《生物技术与人类》课程教学资源（经典阅读）Emerging fungal threats to animal,plant and ecosystem health

REVIEW doi:10.1038/nature10947 Emerging fungal threats to animal,plant and ecosystem health Matthew C.Fisher',Daniel.A.Henk',Cheryl J.Briggs2,John S.Brownstein3,Lawrence C.Madoff,Sarah L.McCraw5 Sarah J.Gurr' The past two decades have seen an increasing number of virulent infectious diseases in natural populations and managed landscapes.In both animals and plants,an unprecedented number of fungal and fungal-like diseases have recently caused some of the most severe die-offs and extinctions ever witnessed in wild species,and are jeopardizing food security.Human activity is intensifying fungal disease dispersal by modifying natural environments and thus creating new opportunities for evolution.We argue that nascent fungal infections will cause increasing attrition of biodiversity, with wider implications for human and ecosystem health,unless steps are taken to tighten biosecurity worldwide. merging infectious diseases(EIDs)caused by fungi are increasingly Batrachochytrium dendrobatidis was discovered in 1997 (ref.13)and recognized as presenting a worldwide threat to food security named in 1999 (ref.14).B.dendrobatidis has been shown to infect over I(Table I and Supplementary Table 1).This is not a new problem 500 species of amphibians in 54 countries,on all continents where and fungi have long been known to constitute a widespread threat to plant amphibians are found,and is highly pathogenic across a wide diversity species.Plant disease epidemics caused by fungi and the fungal-like of species.Studies using preserved amphibian specimens showed that the oomycetes have altered the course of human history.In the nineteenth first appearance of B.dendrobatidis in the Americas coincided with a wave century,late blight led to starvation,economic ruin and the downfall of of population declines that began in southern Mexico in the 1970s and the English government during the Irish potato famine and,in the proceeded through Central America to reach the Panamanian isthmus in twentieth century,Dutch elm blight and chestnut blight laid bare urban 2007 (ref.17).As a consequence of the infection,some areas of central and forest landscapes.The threat of plant disease has not abated,in fact it America have lost over 40%of their amphibian species's,a loss that has is heightened by resource-rich farming practices and exaggerated in the resulted in measurable ecosystem-level changes.This spatiotemporal landscape by microbial adaptation to new ecosystems,brought about by pattern has been broadly mirrored in other continents's,and ongoing trade and transportation',and by climate fluctuations5. reductions in amphibian diversity owing to chytridiomycosis have However,pathogenic fungi(also known as mycoses)have not been contributed to nearly half of all amphibian species being in decline widely recognized as posing major threats to animal health.This per- worldwide20 ception is changing rapidly owing to the recent occurrence of several Fungal infections causing widespread population declines are not high-profile declines in wildlife caused by the emergence of previously limited to crops,bats and frogs;studies show that they are emerging unknown fungis.For example,during March 2007,a routine census of as pathogens across diverse taxa(Table 1),including soft corals(for bats hibernating in New York State revealed mass mortalities.Within a example,sea-fan aspergillosis caused by Aspergillus sydowii),bees group of closely clustered caves,four species of bats were marked by a (the microsporidian fungus Nosema sp.associated with colony collapse striking fungus growing on their muzzles and wing membranes,and the disorder)22,and as human and wildlife pathogens in previously non- name 'white nose syndrome'(WNS)was coined.After the initial out- endemic regions (for example,the emergent virulent VGII lineage break,the ascomycete fungus Geomyces destructans was shown to fulfil of Cryptococcus gattii in the northwest America and Cryptococcus Koch's postulates and was described as the cause of WNS in American neoformans across southeast Asia).The oomycetes have life histories bat species"1.Mortalities exhibiting WNS have subsequently been similar to those of fungi and are also emerging as aggressive pathogens of found in an increasing number of bat overwintering sites and,by animals,causing declines in freshwater brown crayfish(for example,the 2010,the infection was confirmed to have emerged in at least 115 roosts crayfish plague caused by Aphanomyces astaci)2,Tilapia fish (for across the United States and Canada,spanning over 1,200 km (ref.11). example,epizootic ulcerative syndrome caused by A.invadans)2and Bat numbers across affected sites have declined by over 70%and ana- many species of plants7 Although the direct causal relationship is lyses have shown that at least one affected species,the little brown bat uncertain in some of these diverse host-pathogen relationships,it seems Myotis lucifugus,has a greater than 99%chance of becoming locally that pathogenic fungi are having a pronounced effect on the global extinct within the next 16 years (ref.11).Other species of bats across biota this region are declining as a consequence of this infection,and the prognosis for their survival and their role in supporting healthy ecosys- Increasing risk of biodiversity loss by Fungi tems,is poor2 For infectious disease systems,theory predicts that pathogens will co- Cases ofthis sort are nolonger perceived to be atypical The probability evolve with,rather than extirpate,their hosts2930.Such evolutionary of extinction is increasing for some species of North American bats,but dynamics mirror population-level processes in which density depend- another fungal infection has caused the greatest disease-driven loss of ence leads to the loss of pathogens before their hosts are driven extinct biodiversity ever documented.The skin-infecting amphibian fungus For these reasons,infection has not been widely acknowledged as an Department of Infectious Disease Epidemiology.Imperial College,London W2 1PG,UKDepartment of Ecology.Evolution and Marine Biology,University of California,Santa Barbara,Califomia93106 9620,USA.Department of Pediatrics,Harvard Medical School,Children's Hospital Boston,Massachusetts 02115,USA.ProMED.International Society for Infectious Diseases;and Division of Infectious Diseases and Immunology,University of Massachusetts Medical School Massachusetts 01655,USA.Department of Plant Sciences,University of Oxford,Oxford OX1 3RB,UK. 186INATURE VOL APRIL 2012 2012 Macmillan Publishers Limited.All rights reserved

REVIEW doi:10.1038/nature10947 Emerging fungal threats to animal, plant and ecosystem health Matthew C. Fisher1 , Daniel. A. Henk1 , Cheryl J. Briggs2 , John S. Brownstein3 , Lawrence C. Madoff4 , Sarah L. McCraw5 & Sarah J. Gurr5 The past two decades have seen an increasing number of virulent infectious diseases in natural populations and managed landscapes. In both animals and plants, an unprecedented number of fungal and fungal-like diseases have recently caused some of the most severe die-offs and extinctions ever witnessed in wild species, and are jeopardizing food security. Human activity is intensifying fungal disease dispersal by modifying natural environments and thus creating new opportunities for evolution. We argue that nascent fungal infections will cause increasing attrition of biodiversity, with wider implications for human and ecosystem health, unless steps are taken to tighten biosecurity worldwide. E merging infectious diseases (EIDs) caused by fungi are increasingly recognized as presenting a worldwide threat to food security1,2 (Table 1 and Supplementary Table 1). This is not a new problem and fungi have long been known to constitute a widespread threat to plant species. Plant disease epidemics caused by fungi and the fungal-like oomycetes have altered the course of human history. In the nineteenth century, late blight led to starvation, economic ruin and the downfall of the English government during the Irish potato famine and, in the twentieth century, Dutch elm blight and chestnut blight laid bare urban and forest landscapes. The threat of plant disease has not abated, in fact it is heightened by resource-rich farming practices and exaggerated in the landscape by microbial adaptation to new ecosystems, brought about by trade and transportation3 , and by climate fluctuations4,5. However, pathogenic fungi (also known as mycoses) have not been widely recognized as posing major threats to animal health. This per￾ception is changing rapidly owing to the recent occurrence of several high-profile declines in wildlife caused by the emergence of previously unknown fungi6,7. For example, during March 2007, a routine census of bats hibernating in New York State revealed mass mortalities8 . Within a group of closely clustered caves, four species of bats were marked by a striking fungus growing on their muzzles and wing membranes, and the name ‘white nose syndrome’ (WNS) was coined. After the initial out￾break, the ascomycete fungus Geomyces destructans was shown to fulfil Koch’s postulates and was described as the cause of WNS in American bat species9,10. Mortalities exhibiting WNS have subsequently been found in an increasing number of bat overwintering sites and, by 2010, the infection was confirmed to have emerged in at least 115 roosts across the United States and Canada, spanning over 1,200 km (ref. 11). Bat numbers across affected sites have declined by over 70% and ana￾lyses have shown that at least one affected species, the little brown bat Myotis lucifugus, has a greater than 99% chance of becoming locally extinct within the next 16 years (ref. 11). Other species of bats across this region are declining as a consequence of this infection, and the prognosis for their survival and their role in supporting healthy ecosys￾tems, is poor12. Cases of this sort are no longer perceived to be atypical. The probability of extinction is increasing for some species of North American bats, but another fungal infection has caused the greatest disease-driven loss of biodiversity ever documented. The skin-infecting amphibian fungus Batrachochytrium dendrobatidis was discovered in 1997 (ref. 13) and named in 1999 (ref. 14). B. dendrobatidis has been shown to infect over 500 species of amphibians in 54 countries, on all continents where amphibians are found15,16, and is highly pathogenic across a wide diversity of species. Studies using preserved amphibian specimens showed that the first appearance of B. dendrobatidisin the Americas coincided with a wave of population declines that began in southern Mexico in the 1970s and proceeded through Central America to reach the Panamanian isthmus in 2007 (ref. 17). As a consequence of the infection, some areas of central America have lost over 40% of their amphibian species18, a loss that has resulted in measurable ecosystem-level changes19. This spatiotemporal pattern has been broadly mirrored in other continents15, and ongoing reductions in amphibian diversity owing to chytridiomycosis have contributed to nearly half of all amphibian species being in decline worldwide20. Fungal infections causing widespread population declines are not limited to crops, bats and frogs; studies show that they are emerging as pathogens across diverse taxa (Table 1), including soft corals (for example, sea-fan aspergillosis caused by Aspergillus sydowii) 21, bees (the microsporidian fungus Nosema sp. associated with colony collapse disorder)22, and as human and wildlife pathogens in previously non￾endemic regions (for example, the emergent virulent VGII lineage of Cryptococcus gattii in the northwest America23 and Cryptococcus neoformans across southeast Asia24). The oomycetes have life histories similar to those of fungi and are also emerging as aggressive pathogens of animals, causing declines in freshwater brown crayfish (for example, the crayfish plague caused by Aphanomyces astaci) 25, Tilapia fish (for example, epizootic ulcerative syndrome caused by A. invadans) 26 and many species of plants27,28. Although the direct causal relationship is uncertain in some of these diverse host–pathogen relationships, it seems that pathogenic fungi are having a pronounced effect on the global biota1 . Increasing risk of biodiversity loss by Fungi For infectious disease systems, theory predicts that pathogens will co￾evolve with, rather than extirpate, their hosts29,30. Such evolutionary dynamics mirror population-level processes in which density depend￾ence leads to the loss of pathogens before their hosts are driven extinct31. For these reasons, infection has not been widely acknowledged as an 1 Department of Infectious Disease Epidemiology, Imperial College, London W2 1PG, UK. 2 Department of Ecology, Evolution and Marine Biology, University of California, Santa Barbara, California 93106- 9620, USA. 3 Department of Pediatrics, Harvard Medical School, Children’s Hospital Boston, Massachusetts 02115, USA. 4 ProMED, International Society for Infectious Diseases; and Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Massachusetts 01655, USA. 5 Department of Plant Sciences, University of Oxford, Oxford OX1 3RB, UK. 186 | NATURE | VOL 484 | 12 APR IL 2012 ©2012 Macmillan Publishers Limited. All rights reserved

