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Chytrid fungi and global amphibian declines

Abstract

Discovering that chytrid fungi cause chytridiomycosis in amphibians represented a paradigm shift in our understanding of how emerging infectious diseases contribute to global patterns of biodiversity loss. In this Review we describe how the use of multidisciplinary biological approaches has been essential to pinpointing the origins of amphibian-parasitizing chytrid fungi, including Batrachochytrium dendrobatidis and Batrachochytrium salamandrivorans, as well as to timing their emergence, tracking their cycles of expansion and identifying the core mechanisms that underpin their pathogenicity. We discuss the development of the experimental methods and bioinformatics toolkits that have provided a fuller understanding of batrachochytrid biology and informed policy and control measures.

Introduction

The reasons why modern-day amphibians are suffering rates of extinction that far exceed those of any other class of vertebrates long mystified conservation biologists. The discovery of the disease chytridiomycosis and its aetiological agents, chytrid fungi in the genus Batrachochytrium, provided the link between emerging infections and global amphibian declines. Historically underappreciated and infrequently studied, these ancient, aquatic flagellate fungi have earned notoriety as the leading infectious disease threat to biodiversity. Following the concurrent detection of chytridiomycosis in Central America and Australia in the late 1990s1 and identification of the cause2, Batrachochytrium dendrobatidis (Bd) has been found to infect species across all continents where suitable hosts occur3,4. Although the genus Batrachochytrium was initially thought to contain only one species, the local extinction of fire salamanders in the Netherlands by chytridiomycosis in 2010 led to the discovery of another pathogenic species in the genus, Batrachochytrium salamandrivorans sp. nov. (Bsal)5. Both pathogens (here called ‘batrachochytrids’ for brevity) infect the skin of amphibians. This leads to ulceration due to infection of epidermal cells by Bsal, whereas Bd moves on to infect and develop in subcutaneous epidermal cells. Because amphibians need to osmoregulate and respire through their water-permeable skin, skin disruption impairs its essential homeostatic functions and leads to the death of heavily infected individuals.

Despite more than 1,000 studies having been published since the discovery of Bd, the original questions regarding the extent of this panzootic are still relevant today: where did these pathogenic chytrids come from, when did they emerge, how do they cause disease in amphibians, and what can we do to reduce their impact? In this Review, we describe how the adoption of new techniques and methods from across biology and informatics has recently led to a radical change in our understanding of batrachochytrids and chytridiomycosis. We explain how, to achieve these advances, a multidisciplinary scientific community built global networks for sharing data, combined field research with modern biological techniques to dissect complex biological systems and improved the integration of the resulting epidemiological data into policy and law, with the aim of limiting the further spread of these pathogens.

Mapping the chytrid panzootic

By their very definition, panzootics are a global problem and cannot be tackled by individual people or specialities. The realization that similar patterns of amphibian declines were occurring on several continents at the same time was a wake-up call and has highlighted that an interdisciplinary scientific approach is needed to understand and respond to novel conservation threats. In isolation, herpetologists had recorded rapid and persistent amphibian declines as early as the 1970s; however, these declines were only recognized as a global phenomenon at the landmark first World Congress of Herpetology, held in Canterbury in 1989, and only quantified more than a decade after the Canterbury meeting6. Many declines were initially classified as ‘enigmatic’, occurring in pristine habitats largely untouched by habitat destruction. These observations spurred a search for the underlying cause, which ultimately led to the discovery and description of Bd and the illumination its lifecycle through a multidisciplinary collaboration1,2,7.

The development of a non-invasive, robust and probe-based quantitative molecular diagnostic for Bd8 enabled several regional surveillance efforts that eventually were compiled in an online database, the Global Bd Mapping Project. This web-based system for collating Bd incidence and the associated metadata is an early example of a web-accessible database with application programming interfaces (APIs) for data storage, data uploading, summary statistics and visualization of spatial data using Google Maps. The Global Bd Mapping Project is being integrated into the core AmphibiaWeb site, where data compilation will continue in the foreseeable future. Global mapping provided the first overview of the panzootic: as of May 2019, Bd had been found to infect 1,015 of 1,854 species (54%) and to be present at 3,705 of 9,503 field sites (39%) (personal communication by D. H. Olson and K. Ronnenberg, US Forest Service). In 2014, Bd infected 50% of tested frog species (order Anura), 55% of salamander and newt species (clade Caudata) and 29% of caecilian species (Gymnophiona)9, testifying to an extraordinary and heretofore unmatched pathogen host range. By comparison, the host range of Bsal is restricted largely to Caudata, with only transient infection of anurans reported10. Global surveillance and molecular diagnostics enabled rapid outbreak analysis of Bsal in the year of its discovery and in doing so identified an Asian origin of the European Bsal outbreak11,12. As with Bd, the surveillance of Bsal is being managed and coordinated using online databases and informatic tools (the North American Bsal Task Force and Amphibian Disease Portal).

