ophiodiicola, and follow-up laboratory studies demonstrated this fungus to be a primary pathogen and the cause of SFD. By 2015, SFD had been reported in most of the eastern half of the United States and was known to have a broad host range, affecting nearly all groups of snakes native to North America. Re-evaluation of retrospective cases of snakes with skin infections revealed that O. ophiodiicola had a nearly worldwide distribution in captive snakes prior to the disease being observed in wild snakes. This finding spurred concerns that O. ophiodiicola was an exotic pathogen introduced to North America through spillover from the pet trade. However, the spatial and temporal distribution of SFD cases does not indicate a pattern of spread suggestive of an introduced pathogen. Thus, unlike other emerging fungal diseases of wildlife such as white-nose syndrome of bats and chytridiomycosis of amphibians, mechanisms driving emergence of SFD remain unclear. Future work aimed at understanding the dynamics of SFD will be essential in protecting imperiled snake populations from this devastating disease.

Over the past centuries, crop diseases have led to the starvation of the people, the ruination of economies and the downfall of governments. Of the various challenges, the threat to plants of fungal infection outstrips that posed by bacterial and viral diseases combined. Indeed, fungal diseases have been increasing in severity and scale since the mid-20th Century and now pose a serious threat to global food security and ecosystem health.

We face a future blighted by known adversaries, by new variants of old foes and by new diseases. Modern agricultural intensification practices have heightened the challenge - the planting of vast swathes of genetically uniform crops, guarded by one or two inbred resistance genes, and use of single target site antifungals has hastened emergence of new virulent and fungicide-resistant strains. Climate change compounds the saga as we see altered disease demographics - pathogens are on the move poleward in a warming world.

This presentation will highlight some current notable and persistent fungal diseases. It will consider the evolutionary drivers underpinning emergence of new diseases and allude to the accelerators of spread. I will set these points in the context of recent disease modelling, which shows the global distributions of crop pathogens and their predicted movement and will discuss the concept of crop disease saturation.  I shall conclude with some thoughts on future threats and challenges, on fungal disease mitigation and of ways of enhancing global food security.

Many species of fungi and oomycetes are plant pathogens of great economic importance. The genomes of these filamentous plant pathogens have revealed a remarkable diversity in genome size and architecture. Whereas the genomes of many parasites and bacterial symbionts have been reduced over time, the genomes of several lineages of filamentous plant pathogens have been shaped by repeat-driven expansions. In these lineages, the genes encoding proteins involved in host interactions are frequently polymorphic and reside within repeat-rich regions of the genome. This talk will review the properties of these adaptable genome regions and the mechanisms underlying their plasticity. I will also provide an update on our work on genome evolution in the lineage of the Irish potato famine organism Phytophthora infestans. Many plant pathogen species, including those in the P. infestans lineage, have evolved by host jumps followed by adaptation and specialization on distinct plant species. However, the extent to which host jumps and host specialization impact genome evolution remains largely unknown. The genomes of representative strains of four sister species of P. infestans revealed extremely uneven evolutionary rates across different parts of these pathogen genomes - a two-speed genome architecture. Genes in low density and repeat-rich regions show markedly higher rates of copy number variation, presence/absence polymorphisms, and positive selection. These loci are also highly enriched in genes induced in planta, such as disease effectors, implicating host adaptation in genome evolution. These results demonstrate that highly dynamic genome compartments enriched in non-coding sequences underpin rapid gene evolution following host jumps.

Aspergillus fumigatus, a ubiquitously distributed opportunistic pathogen, is the global leading cause of aspergillosis. Azole antifungals play an important role in the management of aspergillosis. However in the last decade azole resistance in A. fumigatus isolates has been increasingly reported, especially in Europe, and this is potentially complicating effective disease management. The higher mortality rates observed in patients with invasive aspergillosis caused by azole resistant A. fumigatus isolates pose serious challenges to the mycologist for timely identification of resistance and appropriate therapeutic interventions. The ‘TR34/L98H’ mutation in the cyp51A gene of A. fumigatus is responsible for most multi-azole resistance seen in European countries, the Middle East, China, Australia and India. Azole-resistant isolates carrying this mutation have been reported from both patients and the environment. In addition, a newly emerging resistance mechanism, TR46/Y121F/T289A, conferring high voriconazole and variable itraconazole MICs was lately described in several European countries, Asia and the American continent. Environmental screening and routine antifungal susceptibility testing of clinically significant isolates should be considered in order to develop guidelines for local and national purposes. Considering that azole antifungal drugs are the mainstay of (oral) therapy, especially for chronic invasive and allergic aspergillosis, emergence of resistance will have profound impact on healthcare. This presentation highlights the global development of azole resistance in A. fumigatus and the possible relation with environmental fungicide use.

Candida albicans, the most prevalent human fungal pathogen, is generally diploid but other ploidy states clearly arise and are found not only in the laboratory but also in clinical isolates.  A major question motivating our work is how ploidy state and ploidy shifts affect pathogen evolution and survival, especially in responses to extreme stresses, such as exposure to antifungal drugs within the host. We are particularly interested in how rapidly different drug responses can be recruited to assist in stress survival. An important clue comes from the observation that 50% of isolates that are resistant to fluconazole (FLC), the most widely used antifungal, are aneuploid and that some specific aneuploidies can confer FLC resistance. Is aneuploidy the cause of resistance or does exposure to antifungals promote the appearance of aneuploidy? Our work indicates that the answer is yes: aneuploidy can be both a cause of drug resistance and a consequence of drug exposure. Furthermore, drug exposure elicits changes in cell cycle progression that lead to whole ploidy shifts. Survival in drug can be due to drug resistance, tolerance, persistence or heteroresistance. We are interested in the degree to which each of these strategies is used as well as the molecular mechanisms used to achieve these different strategies.