REVIEW RESEARCH Table 1|Major fungal organisms posing threats to animal and plant species. Host Pathogen(Phylum) Disease dynamics leading to mass mortality in animal and plant hosts Amphibian species Batrachochytrium Worldwide dispersal of a hypervirulent lineage by trade (for example,the dendrobatidis Ultra-generalist pathogen manifesting spillover between common midwife (Chytridiomycota) tolerant/susceptible species.Extent of chytridiomycosis is toad,Alytes dependent on biotic and abiotic context obstetricans) Rice (Oryza sativa): Magnaporthe oryzae Rice blast disease in 85 countries,causing 10-35%loss of Magnaporthe grisea (Ascomycota) harvest.Global blast population structure determined by species complex on deployment of seeds with inbred race-specific disease 50 grass and sedge resistance(RSR).Invasions occur by 'host hops'and altered species,including pathogen demographics. wheat and barley Bat spp.(little brown Geomyces destructans New invasion of North American bat roosts occurred in bats.Myotis lucifugus) (Ascomycota) approximately 2006,and disease is spreading rapidly Pathogen reservoir may exist in cave soil.Disease is more aggressive compared to similar infections in European bats, possibly owing to differences in roosts and host life historiesss Wheat(Triticum Puccinia graminis Wheat stem rust is present on six continents.Population aestivum):28 Puccinia (Basidiomycota) structure is determined by deployment of RSR cultivars graminis f.tritici and long-distance spread of aeciospores.Strain Ug99 species,but P.graminis poses a notable threat to resistant wheat varieties,causing is found on 365 cereal up to 100%crop loss. or grass species Coral species(for Aspergillus sydowii Sea-fan aspergillosis caused by a common terrestrial soil example,the sea fan, (Ascomycota)） fungus2186.Epizootics are associated with warm- Gorgonia ventalina) temperature anomalies.Coral immunosuppression is probably a factor causing decline. Bee species(for Nosema species Microsporidian fungal infections are associated with colony example,the hive of (Microsporidia) collapse disorder and declining populations.Pathogen the domestic prevalence is probably a part of a multifactorial honeybee (Apis phenomenon that includes environmental stressors and mellifera)suffering polyparasitism7a colony collapse disorder) Sea turtle species Fusarium solani Soil-dwelling saprotroph and phytopathogenic fungus. (the loggerhead (Ascomycota) Infection causes hatch failure in loggerhead turtle nests and turtle,Carettacaretta) suboptimal juveniles44.The disease dynamics fulfil Koch's postulates.Environmental forcing is suspected but not proven. Images in Table 1.with permission:A obstetricans chytridiomycosis mortalities,M.C.F.:M.oryzae,N.Talbot:WNS-affected little brown bats,A Hicks;P.graminis,R.Mago:G ventalina infected with A.sydowil. D.Harvell:A melifera hive suftering from colony collapse disorder.J.Evans:sea turtle eggs infected with F.solani.J.Dieguez-Uribeondo and A Marco. 12 APRIL 2012 VOL 484 I NATURE 187 2012 Macmillan Publishers Limited.All rights reserved

Table 1 | Major fungal organisms posing threats to animal and plant species. Host Pathogen (Phylum) Disease dynamics leading to mass mortality in animal and plant hosts Amphibian species (for example, the common midwife toad, Alytes obstetricans) Batrachochytrium dendrobatidis (Chytridiomycota) Worldwide dispersal of a hypervirulent lineage by trade64. Ultra-generalist pathogen manifesting spillover between tolerant/susceptible species. Extent of chytridiomycosis is dependent on biotic and abiotic context15,82 . Rice (Oryza sativa); Magnaporthe grisea species complex on 50 grass and sedge species, including wheat and barley Magnaporthe oryzae (Ascomycota) Rice blast disease in 85 countries, causing 10–35% loss of harvest. Global blast population structure determined by deployment of seeds with inbred race-specific disease resistance (RSR). Invasions occur by ‘host hops’ and altered pathogen demographics. Bat spp. (little brown bats, Myotis lucifugus) Geomyces destructans (Ascomycota) New invasion of North American bat roosts occurred in approximately 2006, and disease is spreading rapidly8 . Pathogen reservoir may exist in cave soil. Disease is more aggressive compared to similar infections in European bats, possibly owing to differences in roosts and host life histories65. Wheat (Triticum aestivum); 28 Puccinia graminis f. tritici species, but P. graminis is found on 365 cereal or grass species Puccinia graminis (Basidiomycota) Wheat stem rust is present on six continents. Population structure is determined by deployment of RSR cultivars and long-distance spread of aeciospores. Strain Ug99 poses a notable threat to resistant wheat varieties, causing up to 100% crop loss. Coral species (for example, the sea fan, Gorgonia ventalina) Aspergillus sydowii (Ascomycota) Sea-fan aspergillosis caused by a common terrestrial soil fungus21,86. Epizootics are associated with warm￾temperature anomalies. Coral immunosuppression is probably a factor causing decline. Bee species (for example, the hive of the domestic honeybee (Apis mellifera) suffering colony collapse disorder) Nosema species (Microsporidia) Microsporidian fungal infections are associated with colony collapse disorder and declining populations. Pathogen prevalence is probably a part of a multifactorial phenomenon that includes environmental stressors and polyparasitism87,88. Sea turtle species (the loggerhead turtle, Caretta caretta) Fusarium solani (Ascomycota) Soil-dwelling saprotroph and phytopathogenic fungus. Infection causes hatch failure in loggerhead turtle nests and suboptimal juveniles44. The disease dynamics fulfil Koch’s postulates. Environmental forcing is suspected but not proven. Images in Table 1, with permission: A. obstetricans chytridiomycosis mortalities, M.C.F.; M. oryzae, N. Talbot; WNS-affected little brown bats, A. Hicks; P. graminis, R. Mago; G. ventalina infected with A. sydowii, D. Harvell; A. mellifera hive suffering from colony collapse disorder, J. Evans; sea turtle eggs infected with F. solani, J. Die´guez-Uribeondo and A. Marco. REVIEW RESEARCH 12 APR IL 2012 | VOL 484 | NATURE | 187 ©2012 Macmillan Publishers Limited. All rights reserved

RESEARCH REVIEW extinction mechanism owing to such intrinsic theoretical biotic limita- were shown to occur worldwide(Fig.Ib).Web of Science literature tions".Inspection of species conservation databases would seem to searches and compilation of previous meta-analyses of infection-related confirm this idea.The International Union for Conservation of species extinction and regional extirpation events show that fungi com- Nature (IUCN)red list database details threats to species worldwide, prise the highest threat for both animal-host(72%)and plant-host and analysis of the database has shown that of the 833 recorded species (64%)species(Fig.Ic and Supplementary Tables 3 and 4).This effect extinctions,less than 4%(31 species)were ascribed to infectious is more pronounced for animal hosts(39 animal species affected versus disease.Ecological studies on host-pathogen relationships support this 4 plant species);moreover,there is a notable increase in host loss during finding by showing that lower parasite richness occurs in threatened the second half of the twentieth century,driven mainly by the emergence host species,suggesting that parasite decline and'fade out'occurs when of B.dendrobatidis(Fig.Id).This effect is moderated after correcting for hosts become rare3.Therefore,given that macroevolutionary and eco- mass-species loss in regions of high epizootic loss (such as the mass logical processes should promote diversity and prevent infectious dis- extirpations of amphibians in Central America).However,fungi remain eases from driving their host species to extinction,we posed the question the major cause(65%)of pathogen-driven host loss after this correction. of whether we are witnessing increasing disease and extinction events Our estimates are probably conservative owing to the cryptic nature of driven by fungi on an increasingly large scale,or,alternatively,if there is most disease-driven species impacts.For example,the lack of disease- evidence that a reporting bias has skewed our opinion of the current related IUCN red list records is due to a lack of baseline data on the level of threat. incidence of pathogens in natural systems compounded by inadequate EIDs are those pathogens that are increasing in their incidence,geo- disease diagnostics,reporting protocols and a lack of centralized record- graphic or host range,and virulence.Current attempts to detect EID ing mechanisms.Hence,the true numbers of extinctions and extirpa- events centre on capturing changes in the patterns of disease alerts tions caused by fungi and oomycetes are likely to be greater as we have recorded by disease monitoring programmes.ProMED(the Program not been able to categorize the probably high levels of species loss in for Monitoring Emerging Diseases;http://www.promedmail.org)and major plant(such as the Phytophthora dieback in Australia caused by HealthMap (http://healthmap.org)have two approaches for detecting Phytophthora cinnamomi;Supplementary Table 3)or animal outbreaks and monitoring outbreaks worldwide in plant and animal hosts:first,by (for example,the effects of B.dendrobatidis emergence in the American active reporting of disease outbreaks,and second,by capturing diverse wet tropics).We cannot discount the idea that sampling bias owing to online data sources.To ascertain whether there are changing patterns of increasing awareness of pathogenic fungi as EIDs may contribute to the fungal disease,we reviewed all disease alerts in ProMED (1994-2010) patterns that we document.However,because of our observation that and HealthMap(2006-10)for combinations of search terms to cata- increases in the amount of disease caused by fungi are seen across many logue fungal alerts.We then classified these according to their relative sources of data,including disease alerts,the peer-reviewed literature and proportion against the total number of disease alerts,and discriminated previously noted patterns in human fungal EIDs*,we believe that these between plant-or animal-associated fungal pathogens (Supplementary trends are real.Therefore,the answer to our question seems to be that Table 2).We also searched the primary research literature for reports in the data do indeed support the idea that fungi pose a greater threat to which EIDs have caused host extinction events,either at the regional plant and animal biodiversity relative to other taxonomic classes of scale(extirpations)or globally(Supplementary Table 3).These analyses pathogen and hosts,and that this threat is increasing. show a number of positive trends associated with infectious fungi. Overall,fungal alerts comprise 3.5%of the ~38,000 ProMED records Fungal-disease dynamics leading to host extinction screened.However,over the period from 1995 to 2010,the relative Here we illustrate several key biological features of fungi that contribute proportion of fungal alerts increased in the ProMED database from to the epidemiological dynamics underlying contemporary increases in 1%to 7%of the database total(Fig.la and Supplementary Table 2). disease emergence and host extinction(Box 1). This trend is observed for both plant-infecting (0.4%to 5.4%)and animal-infecting (0.5%to 1.4%)fungi.HealthMap shows a recent High virulence (2007-11)positive trend in the proportion of records of fungi infecting Fungi,like some bacterial and viral infections,can be highly lethal to animals (0.1%to 0.3%)and plants (0.1 to 0.2%),and fungal disease alerts naive hosts with rates of mortality approaching 100%(for example, a Figure 1 Worldwide reporting trends in fungal EIDs.a,b,Disease alerts in the ProMED database for pathogenic fungi of animals and plants(a),and 6 .Plant-infecting fungi the spatial location of the associated reports Animal- (b).c,d,Relative proportions of species extinction infecting fung and/or extirpation events for major classes of infectious disease agents(c)and their temporal 3 trends for fungal pathogens (d).Primary data 2 sources are given in the Supplementary Information. 995 Fungi ■Protist 905 ■Viruses / ■Bacteria Helmint 10- ■OhE 5 01 900 2 194 980-200 9 00 188 NATURE VOL APRIL 2012 2012 Macmillan Publishers Limited.All rights reserved