Reconstructing the impact of the emergence of the batrachochytrids on amphibian biodiversity has proved a complex task. This difficulty owes to declines that occurred years before the identification of Bd, frequently in remote areas where amphibian surveillance efforts have been haphazard at best. Nevertheless, a meta-analysis4 synthesized data from multiple sources, including peer-reviewed studies, the International Union for Conservation of Nature (IUCN) Red List of Threatened Species and consultations with scientists investigating the declines, both as the events occurred (for example, see13) and retrospectively (for example, see14,15). This meta-analysis revealed that chytridiomycosis has contributed to the decline of at least 501 species (6.5% of all amphibian species), leading to 90 presumed extinctions and decreases in abundance exceeding 90% in another 124 species. At the time of writing, this represents the greatest documented loss of biodiversity attributable to a nonhuman species. Truly, Bd has earned its nom de guerre as the ‘doomsday fungus’16.

Alongside the collation of epidemiological data, a worldwide effort to collect and archive isolates of Bd for molecular and phenotypic analyses was initiated by the European Union Project RACE (Risk Assessment of Chytridiomycosis to European Amphibian Diversity). This project focused on modifying the original protocols for isolating Bd, developed by Joyce Longcore2, and the methods for cryopreservation17. RACE developed a largely non-destructive procedure for isolating chytrids from amphibians that for a decade was successfully used by a broad collective of researchers working across 5 continents, 23 countries and 62 amphibian species. As a result, Bd was isolated from all three orders of Amphibia and from all continents on which infection occurs18. This project integrated online databases and digital mapping so as to store project-related data in a way that enabled access from study sites using the GPS smartphone-enabled epidemiological software EpiCollect19. With these web tools and smartphone-based technology, research groups working on the batrachochytrids were able to communicate and share data on a scale that had never before been used to track wildlife diseases, which has been essential for subsequent tracing of the evolutionary history of these pathogens.

Origin and emergence

Chytrids ‘out of Asia’

The debate on how chytridiomycosis emerged as a cause of amphibian declines has revolved around two competing arguments. The ‘novel pathogen hypothesis’ (NPH) stated that chytridiomycosis emerged locally after it had been seeded by intercontinental trade routes into naive ecosystems. The counterargument, known as the ‘endemic pathogen hypothesis’ (EPH), held that Bd was a widespread endemic commensal of amphibians that had become more virulent owing to global change forcing imbalanced infection dynamics20. Early molecular clues from multilocus sequence typing supported the NPH, as the isolates of Bd sampled at the time showed no signs of phylogeographic structure among the different regions with amphibian declines owing to chytridiomycosis21,22. This molecular evidence matched the observed patterns of chytridiomycosis observed in the Americas1, Australia20 and the Caribbean islands23 (Fig. 1). Later, sequencing of two complete genomes by the Joint Genome Institute (isolate JAM81 from Rana muscosa in California) and the Broad Institute (isolate JEL423 from Phyllomedusa lemur in Panama) in 2008 (ref.24), along with the development of high-throughput shotgun sequencing, enabled a genome-scale genetic analysis of Bd. Early ABI SOLiD genome resequencing of 20 globally distributed isolates from sites experiencing chytridiomycosis uncovered striking patterns in comparison with sites without the disease. Resequencing identified three deeply diverged lineages: BdGPL (globally distributed), BdCAPE (named owing to its discovery in the Cape region of South Africa) and BdCH (a single, deeply branched isolate from Gamlikon in Switzerland25). Only BdGPL was found across four continents and was associated with epizootics in North America, Central America, the Caribbean, Australia and Europe. The extraordinary global range, limited genomic diversity and relatively high virulence of this lineage, as well as its origin in the early 20th century, based on the phylogeny of BdGPL, supported the NPH over the EPH25. Heterozygous and triallelic single-nucleotide polymorphisms were threefold to fourfold more common than homozygous ones in BdGPL, which was held as evidence that the genesis of BdGPL was the result of a sexual ‘hybridization’ between two dissimilar parental genotypes26.

Fig. 1: Global distribution of Batrachochytrium.
figure1

As of 2019, Batrachochytrium dendrobatidis (Bd) had invaded and caused chytridiomycosis in six regions globally: eastern Australia, the Mesoamerican peninsula, South America, the western United States, Africa and Europe. Five lineages of Bd, as well as recombinants, have been identified. In addition, another species, Batrachochytrium salamandrivorans (Bsal), was discovered in 2010. Batrachochytrids cause severe amphibian declines. The figure shows declines that match the Scheele et al.4 criteria for category 3 or above: 3, extreme decline with >90% of individuals lost; 4, presumed extinct in the wild (no known extant populations, and no individuals detected at known historical locations, but some reasonable doubt that the last individual has died); 5, confirmed extinct in the wild (as per International Union for Conservation of Nature [IUCN] listing). Adapted from ref.65, courtesy of P. Ghosh, Imperial College London, UK.