extinction mechanism owing to such intrinsic theoretical biotic limita￾tions32. Inspection of species conservation databases would seem to confirm this idea. The International Union for Conservation of Nature (IUCN) red list database details threats to species worldwide, and analysis of the database has shown that of the 833 recorded species extinctions, less than 4% (31 species) were ascribed to infectious disease7 . Ecological studies on host–pathogen relationships support this finding by showing that lower parasite richness occurs in threatened host species, suggesting that parasite decline and ‘fade out’ occurs when hosts become rare33. Therefore, given that macroevolutionary and eco￾logical processes should promote diversity and prevent infectious dis￾eases from driving their host species to extinction, we posed the question of whether we are witnessing increasing disease and extinction events driven by fungi on an increasingly large scale, or, alternatively, if there is evidence that a reporting bias has skewed our opinion of the current level of threat. EIDs are those pathogens that are increasing in their incidence, geo￾graphic or host range, and virulence34,35. Current attempts to detect EID events centre on capturing changes in the patterns of disease alerts recorded by disease monitoring programmes. ProMED (the Program for Monitoring Emerging Diseases; http://www.promedmail.org) and HealthMap (http://healthmap.org) have two approaches for detecting and monitoring outbreaks worldwide in plant and animal hosts: first, by active reporting of disease outbreaks, and second, by capturing diverse online data sources. To ascertain whether there are changing patterns of fungal disease, we reviewed all disease alerts in ProMED (1994–2010) and HealthMap (2006–10) for combinations of search terms to cata￾logue fungal alerts. We then classified these according to their relative proportion against the total number of disease alerts, and discriminated between plant- or animal-associated fungal pathogens (Supplementary Table 2). We also searched the primary research literature for reports in which EIDs have caused host extinction events, either at the regional scale (extirpations) or globally (Supplementary Table 3). These analyses show a number of positive trends associated with infectious fungi. Overall, fungal alerts comprise 3.5% of the ,38,000 ProMED records screened. However, over the period from 1995 to 2010, the relative proportion of fungal alerts increased in the ProMED database from 1% to 7% of the database total (Fig. 1a and Supplementary Table 2). This trend is observed for both plant-infecting (0.4% to 5.4%) and animal-infecting (0.5% to 1.4%) fungi. HealthMap shows a recent (2007–11) positive trend in the proportion of records of fungi infecting animals (0.1% to 0.3%) and plants (0.1 to 0.2%), and fungal disease alerts were shown to occur worldwide (Fig. 1b). Web of Science literature searches and compilation of previous meta-analyses of infection-related species extinction and regional extirpation events show that fungi com￾prise the highest threat for both animal-host (72%) and plant-host (64%) species (Fig. 1c and Supplementary Tables 3 and 4). This effect is more pronounced for animal hosts (39 animal species affected versus 4 plant species); moreover, there is a notable increase in host loss during the second half of the twentieth century, driven mainly by the emergence of B. dendrobatidis (Fig. 1d). This effect is moderated after correcting for mass-species loss in regions of high epizootic loss (such as the mass extirpations of amphibians in Central America). However, fungi remain the major cause (65%) of pathogen-driven host loss after this correction. Our estimates are probably conservative owing to the cryptic nature of most disease-driven species impacts. For example, the lack of disease￾related IUCN red list records is due to a lack of baseline data on the incidence of pathogens in natural systems compounded by inadequate disease diagnostics, reporting protocols and a lack of centralized record￾ing mechanisms. Hence, the true numbers of extinctions and extirpa￾tions caused by fungi and oomycetes are likely to be greater as we have not been able to categorize the probably high levels of species loss in major plant (such as the Phytophthora dieback in Australia caused by Phytophthora cinnamomi; Supplementary Table 3) or animal outbreaks (for example, the effects of B. dendrobatidis emergence in the American wet tropics). We cannot discount the idea that sampling bias owing to increasing awareness of pathogenic fungi as EIDs may contribute to the patterns that we document. However, because of our observation that increases in the amount of disease caused by fungi are seen across many sources of data, including disease alerts, the peer-reviewed literature and previously noted patterns in human fungal EIDs35, we believe that these trends are real. Therefore, the answer to our question seems to be that the data do indeed support the idea that fungi pose a greater threat to plant and animal biodiversity relative to other taxonomic classes of pathogen and hosts, and that this threat is increasing. Fungal-disease dynamics leading to host extinction Here we illustrate several key biological features of fungi that contribute to the epidemiological dynamics underlying contemporary increases in disease emergence and host extinction (Box 1). High virulence Fungi, like some bacterial and viral infections, can be highly lethal to naive hosts with rates of mortality approaching 100% (for example, 0 1 2 3 4 5 6 7 Percentage of total alerts Year Plant-infecting fungi Animal￾infecting fungi Fungi Protist Viruses Bacteria Helminth Other 0 5 10 15 20 25 30 35 Number of extinction or extirpation events a b c d 1995 2000 2005 2010 1900–20 1920–40 1940–60 1960–80 1980–2000 2000– Year i st es eria minth r Figure 1 | Worldwide reporting trends in fungal EIDs. a, b, Disease alerts in the ProMED database for pathogenic fungi of animals and plants (a), and the spatial location of the associated reports (b). c, d, Relative proportions of species extinction and/or extirpation events for major classes of infectious disease agents (c) and their temporal trends for fungal pathogens (d). Primary data sources are given in the Supplementary Information. RESEARCH REVIEW 188 | NATURE | VOL 484 | 12 APR IL 2012 ©2012 Macmillan Publishers Limited. All rights reserved

REVIEW RESEARCH BOX I population size to the point at which the species is vulnerable owing to catastrophic collapses as a result of stochastic3z or Allee effects40 Modelling host extinctions caused by pathogenic fungi Long-lived environmental stages Fungi have remarkably resilient dispersal stages (a feature that they share with some spore-forming bacteria,such as Bacillus anthracis).The ability A simple susceptible-infected model shows that the presence of a to survive independently outside of their host,as a free-living saprophyte threshold host population size for disease persistence does not or as durable spores in the environment,is probably the most important prevent host extinction during a disease outbreak,especially in cases feature in driving the emergence of pathogenic fungi,owing to an increased in which a lethal pathogen invades a large host population.In a large risk of transporting the inocula to naive hosts(Fig.2b)".Furthermore, host population transmission is rapid and all hosts can become infected before the host population is suppressed below the threshold. pathogenic fungi with a saprophytic stage(called sapronoses;Fig.2c)can lead to host extirpation because their growth rate is decoupled from host The model follows the dynamics of susceptible (S)and infected ( densities and many fungal diseases threatening natural populations are hosts during the short time duration of an epidemic(deaths that are caused by opportunistic fungi with long-lived environmental stages.Many not due to disease,and births,are ignored):dS/dt=-BS/;dl/ fungi in the phylum Ascomycota are common soil organisms and are dt=BSI-al,where B is the pathogen transmission rate,and a is the tolerant of salinity with the consequence that,when they enter the marine disease-induced death rate.For the parameters shown in Fig.2a,the system through freshwater drainage,they are able to infect susceptible threshold population size below which the pathogen has a negative hosts such as corals (A.sydowii),sea otters (Coccidioides immitis 3)and growth rate is N=20 individuals.Figure 2a shows that large host the nests of loggerhead turtles (Fusarium solani).In terrestrial environ- populations are rapidly driven extinct,but only a fraction of individuals ments,potentially lethal fungi are ubiquitous,such as the causative agent of are killed in small host populations. aspergillosis,Aspergillus fumigatus,and soil surveys have shown that Pathogens with a long-lived infectious stage have an increased potential to cause host extinction.In this model.the disease is Geomyces spp.are common soil organisms.Viable G.destructans has been transmitted through contact between susceptible hosts and free-living recovered from the soil ofinfected bat caves,showing that the pathogen is able to survive and persist in infected roosts when the bats are absent. infectious spores(Z),resulting in infected hosts,I:dS/dt=-BSZ:dl/ dt BSZ-al:dz/dt=-uZ-BNZ,where B is the transmission rate Likewise,long-term persistence of fungal inoculum in the agricultural is the pathogen-induced death rate and is the rate of release of landscape is achieved by quiescent survival on plant debris,such as the spores from infected hosts.Figure 2b shows that fraction of hosts spores of wheat stem rust(Puccinia graminis),which overwinter on straw killed in a disease outbreak increases with the duration of the free- stubble before infecting a secondary host. living infectious spore stage (1/g where u is the spore mortality rate). Saprophytic growth by a pathogen can lead to extinction of the host. Generalist pathogens and opportunistic pathogens and even allow the pathogen to persist in the absence of its host.In this Although many fungi demonstrate extreme host specialization,exem- model,free-living infectious spores are released from infected hosts plified by the gene-for-gene interactions between biotrophic fungi and their plant hosts,broad host ranges twinned with high virulence can be a (with rate )and can increase in abundance through saprophytic growth,with rate a.To illustrate the effects of saprophytic pathogen lethal combination.Fungi exhibit the broadest spectrum of host ranges growth on host and pathogen equilibria(Fig.2c),density-independent for any group of pathogens,and B.dendrobatidis and the oomycete Phytophthora ramorum (the cause of sudden oak death and ramorum host reproduction (with rate b),density-dependent host mortality(with rate do +diN,where N=S+D,and density-dependent spore blight)are known to infect 508 (ref.16)and 109 (ref.3)host species, mortalities (at rate o+Zwere included:dS/dt=bN-(do+dN)S respectively.Different host species vary in their susceptibility to infec- BSZ;dl/dt=BSZ-al-(do +dN)l;dZ/dt=+Z-(uo+u tion and these differences create the potential for parasite-mediated Z-BNZ. competition when the pathogens concerned are generalists.Host The presence of a tolerant host species can lead to the extinction of a species that can tolerate high infection loads while serving as a source susceptible host species.In this model,species A is the tolerant host of infectious stages (known as pathogen spill-over)act as community species,which can become infected and shed infectious spores but 'super spreaders'by maintaining persistent infectious stages in the does not die as a result of the disease,whereas the susceptible host system(Fig.2d).Invasive North American signal crayfish,which tol- species (species B)has a disease-induced per-capita mortality rate of erate infection by the oomycete A.astaci,force the infection into more aB.Figure 2d shows that species B is driven extinct at high densities of susceptible European species that then decline2,and similarly,although species A dSA/dt=bANA-(dAo +dAINA)SA-BASAZ;dlA/ p.ramorum is deadly to Notholithocarpus densiflorus (tanoak)and dt=BASAZ-(dao+dANA)IA:dSa/dt baNA-(dao+dBiNs) several Quercus species,many of its other hosts survive infection but SB-BBSBZ;dlB/dt BBSBZ-(dso+d8NB)8-BlB:dZ/ generate inoculum themselves for new infections.Furthermore,disease- dt=lA+-uZ-BANAZ-BaNBZ,where all parameters are as tolerant life-history stages of otherwise susceptible species can maintain previously defined,but with the subscripts A or B referring to host high pathogen levels leading to extinction dynamics.In chytridiomycosis, species A or B,respectively the long-lived multi-year tadpole stages of amphibians such as the mountain yellow-legged frog Rana muscosa and the midwife toad Alytes obstetricans are not killed by chytrid infections,but they can B.dendrobatidis in amphibians,G.destructans in bats and Ophiostoma build up high loads of B.dendrobatidis that can infect and overwhelm ulmi in elm trees).Virulence is a measure of the relative capacity of a juvenile metamorphs of the same species,leading to rapid population microbe to cause damage to a host,and high virulence is associated with loss2.Ultimately,when host-generalist pathogens manifest long-lived rapid intra-host growth rates,ultimately leading to rapidinter-host trans- environmental stages,conditions may occur that lead to long-distance mission"Fungi have a high reproductive potential and in a large host dispersal and infection of naive hosts and environments3. population this effect can result in all individuals becoming infected before the population is driven to the low densities at which the pathogen Trade and transport promotes globalization of fungi can no longer spread(Fig.2a).Thus,host extirpation can occur before Fungi comprise most of the viable biomass in the air,with an average density dependence limits the rate of transmission,a feature that has human breath containing between one and ten fungal spores4.This contributed to the mass extirpations seen in frog populations across ability of fungi to disperse results in some species with cosmopolitan the US Sierra Nevada mountains".Similarly,even if the pathogen does distributions However,these species are in the minority and it is not drive the host to complete extinction,it may severely reduce the noticeable that few fungi exhibit truly globally distributions;instead they 12 APRIL 2012 VOL 484 NATURE 189 2012 Macmillan Publishers Limited.All rights reserved

B. dendrobatidis in amphibians, G. destructans in bats and Ophiostoma ulmi in elm trees). Virulence is a measure of the relative capacity of a microbe to cause damage to a host36, and high virulence is associated with rapid intra-host growth rates, ultimately leading to rapid inter-host trans￾mission37,38. Fungi have a high reproductive potential and in a large host population this effect can result in all individuals becoming infected before the population is driven to the low densities at which the pathogen can no longer spread (Fig. 2a). Thus, host extirpation can occur before density dependence limits the rate of transmission, a feature that has contributed to the mass extirpations seen in frog populations across the US Sierra Nevada mountains39. Similarly, even if the pathogen does not drive the host to complete extinction, it may severely reduce the population size to the point at which the species is vulnerable owing to catastrophic collapses as a result of stochastic32 or Allee effects40. Long-lived environmental stages Fungi have remarkably resilient dispersal stages (a feature that they share with some spore-forming bacteria, such as Bacillus anthracis). The ability to survive independently outside of their host, as a free-living saprophyte or as durable spores in the environment, is probably the most important featurein driving the emergence of pathogenicfungi, owing to an increased risk of transporting the inocula to naive hosts (Fig. 2b)41. Furthermore, pathogenic fungi with a saprophytic stage (called sapronoses; Fig. 2c) can lead to host extirpation because their growth rate is decoupled from host densities and many fungal diseases threatening natural populations are caused by opportunistic fungi with long-lived environmental stages. Many fungi in the phylum Ascomycota are common soil organisms and are tolerant of salinity with the consequence that, when they enter the marine system through freshwater drainage, they are able to infect susceptible hosts such as corals (A. sydowii42), sea otters (Coccidioides immitis43) and the nests of loggerhead turtles (Fusarium solani44). In terrestrial environ￾ments, potentially lethalfungi are ubiquitous, such as the causative agent of aspergillosis, Aspergillus fumigatus, and soil surveys have shown that Geomycesspp. are common soil organisms. Viable G. destructans has been recoveredfrom the soil of infected bat caves45, showing that the pathogen is able to survive and persist in infected roosts when the bats are absent. Likewise, long-term persistence of fungal inoculum in the agricultural landscape is achieved by quiescent survival on plant debris, such as the spores of wheat stem rust (Puccinia graminis), which overwinter on straw stubble before infecting a secondary host. Generalist pathogens and opportunistic pathogens Although many fungi demonstrate extreme host specialization, exem￾plified by the gene-for-gene interactions between biotrophic fungi and their plant hosts, broad host ranges twinned with high virulence can be a lethal combination. Fungi exhibit the broadest spectrum of host ranges for any group of pathogens, and B. dendrobatidis and the oomycete Phytophthora ramorum (the cause of sudden oak death and ramorum blight) are known to infect 508 (ref. 16) and 109 (ref. 3) host species, respectively. Different host species vary in their susceptibility to infec￾tion and these differences create the potential for parasite-mediated competition when the pathogens concerned are generalists46. Host species that can tolerate high infection loads while serving as a source of infectious stages (known as pathogen spill-over) act as community ‘super spreaders’ by maintaining persistent infectious stages in the system (Fig. 2d). Invasive North American signal crayfish, which tol￾erate infection by the oomycete A. astaci, force the infection into more susceptible European species that then decline25, and similarly, although P. ramorum is deadly to Notholithocarpus densiflorus (tanoak) and several Quercus species47, many of its other hosts survive infection but generate inoculum themselves for new infections. Furthermore, disease￾tolerant life-history stages of otherwise susceptible species can maintain high pathogen levels leading to extinction dynamics. In chytridiomycosis, the long-lived multi-year tadpole stages of amphibians such as the mountain yellow-legged frog Rana muscosa and the midwife toad Alytes obstetricans are not killed by chytrid infections, but they can build up high loads of B. dendrobatidis that can infect and overwhelm juvenile metamorphs of the same species, leading to rapid population loss39. Ultimately, when host-generalist pathogens manifest long-lived environmental stages, conditions may occur that lead to long-distance dispersal and infection of naive hosts and environments5 . Trade and transport promotes globalization of fungi Fungi comprise most of the viable biomass in the air, with an average human breath containing between one and ten fungal spores48. This ability of fungi to disperse results in some species with cosmopolitan distributions5,49,50. However, these species are in the minority and it is noticeable that few fungi exhibit truly globally distributions; instead they BOX 1 Modelling host extinctions caused by pathogenic fungi A simple susceptible–infected model shows that the presence of a threshold host population size for disease persistence does not prevent host extinction during a disease outbreak, especially in cases in which a lethal pathogen invades a large host population. In a large host population transmission is rapid and all hosts can become infected before the host population is suppressed below the threshold. The model follows the dynamics of susceptible (S) and infected (I) hosts during the short time duration of an epidemic (deaths that are not due to disease, and births, are ignored): dS/dt 5 2 bSI; dI/ dt 5 bSI 2 aI, where b is the pathogen transmission rate, and a is the disease-induced death rate. For the parameters shown in Fig. 2a, the threshold population size below which the pathogen has a negative growth rate is NT5 20 individuals. Figure 2a shows that large host populations are rapidly driven extinct, but only a fraction of individuals are killed in small host populations. Pathogens with a long-lived infectious stage have an increased potential to cause host extinction. In this model, the disease is transmitted through contact between susceptible hosts and free-living infectious spores (Z), resulting in infected hosts, I: dS/dt 5 2bSZ; dI/ dt 5 bSZ 2 aI; dZ/dt 5 wI 2 mZ 2 bNZ, where b is the transmission rate, a is the pathogen-induced death rate and w is the rate of release of spores from infected hosts. Figure 2b shows that fraction of hosts killed in a disease outbreak increases with the duration of the free￾living infectious spore stage (1/m, where m is the spore mortality rate). Saprophytic growth by a pathogen can lead to extinction of the host, and even allow the pathogen to persist in the absence of its host. In this model, free-living infectious spores are released from infected hosts (with rate w), and can increase in abundance through saprophytic growth, with rate s. To illustrate the effects of saprophytic pathogen growth on host and pathogen equilibria (Fig. 2c), density-independent host reproduction (with rate b), density-dependent hostmortality (with rate d01 d1N, where N 5 S 1 I), and density-dependent spore mortalities (at rate m01 m1Z) were included: dS/dt 5 bN 2 (d0 1 d1N) S 2 bSZ; dI/dt 5 bSZ 2 aI 2 (d01 d1N)I; dZ/dt 5 wI 1 sZ 2 (m0 1 m1Z) Z 2 bNZ. The presence of a tolerant host species can lead to the extinction of a susceptible host species. In this model, species A is the tolerant host species, which can become infected and shed infectious spores but does not die as a result of the disease, whereas the susceptible host species (species B) has a disease-induced per-capita mortality rate of aB. Figure 2d shows that species B is driven extinct at high densities of species A. dSA/dt 5 bANA2 (dA01 dA1NA)SA2 bASAZ; dIA/ dt 5 bASAZ 2 (dA0 1 dA1NA)IA; dSB/dt 5 bBNA 2 (dB01dB1NB) SB 2 bBSBZ; dIB/dt 5 bBSBZ 2(dB01 dB1NB)IB 2 aBIB; dZ/ dt 5 wAIA1 wBIB 2 mZ 2 bANAZ 2 bBNBZ, where all parameters are as previously defined, but with the subscripts A or B referring to host species A or B, respectively. REVIEW RESEARCH 12 APRIL 2012 | VOL 484 | NATURE | 189 ©2012 Macmillan Publishers Limited. All rights reserved

RESEARCH REVIEW b N。=200 1 200 N。=200 0.9 Ng=50 0.8 0.7 0.6 N%=20 0.5 N。=100 0.4 0.3 50 N6=50 N。=30 0.1 0 0 0 100 150 200 20 40 60 80 100 Time(days) Average duration of free-living stage(1/u) 120 Ro<1 12,000 d Pathogen 70 extinct Host extinct 100 10,000 60. 月a=105 8.000 50 22 60 6,000 40 Pa=10 40 4,000 % 20 2,000 10 0 .0 Pa=10-3 ag 0.5 1.5 2 0 20 30 50 Rate of saprophytic growth (o) Density of tolerant host species (N) Figure 2 Fungal disease dynamics leading to host extinction.a,The and persist with the host.High levels of saprophytic growth lead to extinction of presence of a threshold host population size for disease persistence does not the host,and the pathogen persists in the absence of the host(host intrinsic rate prevent host extinction during a disease outbreak,especially in cases in which a of increase,r=b-do 0.01;density-independent host death rate, lethal pathogen invades a large host population.In a large host population do=1 X 10;strength of density dependence in host death rate,d=1x transmission is rapid and all hosts can become infected before the host 10;pathogen transmission rate,=1 X 10;disease-induced death rate, population is suppressed below the threshold (pathogen transmission rate, =0.02;rate of release of spores from infected hosts,=10,density- B=0.001 per individual per day;disease induced-death rate,=0.02 per day independent spore mortality rate,o=1;strength of density-dependence in simulations start with one infected individual and No susceptible individuals). spore mortality rate,u=1 X 10).d,The presence of a tolerant host species b,Long-lived infectious stages can increase the potential for host extinction. (host species A),which can become infected and shed infectious spores can lead The fraction of hosts killed in a disease outbreak is shown as a function of the to the extinction of a susceptible host species (host species B).Species A does duration of the free-living infectious spore stage(pathogen transmission rate, not die because of the disease,but species B has a disease-induced per-capita B=5X 10;disease-induced death rate,=0.02;rate of release of spores mortality rate of ap.Species Bis driven extinct at high densities of species A.For from infected hosts,10;outbreaks initiated with one infected host in a all parameters,subscripts A or B indicate the host species.Host intrinsic rates of population of No susceptible individuals).c,Saprophytic growth:equilibrium increase,rA=rB=0.01;density-independent host death rates, densities of susceptible and infected hosts and free-living spores as a function of dAo=dBo=1 x 10;host birth rates,bA=bB=ra+dAo:density- the rate of saprophytic growth,o.With no (or low levels of)saprophytic growth, independent death rate for species,Bd=1x10;rate of release of spores the basic reproductive rate of the pathogen(Ro)is less than 1,the pathogen from infected hosts,==10;=0.05;spore mortality rate,=1.The cannot invade the system and the host persists at its disease-free equilibrium density of tolerant species NA was varied by varying dA(the strength of density.Intermediate levels of saprophytic growth allow the pathogen to invade density-dependence in host species A),such that NA=rA/dA. exhibit spatially restricted endemic rangess.In many cases,local adapta- attributable to the many-fold increase in fungal-infected trade products tion and host specificity are thought to underlie fungal endemicitys5 and foods7.The consequences of recent introductions of pathogens in Nevertheless,when local climatic and vegetative constraints are projected association with trade are well known;examples include the Irish globally it becomes clear that potential ranges of pathogenic fungi may be Famine(a consequence of Phytophthora infestans late blight introduc- much larger than their realized range Iffungi are contained spatially by tion from South America),the destruction of the North American chest- the combination of physical limits on dispersal,abiotic conditions,host nutsss(caused by the importation of Cryphonectria parasitica-infected distributions and genetic limits on adaptation,then how are pathogenic Asian chestnut trees to the east coast of the United States in the early fungi able to overcome these barriers?Although fungi have shown the twentieth century)and the Second World War introduction of ability to undergo range expansions in response to environmental Heterobasidion annosum into Italy from the USA(vectored by untreated shifts,human-mediated intercontinental dispersal of unrecognized wooden transport crates)s.Human-mediated intercontinental trade has fungal pathogens is the major component in initiating new chains of also been linked clearly to the spread of animal-pathogenic fungi through transmission. the transportation of infected vector species.B.dendrobatidis has been Pathogenic fungi have dispersed alongside early human migrations, introduced repeatedly to naive populations worldwide as a consequence and several thousand years ago two of these fungi,Coccidioides immitis of the trade in the infected,yet disease-tolerant species such as North and C.neoformans lineage VNI,seem to have invaded South America and American bullfrogs (Rana catesbeiana)and African clawed frogs southeast Asia,respectively,vectored by humans and their domesticated (Xenopus laevis).Whether the emergence of bat WNS constitutes an animals455 Similar ancient patterns of human-associated disease spread introduction of G.destructans into North America from Europe or are detected by studies of the genome diversity of many plant fungal elsewhere remains to be shown.However,the widespread but apparently pathogensse.However,more recent increases in fungal disease are non-pathogenic nature of the infection in European bats tentatively 190 NATURE VOL 484 12 APRIL 2012 2012 Macmillan Publishers Limited.All rights reserved