Subsequent analysis of a larger panel of isolates cast doubt on the findings of this earlier study25, suggesting both greater genetic diversity and an estimated origin of BdGPL 10,000–40,000 years before the present27. The authors interpreted these results as supporting the EPH rather than the NPH. Neither study could resolve the geographic origin of Bd, which was variously proposed to be African28, Japanese29, East Asian30, South American31 or North American32.

O’Hanlon et al.33 resolved much of the debate by publishing new sequence data for 177 Bd isolates collected using the RACE protocols18. The complete dataset of 234 isolates had been collected over nearly two decades and spanned the geographical distribution of Bd, numerous events of lethal chytridiomycosis and all three extant orders of Amphibia. This analysis redefined the evolutionary relationships among the lineages of Bd, aided by the first genome data from Asian isolates. Bd from the Korean peninsula comprised a new, fourth lineage, BdASIA-1, and this lineage showed signs of an ancestral relationship with the other lineages. Bayesian-based haplotype clustering revealed that the hyperdiverse BdASIA-1 lineage shared more diversity with the global population of Bd than did any other lineage and branched at the base of the Bsal-rooted Bd phylogeny. Tellingly, BdASIA-1 was the only lineage in mutation–drift equilibrium, a characteristic of endemism. All other lineages showed pronounced departures from equilibrium values of Tajima’s D statistic34, which are indicative of outbreak dynamics. Molecular screening of museum specimens of amphibians from Korea showed that infection has been present in the region for over 100 years35, and contemporary surveillance has demonstrated a widespread yet patchy and rare distribution of batrachochytrids throughout East Asia12,36,37, further suggesting endemism of Bd in this region. Multilocus genotyping confirmed the results of O’Hanlon et al.33 and discovered a novel fifth lineage, BdASIA-3, also found in East Asia (the Philippines, Indonesia and China)38. This ‘chytrid-out-of-Asia’ hypothesis supporting the NPH was strengthened by the finding that, following discovery of chytridiomycosis caused by Bsal in Europe, this chytrid could only be detected elsewhere in Southeast Asia (Vietnam)12. The comprehensive lack of lethal outbreaks or population declines caused by chytridiomycosis in Asia, despite the widespread occurrence of Bd and Bsal4,11, is evidence for endemic host–pathogen interactions39. Batrachochytrids appear to have been infecting amphibians in the region for over 50 million years, leaving ample time for fungal speciation events and relatively stable host–pathogen dynamics to establish11. Accordingly, there is a need for more intensive pathogen discovery across Southeast Asia, as unmapped batrachochytrid diversity will likely yield further insights into the past emergence and present distribution of these pathogens.

Timing the panzootic

Final proof of the NPH required congruency between the timing of introductions of Bd and the onset of declines caused by chytridiomycosis. Chytridiomycosis declines peaked globally in the 1980s4, in keeping with the timing of regional wave-like dynamics suggesting epizootic spread from point sources40,41. To time introductions, O’Hanlon et al.33 used two quasi-independent genomic regions to generate time-calibrated phylogenies, as well as a Bayesian framework to estimate the time to their most recent common ancestor (TMRCA, Box 1). These analyses estimated a substitution rate for Bd, one that was broadly similar to that estimated for other unicellular fungi. The updated TMRCA for the ancestor of BdGPL ranged between 120 and 50 years ago (1890s–1960s), which broadly agrees with the first inferred chytridiomycosis-related declines in regions that are currently dominated by BdGPL (Australia20,42, the Mesoamerican peninsula13 and South America14,40). Molecular dating also suggests that the widespread, and still largely unattributed, amphibian declines reported in Europe and North America in the 1950s and 1960s were driven by BdGPL, which has now achieved widespread endemicity across these regions6,43.

What has fuelled the global expansion of Bd? That all known lineages of Bd are circulating in globally traded amphibians proves that trade is disseminating amphibian vectors of batrachochytrids worldwide44 today33 (Fig. 2). For example, ‘African’ BdCAPE invaded the island of Mallorca through the reintroduction of captive-reared Mallorcan midwife toads infected in captivity by African endemic amphibians (Xenopus gilli)45. More widely, infection-tolerant species such as the African clawed frogs Xenopus laevis28 and the North American bullfrogs Rana catesbeiana44 are internationally traded in their millions and have been since the early 20th century. Other infection-tolerant species, such as the cane toad Rhinella marinus, have established feral populations from their origins in South and Central America. It is likely that these species had an important role in amplifying the worldwide emergence of Bd, and indeed, molecular methods have identified transcontinental links involving these species46. The evidence therefore suggests that the original out-of-Asia vectors of batrachochytrids were likely amphibians exported for food, research or collections, or perhaps were passively hiding in traded goods. However, identifying these original panzootic ‘sparks’ will likely prove a challenging task.