exhibit spatially restricted endemic ranges51. In many cases, local adapta￾tion and host specificity are thought to underlie fungal endemicity51,52. Nevertheless, when local climatic and vegetative constraints are projected globally it becomes clear that potential ranges of pathogenic fungi may be much larger than their realized range53. If fungi are contained spatially by the combination of physical limits on dispersal, abiotic conditions, host distributions and genetic limits on adaptation, then how are pathogenic fungi able to overcome these barriers? Although fungi have shown the ability to undergo range expansions in response to environmental shifts54, human-mediated intercontinental dispersal of unrecognized fungal pathogens is the major component in initiating new chains of transmission. Pathogenic fungi have dispersed alongside early human migrations, and several thousand years ago two of these fungi, Coccidioides immitis and C. neoformanslineage VNI, seem to have invaded South America and southeast Asia, respectively, vectored by humans and their domesticated animals24,55. Similar ancient patterns of human-associated disease spread are detected by studies of the genome diversity of many plant fungal pathogens56. However, more recent increases in fungal disease are attributable to the many-fold increase in fungal-infected trade products and food57. The consequences of recent introductions of pathogens in association with trade are well known; examples include the Irish Famine4 (a consequence of Phytophthora infestans late blight introduc￾tion from South America), the destruction of the North American chest￾nuts58 (caused by the importation of Cryphonectria parasitica-infected Asian chestnut trees to the east coast of the United States in the early twentieth century) and the Second World War introduction of Heterobasidion annosum into Italy from the USA (vectored by untreated wooden transport crates)59. Human-mediated intercontinental trade has also been linked clearly to the spread of animal-pathogenic fungi through the transportation of infected vector species. B. dendrobatidis has been introduced repeatedly to naive populations worldwide as a consequence of the trade in the infected, yet disease-tolerant species such as North American bullfrogs (Rana catesbeiana) 60–62 and African clawed frogs (Xenopus laevis) 63,64. Whether the emergence of bat WNS constitutes an introduction of G. destructans into North America from Europe or elsewhere remains to be shown. However, the widespread but apparently non-pathogenic nature of the infection in European bats tentatively 0 50 100 150 200 0 50 100 150 200 Susceptible hosts Time (days) N0 = 100 N0 = 50 N0 = 200 N0 = 30 0 10 20 30 40 50 60 70 0 10 20 30 40 50 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 0 20 40 60 80 100 Fraction of host population killed Average duration of free-living stage (1/μ) 0 2,000 4,000 6,000 8,000 10,000 12,000 0 20 40 60 80 100 120 0 0.5 1 1.5 2 Free-living spore density (Z) Host equilibrium densities (S and I) Rate of saprophytic growth (σ) R0 < 1 Pathogen extinct Host extinct S I Z S I βSI S I βSZ αI Z φI μZ S I βSZ (α + d(N))I Z μ(Z)Z bS bI d(N)S SA I A bAI A SB Z μZ a b c d αl N0 = 200 N0 = 50 N0 = 20 Density of susceptible host species (NB) Density of tolerant host species (NA) φAI A φBI B αBI B I B βSBZ bBSB bIB βSAZ bASA βA = 10–5 βA = 10–4 βA = 10–3 φI σZ Figure 2 | Fungal disease dynamics leading to host extinction. a, The presence of a threshold host population size for disease persistence does not prevent host extinction during a disease outbreak, especially in cases in which a lethal pathogen invades a large host population. In a large host population transmission is rapid and all hosts can become infected before the host population is suppressed below the threshold (pathogen transmission rate, b 5 0.001 per individual per day; disease induced-death rate, a 5 0.02 per day; simulations start with one infected individual and N0 susceptible individuals). b, Long-lived infectious stages can increase the potential for host extinction. The fraction of hosts killed in a disease outbreak is shown as a function of the duration of the free-living infectious spore stage (pathogen transmission rate, b 5 5 3 1026 ; disease-induced death rate, a 5 0.02; rate of release of spores from infected hosts, w 5 10; outbreaks initiated with one infected host in a population of N0 susceptible individuals). c, Saprophytic growth: equilibrium densities of susceptible and infected hosts and free-living spores as a function of the rate of saprophytic growth, s.With no (or low levels of) saprophytic growth, the basic reproductive rate of the pathogen (R0) is less than 1, the pathogen cannot invade the system and the host persists at its disease-free equilibrium density. Intermediate levels of saprophytic growth allow the pathogen to invade and persist with the host. High levels of saprophytic growth lead to extinction of the host, and the pathogen persists in the absence of the host (host intrinsic rate of increase, r 5 b 2 d0 5 0.01; density-independent host death rate, d0 5 1 3 1023 ; strength of density dependence in host death rate, d1 5 1 3 1024 ; pathogen transmission rate, b 5 1 3 1025 ; disease-induced death rate, a 5 0.02; rate of release of spores from infected hosts, w 5 10, density￾independent spore mortality rate, m0 5 1; strength of density-dependence in spore mortality rate, m1 5 1 3 1024 ). d, The presence of a tolerant host species (host species A), which can become infected and shed infectious spores can lead to the extinction of a susceptible host species (host species B). Species A does not die because of the disease, but species B has a disease-induced per-capita mortality rate of aB. Species B is driven extinct at high densities of species A. For all parameters, subscripts A or B indicate the host species. Host intrinsic rates of increase, rA5 rB5 0.01; density-independent host death rates, dA0 5 dB05 1 x 1023 ; host birth rates, bA5 bB5 rA1 dA0; density￾independent death rate for species, B dB1 5 1 x 10-4; rate of release of spores from infected hosts, wA 5 wB 5 10; aB 5 0.05; spore mortality rate, m 5 1. The density of tolerant species NA was varied by varying dA1 (the strength of density-dependence in host species A), such that NA 5 rA/dA1. RESEARCH REVIEW 190 | NATURE | VOL 484 | 12 APRIL 2012 ©2012 Macmillan Publishers Limited. All rights reserved

REVIEW RESEARCH suggests that the disease may have been vectored from this region in increased ozone,have been shown to have the opposite effect (for contaminated soil. example,in Puccinia recondita"). Evidence for the idea that climate change has an impact on the Accelerated evolution of virulence in pathogenic fungi dynamics and distribution of animal-infecting fungi is less clear-cut than Human activities are not only associated with the dispersal of patho- that in relation to plant-infecting fungi and,although arguments have genic fungi,they also interact with key fungal characteristics,such as been made that warming trends may have contributed to the emergence habitat flexibility,environmental persistence and multiple reproductive of B.dendrobatidis in Central America and Europe,there is active modes,to cause the emergence of disease.Importantly,many fungi are debate about these conclusions Regardless,it is clear that the disease flexible in their ability to undergo genetic recombination,hybridization state,chytridiomycosis,is linked to environmental factors;regional or horizontal gene transfer causing the clonal emergence of patho- climate warming can increase the local range of the pathogens and genic lineages but also allowing the formation of novel genetic diversity disease risk is inversely related to rates of deforestation.Correlations leading to the genesis of new pathogensReproductive barriers in between ecosystem change and a rise in infection by opportunistic patho- fungi are known to evolve more rapidly between sympatric lineages that gens has been proposed to account for the occurrence of coral reef are in the nascent stages of divergence than between geographically declines worldwide.For example,disease caused by a variety of microbes separated allopatric lineages,in a process known as reinforcements threatens hard corals to the extent that two of the most abundant As a consequence,anthropogenic mixing of previously allopatric fungal Caribbean reef-builders (staghorn and elkhorn corals)are now listed lineages that still retain the potential for genetic exchange can drive under the US Endangered Species Act.Across varied reef systems,the rapid macroevolutionary change.Although many hybrids are inviable occurrence of warm-temperature anomalies leading to bleaching events owing to genome incompatibilities,large phenotypic leaps can be is associated with increases in disease caused by opportunistic pathogens achieved by the resulting 'hopeful monsters',leading to host jumps such as A.sydowir.In an allied colonial system,colony collapse disorder and increased virulence'.Such mechanisms are thought to drive the has resulted in steep declines of the European honeybee Apis mellifera in formation of new pathotypes in plant pathogens,and oomycetes as Europe and North America.These losses seem to be influenced by a well as fungi exhibit the genesis of new interspecific hybrids as lineages mixture of aetiological agents that are fungal (for example,micro- come into contact72.Evidence of the effect of multiple fungal co- sporidian (Nosema ceranae)),viral (for example,Kashmir bee virus dispersal events and recombination can also be seen in the recent and Israeli acute paralysis virus)and ectoparasitic (for example,Varroa C.gattii outbreaks in northwestern North America.In this case,strains destructor)in origin.So far,no single environmental cause has been that do not normally recombine have increased their virulence by identified that can account for the apparent reduction in the ability of undergoing recombination and adaptation to overcome mammalian honeybee colonies to resist these infections,and agricultural chemicals, immune responses2367.Recent studies based on the resequencing of malnutrition and modern beekeeping practices have all been suggested as B.dendrobatidis genomes have shown that,although several lineages potential cofactors for colony-collapse disorder.The increasing use of exist,only a single lineage (known as the B.dendrobatidis global azole-based agricultural chemicals has been implicated as a factor under- panzootic lineage)has emerged in at least five continents during the pinning the increase in the frequency of multiple-triazole-resistant twentieth century to cause epizootic amphibian decliness.Notably,the (MTR)isolates of A.fumigatus infecting humans.The widespread agri- genome of the B.dendrobatidis global panzootic lineage shows the cultural use of azoles as a means of combating crop pathogens is specu- hallmarks of a single hybrid origin and,when compared against other lated to have led to selection for MTRalleles,an idea that is supported by the recent discovery that resistance clusters onto a single lineage in Dutch newly discovered lineages of B.dendrobatidis,is more pathogenic, suggesting that transmission and onward spread of the lineage has been populations of the fungus.Efforts must now be turned to integrating epidemiological studies with those on environmental change so that the facilitated by an increase in its virulence.Given that the rate of intra-and many possible interactions and outcomes can be assessed,as making inter-lineage recombination among fungi will be proportional to the blanket predictions for fungal diseases is currently impossible.The contact rates between previously geographically separate populations highly coordinated response to the recent outbreak of wheat stem rust and species,these data from across plant and animal fungal patho- systems suggest that the further evolution of new races is inevitable given (P.graminis,strain Ug99)is a positive step towards this goal current rates of homogenization of previously allopatric,geographically Fungal EIDs impact food security and ecosystem services separated,fungal lineages. Impacts of fungal diseases are clearly manifested in crops and there are Environmental change as a driver of fungal EIDs direct measurable economic consequences associated with die-off in forest and urban environments.Losses that are due to persistent and Climate fluctuation can be a potent cofactor in forcing changing epidemic outbreaks of fungal and oomycete infection in rice(rice blast patterns of fungal phenology?3 and are known to govern plant fungal caused by Magnaporthe oryzae),wheat (rust caused by p.graminis), EIDs.Models of climate change for the coming decades predict increases maize(smut caused by Ustilago maydis),potatoes (late blight caused in global temperature,atmospheric CO2,ozone and changes in humidity, by P.infestans)and soybean(rust caused by Phakospora pachyrizi)vary rainfall and severe weather?.For this reason,many interactions must be regionally but pose a current and growing threat to food security2.Our taken into consideration when attempting to predict the future effects of estimates of loss of food are based on the 2009-10 world harvest stat- climate change on plant diseases?s.First,the physiological and spatial istics of five of our most important crops and make certain basic changes that plants may undergo in response to the various different assumptions of calorific value and worldwide average production components of climate change and the resulting effects on the patho- (Supplementary Table 1).Our calculations show that even low-level gen?,and second,the effects on the pathogen's physiology and dispersal persistent disease leads to losses that,if mitigated,would be sufficient external to their plant hosts'.Frequently,however,experimental models to feed 8.5%of the 7 billion humans alive in 2011.If severe epidemics in have only taken into account one element of climate change,a common all five crops were to occur simultaneously,this would leave food suf- example being the free-air COz enrichment (FACE)studies that model ficient for only 39%of the world's population,but the probability of such the effects ofelevated atmospheric COz(ref.77).A notable result here has an event occurring is very low indeed. been rice blast severity being higher at higher COz levels".However, Invasive tree diseases have caused the loss of approximately 100 million although there has been a general trend for increased disease severity elm trees in the United Kingdom and the United States,and3.5 billion under simulated climate-change conditions",and although some species chestnut trees have succumbed to chestnut blight in the United States are thought to be changing their distribution in response to these changes (Supplementary Table 5).Losses of western Canadian pine trees to the (for example,P.graminis"),other elements of climate change,such as mountain pine beetle-blue-stain fungus association will result in the 12 APRIL 2012 VOL 484 2012 Macmillan Publishers Limited.All rights reserved

suggests that the disease may have been vectored from this region in contaminated soil65. Accelerated evolution of virulence in pathogenic fungi Human activities are not only associated with the dispersal of patho￾genic fungi, they also interact with key fungal characteristics, such as habitat flexibility, environmental persistence and multiple reproductive modes, to cause the emergence of disease. Importantly, many fungi are flexible in their ability to undergo genetic recombination, hybridization or horizontal gene transfer66, causing the clonal emergence of patho￾genic lineages but also allowing the formation of novel genetic diversity leading to the genesis of new pathogens56, 67,. Reproductive barriers in fungi are known to evolve more rapidly between sympatric lineages that are in the nascent stages of divergence than between geographically separated allopatric lineages, in a process known as reinforcement68,69. As a consequence, anthropogenic mixing of previously allopatric fungal lineages that still retain the potential for genetic exchange can drive rapid macroevolutionary change. Although many hybrids are inviable owing to genome incompatibilities, large phenotypic leaps can be achieved by the resulting ‘hopeful monsters’, leading to host jumps and increased virulence70. Such mechanisms are thought to drive the formation of new pathotypes in plant pathogens52, and oomycetes as well as fungi exhibit the genesis of new interspecific hybrids as lineages come into contact71,72. Evidence of the effect of multiple fungal co￾dispersal events and recombination can also be seen in the recent C. gattii outbreaks in northwestern North America. In this case, strains that do not normally recombine have increased their virulence by undergoing recombination and adaptation to overcome mammalian immune responses23,67. Recent studies based on the resequencing of B. dendrobatidis genomes have shown that, although several lineages exist, only a single lineage (known as the B. dendrobatidis global panzootic lineage) has emerged in at least five continents during the twentieth century to cause epizootic amphibian declines64. Notably, the genome of the B. dendrobatidis global panzootic lineage shows the hallmarks of a single hybrid origin and, when compared against other newly discovered lineages of B. dendrobatidis, is more pathogenic, suggesting that transmission and onward spread of the lineage has been facilitated by an increase in its virulence. Given that the rate of intra- and inter-lineage recombination among fungi will be proportional to the contact rates between previously geographically separate populations and species, these data from across plant and animal fungal patho￾systems suggest that the further evolution of new races is inevitable given current rates of homogenization of previously allopatric, geographically separated, fungal lineages. Environmental change as a driver of fungal EIDs Climate fluctuation can be a potent cofactor in forcing changing patterns of fungal phenology73 and are known to govern plant fungal EIDs. Models of climate change for the coming decades predict increases in global temperature, atmospheric CO2, ozone and changes in humidity, rainfall and severe weather74. For this reason, many interactions must be taken into consideration when attempting to predict the future effects of climate change on plant diseases75. First, the physiological and spatial changes that plants may undergo in response to the various different components of climate change and the resulting effects on the patho￾gen76, and second, the effects on the pathogen’s physiology and dispersal external to their plant hosts75. Frequently, however, experimental models have only taken into account one element of climate change, a common example being the free-air CO2 enrichment (FACE) studies that model the effects of elevated atmospheric CO2 (ref. 77). A notable result here has been rice blast severity being higher at higher CO2 levels78. However, although there has been a general trend for increased disease severity under simulated climate-change conditions79, and although some species are thought to be changing their distribution in response to these changes (for example, P. graminis80), other elements of climate change, such as increased ozone, have been shown to have the opposite effect (for example, in Puccinia recondita77). Evidence for the idea that climate change has an impact on the dynamics and distribution of animal-infecting fungi is less clear-cut than that in relation to plant-infecting fungi and, although arguments have been made that warming trends may have contributed to the emergence of B. dendrobatidis in Central America and Europe81,82, there is active debate about these conclusions83,84. Regardless, it is clear that the disease state, chytridiomycosis, is linked to environmental factors; regional climate warming can increase the local range of the pathogen54 and disease risk is inversely related to rates of deforestation85. Correlations between ecosystem change and a rise in infection by opportunistic patho￾gens has been proposed to account for the occurrence of coral reef declines worldwide. For example, disease caused by a variety of microbes threatens hard corals to the extent that two of the most abundant Caribbean reef-builders (staghorn and elkhorn corals) are now listed under the US Endangered Species Act. Across varied reef systems, the occurrence of warm-temperature anomalies leading to bleaching events is associated with increases in disease caused by opportunistic pathogens such as A. sydowii86. In an allied colonial system, colony collapse disorder has resulted in steep declines of the European honeybee Apis mellifera in Europe and North America87. These losses seem to be influenced by a mixture of aetiological agents that are fungal (for example, micro￾sporidian (Nosema ceranae)), viral (for example, Kashmir bee virus and Israeli acute paralysis virus) and ectoparasitic (for example, Varroa destructor) in origin. So far, no single environmental cause has been identified that can account for the apparent reduction in the ability of honeybee colonies to resist these infections, and agricultural chemicals, malnutrition and modern beekeeping practices have all been suggested as potential cofactors for colony-collapse disorder88. The increasing use of azole-based agricultural chemicals has been implicated as a factor under￾pinning the increase in the frequency of multiple-triazole-resistant (MTR) isolates of A. fumigatus infecting humans89. The widespread agri￾cultural use of azoles as a means of combating crop pathogens is specu￾lated to have led to selection for MTR alleles, an idea that is supported by the recent discovery that resistance clusters onto a single lineage in Dutch populations of the fungus90. Efforts must now be turned to integrating epidemiological studies with those on environmental change so that the many possible interactions and outcomes can be assessed, as making blanket predictions for fungal diseases is currently impossible91. The highly coordinated response to the recent outbreak of wheat stem rust (P. graminis, strain Ug99) is a positive step towards this goal77,92. Fungal EIDs impact food security and ecosystem services Impacts of fungal diseases are clearly manifested in crops and there are direct measurable economic consequences associated with die-off in forest and urban environments. Losses that are due to persistent and epidemic outbreaks of fungal and oomycete infection in rice (rice blast caused by Magnaporthe oryzae), wheat (rust caused by P. graminis), maize (smut caused by Ustilago maydis), potatoes (late blight caused by P. infestans) and soybean (rust caused by Phakospora pachyrizi) vary regionally but pose a current and growing threat to food security2 . Our estimates of loss of food are based on the 2009–10 world harvest stat￾istics of five of our most important crops and make certain basic assumptions of calorific value and worldwide average production (Supplementary Table 1). Our calculations show that even low-level persistent disease leads to losses that, if mitigated, would be sufficient to feed 8.5% of the 7 billion humans alive in 2011. If severe epidemics in all five crops were to occur simultaneously, this would leave food suf￾ficient for only 39% of the world’s population, but the probability of such an event occurring is very low indeed. Invasive tree diseases have caused the loss of approximately 100 million elm trees in the United Kingdom and the United States52,93, and 3.5 billion chestnut trees have succumbed to chestnut blight in the United States (Supplementary Table 5). Losses of western Canadian pine trees to the mountain pine beetle–blue-stain fungus association will result in the REVIEW RESEARCH 12 APR IL 2012 | VOL 484 | NATURE | 191 ©2012 Macmillan Publishers Limited. All rights reserved