Fig. 2: Global spread of Batrachochytrium dendrobatidis and the amphibian trade.
figure2

Intercontinental movements of Batrachochytrium dendrobatidis (Bd) have been inferred from the genome sequences of geographically separated isolates that form closely related phylogenetic clades, with high bootstrap support (≥90%; data from ref.33). Numbers show where isolates of Bd have been recovered from traded amphibians, with pictures of the species involved shown at the bottom of the figure. Also shown are the movements of traded, CITES-listed amphibians, showing the global connectivity of the amphibian trade, which involved over 15 million specimens during the period 2000–2010. Data are from TRAFFIC (a global network that monitors wildlife trade), CITES and refs131,132.

Cycles and circles of expansion

The occurrence of the divergent BdCAPE variant in Africa, Central America and Europe33,38; BdASIA-2/BRAZIL in the Brazilian Atlantic forests31 and Korea33; and the ASIA-1-like BdCH in Switzerland show that the evolutionary history of Bd is complex and has been characterized by at least three out-of-Asia emergences of lineages other than BdGPL. With too few isolates to allow for confidently deriving measurable evolutionary rates, the TMRCAs for these lineages have thus far not been estimated. Notwithstanding this fact, levels of diversity exceed those seen in BdGPL, suggesting that their out-of-Asia dispersal predates that of BdGPL33. The detection of molecular signatures of Bd in Brazilian museum collections of amphibians indicates that Brazil was invaded by Bd as far back as 1894 (ref.31). While molecular confirmation is needed, it appears that the early invasion was by BdASIA-2/BRAZIL, followed by a secondary introduction of BdGPL into Brazil in the 1970s. The result was a peak of declines in the 1970s, owing to the higher virulence of this lineage14 and the founding of a region of contact between the two lineages in the Brazilian Atlantic forest47,48,49. To complicate matters further, BdASIA-2/BRAZIL is itself found in Korean populations of introduced North American bullfrogs, suggesting that these widely traded frogs have been vectors for this lineage, re-establishing it in its ancestral Asian homeland33.

Surveillance across Africa shows that this continent also has a complex history of Bd introductions50. The pathogen is widely present, occurring in Cameroon from at least 1933, Kenya in 1934, Uganda in 1935, South Africa in 1938, the Democratic Republic of Congo in 1950 and the island Bioko in 1966 (refs28,51,52,53,54). The infection status of the amphibians of Madagascar remains unclear18,55,56. The extent to which Africa has suffered amphibian declines as a consequence of chytridiomycosis is largely undetermined. However, at least one extinction in the wild has occurred (the Tanzanian Kihansi spray toad, Nectophrynoides asperginis15), and the presence of Bd has been correlated with declines of amphibian species in Cameroon57 and South Africa58. Genome sequencing33 and multilocus genotyping38 have shown the widespread occurrence of both BdCAPE and BdGPL, the former widely distributed in Cameroon, including in caecilians59, and the latter occurring in both Ethiopia and Uganda. Both lineages occur in Southern Africa, where, as in Brazil, different lineages are in spatial contact. The patchy distribution of BdCAPE in Central America and Europe suggests that secondary waves of expansion for this lineage have occurred.

Recombinants, not hybrids

Genotyping has identified recombinants of BdASIA-2/BRAZIL and BdGPL in the Brazilian Atlantic forest48, as well as genetic mosaics of BdCAPE and BdGPL in South Africa33. Within lineages, alleles segregate47,60, intrachromosomal recombination breakpoints have been detected25, and when single-nucleotide polymorphisms have been phased, crossovers have been observed in all lineages tested26. Clearly the extreme genetic bottlenecks that characterize the out-of-Asia evolutionary history of Bd have not impaired the ability of this species to recombine. Whereas chytrids such as Allomyces and Rhizophydium undergo meiosis, recombinant mating structures have not been described for Bd or Bsal, nor have canonical fungal mating-type alleles been identified, suggesting that recombination in batrachochytrids may not be meiotic. In support of this idea, some ‘meiotic toolbox’ genes defined in yeast are missing in the genome of Bd, and signatures of sex-associated, repeat-induced point mutations in transposable elements are also absent61. Furthermore, widespread chromosomal copy number variation26 is also evidence that recombination may not be due to meiosis. Accordingly, it has been proposed25,62 that non-meiotic recombination (called ‘parasexual’ recombination) may be generating the polyploid heterozygous mosaics that characterize Bd. However, the cell biology that underpins the widespread recombination in Bd, either meiotic or non-meiotic, remains wholly unexplored.