RESEARCH REVIEW release of270 megatonnesofCO2 over the period from 2000 to 2020,with policy makers.If this occurs,then there will be more sympathy for a clearly ascribed economic cost both for the wood itself and the carbon attempts to improve the regulatory frameworks that are associated with released.These,and other diseases such as 'sudden oak death'in biosecurity in international trade,as this is the most important tool to California and foliar and twig blight'and 'dieback'on ornamental trees, tackle both plant and animal fungal EIDs now and in the future.The woody shrubs and forestry plants in the European Union,affect eco- monitoring of fungal inocula in wild populations should be the utmost logical diversity,are costly to manage and account for huge losses of fixed priority and tighter control of international trade in biological material CO2.Indeed,we calculate regional losses of absorbed COz to total 230- must be imposed,and with considerable haste.Inadequate biosecurity 580 megatonnes for just a handful of diseases(Supplementary Table 5) will mean that new fungal EIDs and virulent races will emerge at an with the higher figure equating to 0.069%of the global atmospheric COz. increasingly destructive rate.In addition to better global monitoring and We have included both emerging (Jarrah dieback,sudden oak death and control,attention must also be turned to increasing our understanding pine beetle-blue-stain fungus)and emergent diseases(Dutch elm blight of the interactions between hosts,pathogens and the environment, and chestnut blight),as these represent the few examples for which across regional and global scales.Integrated approaches encompassing informed estimates are possible.We are unable to quantify any of the theoretical and practical epidemiology,climate forecasting,genomic many other recent emerging diseases,such as red band needle blight of surveillance and monitoring molecular evolution are needed.These pines,Phytophthora alni on alders or pitch pine canker on Monterey should be facilitated by scientists from currently disparate research fields pines,owing to a lack of data and economic interest,both of which are entering into regular global discussions to develop clear and urgent trends that must be reversed.Assessing the economic burden of fungal strategies for working towards the elusive magic bullet for emerging mycoses in animals is a challenging task Although the impact of fungal fungal diseases:effective prevention and timely control EIDs is manifested in domestic animal settings,particularly the amphibian trades and in regions where virulent lineages have establisheds,reporting 1. The Institute of Medicine.Fungal Diseases:an Emerging Threatto Human Animal and mechanisms for outbreaks do not widely exist.In natural settings,valua- Wildlife Health (National Academy of Sciences,2011). The output of a key workshop assessing the risk of novel fungal diseases. tions have recently estimated the losses to US agriculture that are the result Pennisi,E.Armed and dangerous.Science 327,804-805(2010). of declines in bat populations at more than US$3.7 billion per year(ref.12). 3. Grunwald,N.J.,Goss,E.M.Press,C.M.Phytophthora ramorum:a pathogen with a However,although broad ecosystem-level impacts of other fungal EIDs of remarkably wide host range causing sudden oak death on oaks and ramorum blight on woody ornamentals.Mol.Plant Pathol.9.729-740(2008) wildlife are suspected,economic valuations of the ecosystem services that 4. Anderson,P.K.etal.Emerging infectious diseases of plants:pathogen pollution. these species support are wholly lacking. climate change and agrotechnology drivers.Trends Ecol Evol.19,535-544 (2004) Mitigating fungal EIDs in animals and plants The first meta-analysis of emerging plant diseases.Reasons for this emergence are proposed and the cost to hu welfare and biodiversity is estimated. The high socioeconomic value of crops means that detection and control 5. Brown,J.K.M.Hovmoller,M.S.Aerial dispersal of pathogens on the global and of fungal diseases in agriculture far outpaces that in natural habitats. continental scales and its impact on plant disease.Science 297,537-541(2002). Daszak,P.,Cunningham,A.A.Hyatt,A.D.Emerging infectious diseases of Epidemiological models have been developed to predict the risk of wildlife-threats to biodiversity and human health.Science 287,443-449(2000) seasonally specific crop pathogens,allowing targeted control,and spe- 7. Smith,K.F.Sax,D.F.Lafferty,K.D.Evidence for the role of infectious disease in cific threats are assessed through consortia of research,governmental species extinction and endangerment Conserv.Biol.20.1349-1357(2006). 8. Blehert,D.S.et al.Bat white-nose syndrome:an emerging fungal pathogen? and global non-governmental organizations,led by the United Nations Science323,227(2009). Food and Agricultural Organization(FAO),and related organizations. 9. Gargas,A,Trest,M.T,Christensen,M.Volk,T.J.Blehert,D.S.Geomyces Scientifically led development of disease-resistant crop varieties has been destructans sp.nov.associated with bat white-nose syndrome.Mycotaxon 108, 147-154(2009). mainly successful,although monocultures have in some instances vastly 10.Lorch,J.M.et al.Experimental infection of bats with Geomyces destructans causes increased the susceptibility of harvests to highly virulent pathogens,a white-nose syndrome.Nature 480,376-378(2011). pertinent example being P.graminis Ug99.Conversely,although there 11. Frick,W.F.et al.An emerging disease causes regional population collapse of a common North American bat species.Science 329,679-682(2010). have been some attempts to mitigate the fungal disease burden in wildlife Population viability analysis showing the high risk of extinction of little brown in situ-most notably efforts to eliminate B.dendrobatidis in infected bats caused by the emergence of a pathogenic fungus. populations with the antifungal itraconazole"and the use of probiotic 12. Boyles,J.G.Cryan,P.M.McCracken,G.F.Kunz,T.H.Economic importance of bats in agriculture.Science 332,41-42(2011). bacteria-communicable wildlife EIDs are essentially unstoppable 13. Berger,L.et al Chytridiomycosis causes amphibian mortality associated with once they have emerged.International biosecurity against the spread population declines in the rain forests of Australia and Central America.Proc.Natl of plant fungal pathogens,although not perfect,is more advanced than Acad.Sci.US495.9031-9036(1998). protocols to protect against the introduction of animal-associated fungi The first study describing the discovery of amphibian chytridiomycosis in the tropics. Fundamentally,this is the result of a financial dynamic:wildlife is not 14.Longcore,J.E.,Pessier,A.P.&Nichols,D.K.Batrachochytrium dendrobatidis gen.et correctly valued economically,whereas crops are. sp.Nov.,a chytrid pathogenic to amphibians.Mycologia 91,219-227 (1999). The World Organisation for Animal Health(also known as the OIE) 15.Fisher,M.C.Garner,T.W.J.Walker,S.F.Global emergence of Batrachochytrium dendrobatidis and amphibian chytridiomycosis in space,time,and host.Annu.Rev. and the FAO may be the best-placed authorities to coordinate tighter Microbiol.63,291-310(2009) biosecurity controls for trade-associated fungal pathogens of animals. 16. Bd-Maps.(http://www.bd-maps.net/)(accessed,February 2012). The OIE has listed B.dendrobatidis and the crayfish pathogen A.astaci 17.Cheng,T.L.,Rovito,S.M.,Wake,D.B.Vredenburg,V.T.Coincident mass extirpation of neotropical amphibians with the emergence of the infectious fungal in the Aquatic Animal Health Code as internationally notifiable pathogen Batrachochytrium dendrobatidis.Proc.Natl Acad.Sci.USA 108, infections,and the FAO compiles outbreak data on transboundary 6502-9507(2011) animal diseases using the emergency prevention information system 18. Crawford,A J.,Lips,K.R.Bermingham,E Epidemic disease decimates (EMPRES-i).Similarly,the IUCN Wildlife Health Specialist Group amphibian abundance,species diversity,and e wolutionary history in the highlands of central Panama.Proc.Nat/Acad.Sci.USA 107,13777-13782(2010). determines policy that is specific to combating emerging wildlife disease 19. Colon-Gaud,C.etal.Assessing ecological responses to catastrophic amphibian internationally.On national scales there are a number of initiatives declines:patterns of macroinvertebrate production and food web structure in being deployed and in the United States the National Wildlife Health upland Panamanian streams Limnol.Oceanogr.54,331-343(2009). 20.Stuart,S.N.et al Status and trends of amphibian declines and extinctions Centre has developed the national federal plan to mitigate WNS in worldwide.Science 306,1783-1786(2004). bats.Intensive monitoring and surveillance will be increasingly import- Analysis describing the high levels of amphibian extinctions caused by many environmental factors and disease. ant in the coming years because predictive modelling and small-scale 21. Kim,K.Harvell,C.D.The rise and fall of a six-year coral-fungal epizootic.Am.Nat experiments can never fully predict future disease spread and severity. 164.S52-S63(2004). An increased political and public profile for the effects of fungal diseases Cameron,S.A et al.Patterns of wides ead decline in North American bumble bees.Proc.Natl Acad.Sci.USA 108,662-667 (2011). in natural habitats is needed to highlight the importance of fungal 23.Bymes,E J.Ill etal Emergence and pathogenicity of highly virulent Cryptococcus disease control outside of the managed agricultural environment to gatti genotypes in the northwest United States.PLoS Pathog.6,e1000850(2010) 192 NATURE VOL 484 12 APRIL 2012 2012 Macmillan Publishers Limited.All rights reserved

release of 270 megatonnes of CO2 over the periodfrom 2000 to 2020, with a clearly ascribed economic cost both for the wood itself and the carbon released94. These, and other diseases such as ‘sudden oak death’ in California and ‘foliar and twig blight’ and ‘dieback’ on ornamental trees, woody shrubs and forestry plants in the European Union, affect eco￾logical diversity, are costly to manage and account for huge losses of fixed CO2. Indeed, we calculate regional losses of absorbed CO2 to total 230– 580 megatonnes for just a handful of diseases (Supplementary Table 5) with the higher figure equating to 0.069% of the global atmospheric CO2. We have included both emerging (Jarrah dieback, sudden oak death and pine beetle–blue-stain fungus) and emergent diseases (Dutch elm blight and chestnut blight), as these represent the few examples for which informed estimates are possible. We are unable to quantify any of the many other recent emerging diseases, such as red band needle blight of pines, Phytophthora alni on alders or pitch pine canker on Monterey pines, owing to a lack of data and economic interest, both of which are trends that must be reversed. Assessing the economic burden of fungal mycoses in animals is a challenging task. Although the impact of fungal EIDs is manifested in domestic animal settings, particularly the amphibian trade95 and in regions where virulent lineages have established96, reporting mechanisms for outbreaks do not widely exist. In natural settings, valua￾tions have recently estimated the losses to US agriculture that are the result of declines in bat populations at more than US$3.7 billion per year (ref. 12). However, although broad ecosystem-level impacts of other fungal EIDs of wildlife are suspected, economic valuations of the ecosystem services that these species support are wholly lacking. Mitigating fungal EIDs in animals and plants The high socioeconomic value of crops means that detection and control of fungal diseases in agriculture far outpaces that in natural habitats. Epidemiological models have been developed to predict the risk of seasonally specific crop pathogens, allowing targeted control, and spe￾cific threats are assessed through consortia of research, governmental and global non-governmental organizations, led by the United Nations Food and Agricultural Organization (FAO), and related organizations. Scientifically led development of disease-resistant crop varieties has been mainly successful, although monocultures have in some instances vastly increased the susceptibility of harvests to highly virulent pathogens, a pertinent example being P. graminis Ug99. Conversely, although there have been some attempts to mitigate the fungal disease burden in wildlife in situ—most notably efforts to eliminate B. dendrobatidis in infected populations with the antifungal itraconazole97 and the use of probiotic bacteria98—communicable wildlife EIDs are essentially unstoppable once they have emerged. International biosecurity against the spread of plant fungal pathogens, although not perfect, is more advanced than protocols to protect against the introduction of animal-associated fungi. Fundamentally, this is the result of a financial dynamic: wildlife is not correctly valued economically, whereas crops are. The World Organisation for Animal Health (also known as the OIE) and the FAO may be the best-placed authorities to coordinate tighter biosecurity controls for trade-associated fungal pathogens of animals. The OIE has listed B. dendrobatidis and the crayfish pathogen A. astaci in the Aquatic Animal Health Code as internationally notifiable infections, and the FAO compiles outbreak data on transboundary animal diseases using the emergency prevention information system (EMPRES-i). Similarly, the IUCN Wildlife Health Specialist Group determines policy that is specific to combating emerging wildlife disease internationally. On national scales there are a number of initiatives being deployed and in the United States the National Wildlife Health Centre has developed the national federal plan99 to mitigate WNS in bats. Intensive monitoring and surveillance will be increasingly import￾ant in the coming years because predictive modelling and small-scale experiments can never fully predict future disease spread and severity. An increased political and public profile for the effects of fungal diseases in natural habitats is needed to highlight the importance of fungal disease control outside of the managed agricultural environment to policy makers. If this occurs, then there will be more sympathy for attempts to improve the regulatory frameworks that are associated with biosecurity in international trade, as this is the most important tool to tackle both plant and animal fungal EIDs now and in the future. The monitoring of fungal inocula in wild populations should be the utmost priority and tighter control of international trade in biological material must be imposed, and with considerable haste. Inadequate biosecurity will mean that new fungal EIDs and virulent races will emerge at an increasingly destructive rate. In addition to better global monitoring and control, attention must also be turned to increasing our understanding of the interactions between hosts, pathogens and the environment, across regional and global scales. Integrated approaches encompassing theoretical and practical epidemiology, climate forecasting, genomic surveillance and monitoring molecular evolution are needed. These should be facilitated by scientists from currently disparate research fields entering into regular global discussions to develop clear and urgent strategies for working towards the elusive magic bullet for emerging fungal diseases: effective prevention and timely control. 1. The Institute ofMedicine. Fungal Diseases: an Emerging Threat to Human Animal and Wildlife Health (National Academy of Sciences, 2011). The output of a key workshop assessing the risk of novel fungal diseases. 2. Pennisi, E. Armed and dangerous. Science 327, 804–805 (2010). 3. Gru¨nwald, N. J., Goss, E. M. & Press, C. M. Phytophthora ramorum: a pathogen with a remarkably wide host range causing sudden oak death on oaks and ramorum blight on woody ornamentals. Mol. Plant Pathol. 9, 729–740 (2008). 4. Anderson, P. K. et al. Emerging infectious diseases of plants: pathogen pollution, climate change and agrotechnology drivers. Trends Ecol. Evol. 19, 535–544 (2004). The first meta-analysis of emerging plant diseases. Reasons for this emergence are proposed and the cost to human welfare and biodiversity is estimated. 5. Brown, J. K. M. & Hovmoller, M. S. Aerial dispersal of pathogens on the global and continental scales and its impact on plant disease. Science 297, 537–541 (2002). 6. Daszak, P., Cunningham, A. A. & Hyatt, A. D. Emerging infectious diseases of wildlife—threats to biodiversity and human health. Science 287, 443–449 (2000). 7. Smith, K. F., Sax, D. F. & Lafferty, K. D. Evidence for the role of infectious disease in species extinction and endangerment. Conserv. Biol. 20, 1349–1357 (2006). 8. Blehert, D. S. et al. Bat white-nose syndrome: an emerging fungal pathogen? Science 323, 227 (2009). 9. Gargas, A., Trest, M. T., Christensen, M., Volk, T. J. & Blehert, D. S. Geomyces destructans sp. nov. associated with bat white-nose syndrome. Mycotaxon 108, 147–154 (2009). 10. Lorch, J. M. et al. Experimental infection of bats with Geomyces destructans causes white-nose syndrome. Nature 480, 376–378 (2011). 11. Frick, W. F. et al. An emerging disease causes regional population collapse of a common North American bat species. Science 329, 679–682 (2010). Population viability analysis showing the high risk of extinction of little brown bats caused by the emergence of a pathogenic fungus. 12. Boyles, J. G., Cryan, P. M., McCracken, G. F. & Kunz, T. H. Economic importance of bats in agriculture. Science 332, 41–42 (2011). 13. Berger, L. et al. Chytridiomycosis causes amphibian mortality associated with population declines in the rain forests of Australia and Central America. Proc. Natl Acad. Sci. USA 95, 9031–9036 (1998). The first study describing the discovery of amphibian chytridiomycosis in the tropics. 14. Longcore, J. E., Pessier, A. P. & Nichols, D. K. Batrachochytrium dendrobatidis gen. et sp. Nov., a chytrid pathogenic to amphibians. Mycologia 91, 219–227 (1999). 15. Fisher, M. C., Garner, T. W. J. & Walker, S. F. Global emergence of Batrachochytrium dendrobatidis and amphibian chytridiomycosis in space, time, and host.Annu. Rev. Microbiol. 63, 291–310 (2009). 16. Bd-Maps. Æhttp://www.bd-maps.net/æ (accessed, February 2012). 17. Cheng, T. L., Rovito, S. M., Wake, D. B. & Vredenburg, V. T. Coincident mass extirpation of neotropical amphibians with the emergence of the infectious fungal pathogen Batrachochytrium dendrobatidis. Proc. Natl Acad. Sci. USA 108, 9502–9507 (2011). 18. Crawford, A. J., Lips, K. R. & Bermingham, E. Epidemic disease decimates amphibian abundance, species diversity, and evolutionary history in the highlands of central Panama. Proc. Natl Acad. Sci. USA 107, 13777–13782 (2010). 19. Colo´n-Gaud, C. et al. Assessing ecological responses to catastrophic amphibian declines: patterns of macroinvertebrate production and food web structure in upland Panamanian streams. Limnol. Oceanogr. 54, 331–343 (2009). 20. Stuart, S. N. et al. Status and trends of amphibian declines and extinctions worldwide. Science 306, 1783–1786 (2004). Analysis describing the high levels of amphibian extinctions caused by many environmental factors and disease. 21. Kim, K. & Harvell, C. D. The rise and fall of a six-year coral-fungal epizootic. Am. Nat. 164, S52–S63 (2004). 22. Cameron, S. A. et al. Patterns of widespread decline in North American bumble bees. Proc. Natl Acad. Sci. USA 108, 662–667 (2011). 23. Byrnes, E. J. III et al. Emergence and pathogenicity of highly virulent Cryptococcus gattii genotypes in the northwest United States.PLoS Pathog.6, e1000850 (2010). 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REVIEW RESEARCH 12 APR IL 2012 | VOL 484 | NATURE | 193 ©2012 Macmillan Publishers Limited. All rights reserved

RESEARCH REVIEW 93.Loo,J.A Ecological impacts of non-indigenous invasive fungi as forest pathogens. Acknowledgements M.C.F.was supported by grants from the Wellcome Trust, Biol Invasions 11,81-96(2009). Natural Environment Research Council (NERC),and the European Research Area 94.Kurz,W.A.et al Mountain pine beetle and forest carbon feedback to climate (ERA)-net project BiodivERsA.D.A.H.was supported by a grant from the change.Nature452,987-990(2008). Leverhulme Trust,C.J.B.was supported by the US National Science Foundation Study describing pest-and pathogen-induced loss of forest carbon sinks. (NSF)Ecology of Infectious Disease grant EF-0723563.S.J.G.was supported by 95.Mazzoni,R.et al.Emerging pathogen of wild amphibians in frogs (Rana grants from the UK Biotechnology and Biological Sciences Research Council catesbeiana)farmed for international trade.Emerg.Infect Dis.9,9999(2003). (BBSRC)and the John Fell Fund of the University of Oxford,and S.L.M.was 96.Bymes,E.J.Il,Bildfell,R.J.Dearing.P.L.,Valentine,B.A.Heitman,J. supported by a graduate scholarship from Magdalen College,University of Oxford Cryptococcus gattii with bimorphic colony types in a dog in western Oregon: J.S.B.was supported by Google.org and the National Institutes of Health grant additional evidence for expansion of the Vancouver Island outbreak.J.Vet.Diagn. 5R01LM010812-02.N.Knowlton and J.Heitman provided impetus to develop this west21,133-136(2009) review. 97.Lubick,N.Emergency medicine for frogs.Nature 465,680-681 (2010). 98.Harris,R.N.etal Skin microbeson frogs prevent morbidity and mortality caused Author Contributions M.C.F.,D.A.H.,C.J.B.,S.LM.and SJ.G designed,analysed and by a lethal skin fungus.ISME J.3,818-824(2009). wrote the paper.Data were collected and analysed by J.S.B.and L.C.M. 99.U.S.Fish and Wildlife Service.A national plan for assisting states,federal agencies and tribes in managing white-nose syndrome in bats.(http://www.fws.gov/ Author Information Reprints and permissions information is available at WhiteNoseSyndrome/pdf/WNSnationalplanMay2011.pdf)(2011). www.nature.com/reprints.The authors declare no competing financial interests Readers are welcome to comment on the online version of this article at Supplementary Information is linked to the online version of the paper at www.nature.com/nature.Correspondence should be addressed to M.C.F www.nature.com/nature. (matthew.fisher@imperial.ac.uk)or S.J.G.(sarah.gur@plants.ox.ac.uk). 194 NATURE VOL 48412 APRIL 2012 2012 Macmillan Publishers Limited.All rights reserved

93. Loo, J. A. Ecological impacts of non-indigenous invasive fungi as forest pathogens. Biol. Invasions 11, 81–96 (2009). 94. Kurz, W. A. et al. Mountain pine beetle and forest carbon feedback to climate change. Nature 452, 987–990 (2008). Study describing pest- and pathogen-induced loss of forest carbon sinks. 95. Mazzoni, R. et al. Emerging pathogen of wild amphibians in frogs (Rana catesbeiana) farmed for international trade. Emerg. Infect. Dis. 9, 995–998 (2003). 96. Byrnes, E. J. III, Bildfell, R. J., Dearing, P. L., Valentine, B. A. & Heitman, J. Cryptococcus gattii with bimorphic colony types in a dog in western Oregon: additional evidence for expansion of the Vancouver Island outbreak. J. Vet. Diagn. Invest. 21, 133–136 (2009). 97. Lubick, N. Emergency medicine for frogs. Nature 465, 680–681 (2010). 98. Harris, R. N. et al. Skin microbes on frogs prevent morbidity and mortality caused by a lethal skin fungus. ISME J. 3, 818–824 (2009). 99. U.S. Fish and Wildlife Service. A national plan for assisting states, federal agencies, and tribes in managing white-nose syndrome in bats. Æhttp://www.fws.gov/ WhiteNoseSyndrome/pdf/WNSnationalplanMay2011.pdfæ (2011). Supplementary Information is linked to the online version of the paper at www.nature.com/nature. Acknowledgements M.C.F. was supported by grants from the Wellcome Trust, Natural Environment Research Council (NERC), and the European Research Area (ERA)-net project BiodivERsA. D.A.H. was supported by a grant from the Leverhulme Trust, C.J.B. was supported by the US National Science Foundation (NSF) Ecology of Infectious Disease grant EF-0723563. S.J.G. was supported by grants from the UK Biotechnology and Biological Sciences Research Council (BBSRC) and the John Fell Fund of the University of Oxford, and S.L.M. was supported by a graduate scholarship from Magdalen College, University of Oxford. J.S.B. was supported by Google.org and the National Institutes of Health grant 5R01LM010812-02. N. Knowlton and J. Heitman provided impetus to develop this review. Author Contributions M.C. F., D.A.H., C.J.B., S.L.M. and S.J.G designed, analysed and wrote the paper. Data were collected and analysed by J.S.B. and L.C.M. Author Information Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests. Readers are welcome to comment on the online version of this article at www.nature.com/nature. Correspondence should be addressed to M.C.F. (matthew.fisher@imperial.ac.uk) or S.J.G. (sarah.gurr@plants.ox.ac.uk). RESEARCH REVIEW 194 | NATURE | VOL 484 | 12 APR IL 2012 ©2012 Macmillan Publishers Limited. All rights reserved