The description of the global Bd population as stemming from a genetically diverse Asian population in mutation–drift equilibrium and recombining when the opportunity arises shows that the global Bd population is currently behaving as a cohesive biological species. Prior to the discovery of this Asian origin, interlineage recombination events were termed ‘hybridizations’, and BdGPL was suggested to result from a hybridization event among two related chytrid species25. However, the simplest description of the global population genetic structure of Bd is that each lineage represents a separate genealogical ‘draw’ from a recombining parental population that is most likely Asian. As multiple founding events do not appear to have appreciably blunted the ability of Bd to shuffle its genome if given the opportunity, it is premature to give these lineages species status and to name recombinants ‘hybrids’. Accordingly, the most biologically accurate description of the genomic mosaics that are increasingly being described is ‘recombinants’.

The finding that Bd is a recombining species is not only academically interesting; the process of recombination through secondary contact is likely important in an epidemiological context. Outcrossing can purge deleterious alleles and generate variation that may facilitate host exploitation, exacerbating epizootics. Theory and experimentation have shown that interactions between diverse genotypes can lead to competitive interactions that result in increased transmission and may exacerbate infection dynamics63,64. Co-infections of Bd lineages have been observed in South Africa where BdGPL and BdCAPE co-occur65, and in the absence of a defined environmental developmental stage, co-infection is when recombination events will occur. That recombination can affect the virulence of Bd was demonstrated in a study49 that showed that BdGPL and BdASIA-2/BRAZIL recombinant genotypes were more aggressive than either of the parent genotypes in two amphibian species. This result suggests that outcrossing in Bd results in genetic dominance and enhanced fitness. Whereas these hybrids were inferred to be F1, an F2 backcross in Brazil has been observed, suggesting that recombinants can survive beyond their immediate F1 genesis48.

Batrachochytrid virulence

Infection of amphibians by Bd and Bsal is a remarkably complex process that can have markedly different outcomes, ranging from mild or no symptoms to death (Fig. 3). Here we discuss the genetic factors that underpin the expression of the batrachochytrids’ intrinsic ability to infect the amphibian dermis, as well as the biotic and abiotic factors that modify the outcome of these host–pathogen interactions.

Fig. 3: Factors influencing the virulence of batrachochytrids.
figure3

The host response to batrachochytrid ranges from resistance to lethal infection. Several factors have been identified that contribute to this variability. For one, pathogen lineages vary in their genetic repertoires of proved and suspected virulence factors, including proteases, carbohydrate-binding modules, Crinkler-like proteins and other secreted proteins, such as tribes of expanded gene families. The genomic potential for virulence is influenced by the genome plasticity of batrachochytrids, which has contributed to the expansion and radiation of gene families with potential roles in pathogenicity. Host susceptibility also varies greatly, depending on the host immune responses, prior exposure to chytrids and/or other pathogens, the host microbiota and the host life history (for example, developmental stage). Amphibian larva, as well as other alternative hosts such as crayfish, can function as pathogen reservoirs. Finally, abiotic, environmental variables, such as climate, a water system’s properties, pesticides, fertilizers and other factors, also influence the outcome of batrachochytrid exposure.

Genetic factors

The identification of significant variation in virulence both within and among lineages has raised more questions than have been answered. We and others have shed some light on which intrinsic genetic factors underpin virulence in batrachochytrids (Fig. 4).

Fig. 4: Pathogenic potential of batrachochytrids.
figure4

a | Genome alignments have shown gene family expansions that discriminate pathogenic batrachochytrids (Batrachochytrium dendrobatidis (Bd) and Batrachochytrium salamandrivorans (Bsal)) from non-pathogenic chytrids (Homolaphlyctis polyrhiza (Hp) and Spizellomyces punctatus (Sp)). b | For example, the M36 metalloproteinases, a gene family involved in infection, have been amplified in the genomes of pathogenic batrachochytrid lineages and especially in the genome of Bsal. c | Bd growing on explanted amphibian skin secretes proteases, which cause extensive skin digestion (far right), whereas the non-pathogenic Hp (middle) leaves the skin intact. d | Bd but not Bsal zoospores show high concentrations of proteases prior to infection, suggesting that the proteases have a role in the initial establishment of infection for Bd but not for Bsal. Parts a, b and d are adapted from ref.66, CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/), and part c is adapted from ref.24, CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/).

Comparisons with the genomes of free-living saprobic chytrids have shown greater secreted protein repertoires and extensive gene family radiations in the pathogenic batrachochytrids66,67. Metalloproteinases in the M36 metalloproteinase fungalysin family are important pathogenicity determinants in a number of skin-infecting fungi and are strikingly expanded in both Bsal and Bd, with 110 and 35 of these proteases, respectively, compared with the free-living saprobic chytrids Spizellomyces punctatus and Homolaphlyctis polyrhiza, which have 2 and 3, respectively24,66. That the M36 metalloproteinases are highly expressed in vivo and in vitro is in line with their role as virulence factors; however, differences in the numbers of copies and the timing of their expression between Bsal and Bd suggest different roles in pathogenicity66. Carbohydrate-binding modules (CBMs) are markedly expanded in both batrachochytrids compared with free-living Chytridiomycota and may be important in host recognition and adhesion66,68. The pronounced divergence present in other gene families could explain the substantial variation in the host range and epidemiology of Bd and Bsal. Bd’s significantly smaller genome (23.7 Mb, versus 32.6 Mb for Bsal) contains regions of low gene density characterized by a proliferation of Crinkler-and-necrosis (CRN)-like genes, which are expressed during the early stages of infection, whereas the Bsal genome contains two expanded secreted tribes of genes of unknown function, which are highly expressed during infection. Clearly, although mining the genomes of the batrachochytrids has identified features linked to infection, further exploration will be needed in order to understand the role of these diverse expanded gene families in infection. The development of new models of infection will likewise be needed in order to increase our understanding of batrachochytrid biology. Recent advances, such as amphibian cell culture, skin-explant models69 and in vivo zebrafish Bd infection models70, are exciting developments.

The observation that different genotypes and lineages show some variation in plastic morphological traits such as the number and size of infectious zoospores suggests that virulence traits may to some extent be governed by simple parameters such as growth rate and fecundity71,72. Genetic factors that modify growth rate and investment in zoospores may be found in the large number of genes that are upregulated during infection. Additionally, secreted putative virulence factors affect host colonization rates, the first step in the pathogen life cycle. Despite its prevalence in recent evolutionary history, the virulence of BdGPL genotypes is highly variable under controlled experimental settings, and virulence to a large extent is determined by how rapidly Bd establishes an infection25,33. Moreover, within the laboratory, passaged isolates show high evolvability26, attenuation73,74 and phenotypic variation75. As we described above, the genome architecture is highly plastic across short timescales, involving large-scale rearrangements that should affect traits that are involved in host damage26,76. The plasticity in virulence observed in BdGPL seems to be mirrored in other lineages, with substantial lethality being observed in experimental exposures (for example, see39,49). Although less is known about variation in the virulence of Bsal, owing to all isolates currently stemming from a single epizootic clone, the discovery of an environmentally persistent encysted zoospore suggests that this species also may manifest phenotypically plastic life history traits that affect virulence10.

Abiotic factors

Batrachochytrids may carry a diverse and variable array of genetic traits that influence virulence, but the global emergence of chytridiomycosis is a radically novel epidemiological event, affecting hundreds of host species near simultaneously and interacting intimately with the diverse environments they occupy (Fig. 3). Despite the overwhelming evidence that batrachochytrids are invasive outside of East Asia, once the fungus is established, environmental factors play an important role in disease outcomes, and infection dynamics may map more closely with the predictions of the EPH. Indeed, a number of ecological factors have been identified as important determinants of disease outcomes, such as climate and altitude77,78, seasonality79,80,81,82, ultraviolet exposure83,84 and agrochemicals85. Combining field observations with experiments has illustrated the processes through which the environment affects infection and disease. These processes include the importance of reservoirs of transmission86,87, how the environment affects the survival and abundance of infectious zoospores81,88,89,90 and how increasing zoospore density drives host mortality through increasing burdens of infection91,92. Trophic interactions can also affect the density of the infectious zoosporic stages in the environment10,93. We advise caution here: laboratory measurements of virulence that disregard the ecological variation identified in field studies can have limited predictive utility. For instance, repeated experimental observations that the virulence of BdGPL exceeds that of BdCAPE25,33 do not explain why the two lineages are equally likely to be associated with chytridiomycosis and amphibian declines in nature33. Even the endemic Korean BdASIA-1 has been shown to be virulent in non-Korean amphibians39, showing that its long co-evolutionary history has not blunted this lineage’s virulence.

Extrapolating environmentally driven processes to global change has been predominantly a macro-ecological exercise94, and changing climates have been shown to force patterns of chytridiomycosis. For instance, although early analyses suggesting that climate change drove patterns of chytridiomycosis in Costa Rica95 were only weakly supported statistically94, associations between El Niño events and chytridiomycosis have been demonstrated96. Increasingly, studies are attempting to incorporate environmental factors into epidemiological models that attempt to predict the outcome of infection at the population level, with a focus on single, highly susceptible host species such as midwife toads37,80,97. In these studies, host species that were infected during seasonal ‘outlier’ events experienced mass mortality events that did not occur after colder, longer winters, including a species previously predicted by a macro-ecological analysis to be at low risk of disease98. In a less disconcerting finding, a 16-year time series99 disentangled the impacts of Bd and climate warming on nine montane species in Iberia. Surprisingly, only a small subset of the host community appeared to be affected by chytridiomycosis, and regional warming promoted range expansions of some species into the region where disease had decimated one host species decades previously; only a single species showed reasonably tight links between temperature fluctuations and infection dynamics99.

Biotic factors

Host responses to chytridiomycosis vary on different levels, ranging from individual to population and host community structure (Fig. 3). At the individual level, evidence exists for both resistance and tolerance strategies that may involve adaptive and innate immune responses100. Bd can evade lymphocyte responses as part of adaptive immunity101, but evidence exists that hosts can to some degree improve repressed immune responses over time102. Whether or not chytridiomycosis has exerted selective pressure on these and other components of adaptive immunity is uncertain, but at least for some host species evidence supports this scenario or, alternatively, the pre-existence of host genetic variation that preceded the emergence of the global panzootic and facilitated tolerance to infection when the initial outbreak occurred103. Equally, or possibly even more, important is the innate arm of the amphibian immune response, which has been predominantly explored through investigations of secreted antimicrobial peptides (AMPs)100. An example of the importance of AMPs is the threatened European salamander genus Speleomantes, all species of which secrete skin peptides that decrease zoospore survival and thereby prevent infection104. As with adaptive immunity, the innate immunity afforded by AMPs is influenced by exposure to batrachochytrids. Adaptation of AMPs appears to be the primary driver behind the recovery of some anurans that had experienced catastrophic declines owing to the emergence of chytridiomycosis in Central America105. For most amphibians, adaptive and innate immunity vary substantially across host life history stages and age classes, and as a result, so does host susceptibility to infection and disease. This means that, within a single population, one species can simultaneously be an infection-tolerant, often larval, reservoir while being at risk of decline owing to chytridiomycosis in its mature stages84,86.

A particularly topical vein of research is exploring how transkingdom interactions between commensal fungi and bacteria of the amphibian skin microbiota may limit batrachochytrid infections93,106,107,108,109. An extension of this question is to understand how pathogen competition can alter batrachochytrid infection dynamics and virulence. Although they are at very early stages, experiments have illustrated how intraspecific competition among Bd lineages may in part be responsible for the emergence of the global pandemic lineage BdGPL110, and co-infections may be a precursor for the patterns of recombination we have discussed above33. Furthermore, batrachochytrids will interact with other amphibian pathogens, such as the emerging ranavirus, and field data suggest that host population declines owing to co-circulating pathogens exceed what would be predicted if the interactions were additive111. Whether this is attributable to shifts in batrachochytrid virulence is uncertain, and a more likely explanation is that sublethal Bd exposures are facilitating the invasion of a viral pathogen (T. W. J. Garner, unpublished data). In either case, interactions between batrachochytrids and other pathogens can shift epidemiological patterns, through dynamical processes, natural selection, or both.

Mitigating batrachochytrid threats

Studies80,99 showing species-specific and variable responses have illustrated that we cannot generalize the impacts of batrachochytrids. The emergence of lethal chytridiomycosis can be persistent or transient, and the effects on host communities can in themselves modify the virulence of batrachochytrids4,105. Nevertheless, the global increase in incidence of new fungal infections alongside those that have evolved to evade control has led to the recognition that we urgently need to strengthen our detection, monitoring and control of fungal disease112,113. The identification of East Asia as a hotspot of batrachochytrid diversity, alongside its relatively unsurveyed status, suggests undiscovered chytrid biodiversity in this region that requires urgent investigation. The finding that all known lineages of Bd are circulating in globally traded amphibians has proved that, despite listing of diseases by the World Organisation for Animal Health, trade is still disseminating amphibian vectors33 (Fig. 2). Stage-specific goals and management actions can theoretically be deployed in order to prevent and/or manage wildlife disease114. Before the emergence of wildlife pathogens, biosecurity is a first line of defence and therefore needs strengthening through import controls and the establishment of an infection-free trade115. Motivated by the discovery of Bsal, the European Union has implemented health protection measures for the trade of salamanders116, and similar measures have been adopted by the US117 and Canada118. These pre-emergence ‘prezootic’ biosecurity-oriented strategies remain the best option for avoiding disease emergence, and they should be adopted with some urgency across uninfected regions and countries.

Combating wildlife diseases after invasion is extremely challenging, with only one partially successful example for chytridiomycosis. In this example, a chemical-led approach using the antifungal itraconazole and the environmental disinfectant virkon was applied in order to eradicate Bd from Mallorca and, as noted, only partially succeeded. However, this approach is not likely applicable to more ecologically complex settings45,119. Bio-augmentation of amphibian cutaneous microbiota and vaccination have been proposed as methods to strengthen the resilience of amphibians against invasive chytrids. However, despite promising in vivo studies (reviewed by115,120), this approach has yet to be successfully implemented (but see121). In situations in which species are highly threatened by the pathogen, their safeguarding through establishing ex situ captive breeding programmes currently remains the only active conservation method geared to avoiding species loss after invasion. Amphibian arks maintain the possibility for selective breeding or genetic modification of amphibians for resistance, and it is likely that advances in gene editing will be used to augment amphibian immune responses to batrachochytrids in the future115. Clearly, the factors discussed above do not operate in isolation. Interactions between chytridiomycosis and other threatening processes are well described, and we are beginning to explore how pathogen genotype, host immunity and environmental conditions generate nonlinear patterns of infection and disease. There is every possibility that strategies for mitigating chytridiomycosis in nature will involve largely ignoring the pathogen and focusing on mitigating other threats or modifying environments and host communities so that the host responses may operate more effectively. Whatever our responses, the main lesson from the panzootic of chytridiomycosis has been that biodiversity is far less resilient against emerging infections than was previously believed122. This has been further confirmed in other systems, as microorganisms continue to cross continental barriers; the devastating emergence of bat white nose syndrome is a case in point123. The fragility of wildlife health in the face of globalization eroding the geographical constraints to pathogen spread is exemplified by panzootic chytridiomycosis. It is heartening to see that rapid policy measures enacted following scientific advances are on the rise, now that the consequences of failing to prevent batrachochytrid introductions are more widely realized. Although we believe that research will eventually yield the means to mitigate the emergence of wildlife diseases, for research to have its full impact, reinforcing the links between science, policy and the public will be key to success.

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Acknowledgements

We acknowledge funding from the Natural Environment Research Council (NERC) (NE/E006701/1, NE/E006841/1, NE/G002193/1, NE/K014455/1, NE/K012 509/1, NE/M000591/1, NE/N009800/1, NE/N009967/1, NE/S000844/1, NE/S000992/1), The Morris Animal Foundation (D12ZO-002 and D16ZO-022) and the Leverhulme Trust (RPG-2014-273). We thank S. O’Hanlon and P. Ghosh, who assisted with drafting the figures. M.C.F. is a Fellow in the CIFAR ‘Fungal Kingdom’ Program.

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Correspondence to Matthew C. Fisher.

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Nature Reviews Microbiology thanks T. James and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

Amphibian Disease Portal: https://amphibiandisease.org

AmphibiaWeb: https://amphibiaweb.org

CITES: http://www.cites.org

EpiCollect: https://five.epicollect.net/project/bd-global-isolation-protocol

North American Bsal Task Force: http://www.salamanderfungus.org/about-bsal/

TRAFFIC: https://www.traffic.org/

Glossary

Panzootic

Global outbreak of an infectious disease in animals.

Multilocus sequence typing

Matching the DNA sequences of fragments of multiple housekeeping genes in order to assay genetic diversity.

Epizootics

Local outbreaks of an infectious disease in animals.

Bayesian-based haplotype clustering

Population assignment using large numbers of resequenced genomes.

Mutation–drift equilibrium

State of balance in which the rate at which variation is lost through genetic drift is equal to the rate at which new variation is created by mutation.

Tajima’s D statistic

Population genetic test statistic distinguishing between DNA sequences that evolve neutrally (at mutation–drift equilibria) and those that evolve in response to a nonrandom process, such as demographic change or natural selection.

Phased

Subjected to a process of assigning alleles to the paternal and maternal chromosomes.

Crossovers

Segregation of alleles between homologous chromosomes through DNA breaks and reconnections.

Meiosis

Sexual recombination resulting in crossovers.

Mating-type alleles

Genes that regulate compatibility leading to meiosis in fungi, also called mating-type ‘idiomorphs’.

Chromosomal copy number variation

State in which the number of copies of a haplotype varies between one individual and another, also known as ‘aneuploidy’.

Amphibian arks

Ex situ breeding of threatened species in biocontainment facilities.

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Fisher, M.C., Garner, T.W.J. Chytrid fungi and global amphibian declines. Nat Rev Microbiol 18, 332–343 (2020). https://doi.org/10.1038/s41579-020-0335-x

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