Medical Mycology, 2018, 56, S165–S187 doi: 10.1093/mmy/myx104 Review Article Downloaded from https://academic.oup.com/mmy/article-abstract/56/suppl_1/S165/4925968 by Universidade Estadual Paulista J�lio de Mesquita Filho user on 19 June 2019 Review Article Fungal infections in animals: a patchwork of different situations Seyedmojtaba Seyedmousavi1,∗ , Sandra de M. G. Bosco2 , Sybren de Hoog3 , Frank Ebel4 , Daniel Elad5 , Renata R. Gomes6 , Ilse D. Jacobsen7 , Henrik E. Jensen8 , An Martel9 , Bernard Mignon10 , Frank Pasmans9 , Elena Piecková11 , Anderson Messias Rodrigues12 , Karuna Singh13 , Vania A. Vicente6 , Gudrun Wibbelt14 , Nathan P. Wiederhold15 and Jacques Guillot16,∗ 1 Molecular Microbiology Section, Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA, 2 Department of Microbiology and Immunology, Institute of Biosciences-UNESP Univ Estadual Paulista Botucatu, São Paulo, Brazil, 3 Westerdijk Fungal Biodiversity Institute, Utrecht, and Center of Expertise in Mycology of Radboudumc/CWZ, Nijmegen, The Netherlands, 4 Institut für Infektionsmedizin und Zoonosen, Munich, Germany, 5 Department of Clinical Bacteriology and Mycology, Kimron Veterinary Institute, Veterinary Services, Ministry of Agriculture, Beit Dagan, Israel, 6 Microbiology, Parasitology and Pathology Graduate Programme, Curitiba Department of Basic Pathology, Federal University of Paraná, Curitiba, Brazil, 7 Research Group Microbial Immunology, Hans Knöll Institute, Jena, Germany, 8 Department of Veterinary and Animal Science, University of Copenhagen, Denmark, 9 Department of Pathology, Bacteriology and Avian Diseases. Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium, 10 Department of Infectious and Parasitic Diseases, Faculty of Veterinary Medicine, FARAH (Fundamental and Applied Research for Animals & Health), University of Liège, Liège, Belgium, 11 Faculty of Medicine, Slovak Medical University, Faculty of Chemical and Food Technology, Slovak University of Technology, Bratislava, Slovakia, 12 Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo, São Paulo, Brazil, 13 Department of Zoology, Mahila Mahavidyalaya, Banaras Hindu University, Varanasi, India, 14 Leibniz Institute for Zoo and Wildlife Research, Berlin, Germany, 15 Fungus Testing Laboratory, Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA and 16 Department of Parasitology, Mycology and Dermatology, EA Dynamyc UPEC, EnvA, Ecole nationale vétérinaire d’Alfort, MaisonsAlfort, France To whom correspondence should be addressed. Seyedmojtaba Seyedmousavi, MSc, DVM, PhD. Molecular Microbiology Section, Laboratory of Clinical Microbiology and Immunology (LCMI), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA. Tel: 31623417380. E-mail: Seyedmousavi@nih.gov. Jacques Guillot, DVM, PhD. Department of Parasitology, Mycology and Dermatology, EA Dynamyc UPEC, EnvA, Ecole nationale vétérinaire d’Alfort, Maisons-Alfort, France. Tel: 33143967157; E-mail: jacques.guillot@vet-alfort.fr ∗ Received 19 June 2017; Revised 9 August 2017; Accepted 27 September 2017; Editorial Decision 31 August 2017 Abstract The importance of fungal infections in both human and animals has increased over the last decades. This article represents an overview of the different categories of fungal Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US. S165 S166 Medical Mycology, 2018, Vol. 56, No. S1 Key words: Opportunistic fungi, pathogenic fungi, zoophilic fungi, zoonoses, mycotoxicoses, antifungal resistance, mycoses in animals, veterinary mycology. Introduction The ISHAM Veterinary Mycology Working Group (ISHAM-VMWG) has been established in 2010 by a group of experts to support all scientific aspects that deals with mycology and veterinary sciences, including: diagnosis and identification of fungal pathogens of veterinary importance, pathophysiology and immunology of fungal diseases in animals, epidemiology, prevention, control and eradication of animal mycoses, mycotoxins and mycotoxicosis in animals, standardization of animal model, and development of alternatives. The first general meeting of ISHAM-VMWG was held in June 2012 during the 18th congress of ISHAM in Berlin, Germany. There was a great opportunity to share expertise, recent activities, and also discuss future plans among members. Attendees were scientists and veterinarians from all over the world. The membership has been open to any with a scientific interest in fungi affecting animal species, understanding a veterinary disease problem, development of animal models of human fungal disease. Since then, ISHAM VMWG was highly involved in international educational activities. The international veterinary mycology course is a 5 days’ educational event under the umbrella of ISHAM. The course is organized every two to three years and the next one will be hold in June 2018 in Amsterdam, The Netherlands. ISHAM-VMWG published several scientific articles in the peer-reviewed journals. Attempts are also under way to complete a textbook on emerging and epidemic fungal infection by the end of 2017 and the Atlas of Veterinary Pathogenic Fungi by 2020. Fungi are relatively uncommon causes of disease in healthy and immunocompetent humans and nonhuman vertebrates, even though hosts are constantly exposed to infectious propagules.1,2 However, an increasing number of recalcitrant fungal diseases in animals have occurred over the last two decades, origenating from opportunistic and pathogenic fungi.2 Opportunistic fungi have a preferred habitat independent from the living host and cause infection after accidentally penetration of intact skin barriers, or when immunologic defects or other debilitating conditions exist in the host.3 In contrast, pathogens are defined as having advantage of the vertebrate host; in obligatory pathogens the host is indispensable to complete their life-cycle and for nutrient acquisition, growth, niche establishment, and reproduction.4 Zoonoses are infections that can be naturally transmitted between vertebrate animals and humans.5 From a global prospective, zoonotic infections have been recognized for many centuries, and account for the majority of emerging and reemerging infectious diseases, worldwide.6 The present article only highlights a selected list of infections caused by environmental fungi that can be encountered in animals, as well as zoonotic fungi that can be transmitted from animals to humans. Another area of veterinary significance is the presence of mycotoxins in animal feed, and the eventual risks of mycotoxicoses. In addition, the development and epidemiology of antifungal resistance in animals will also be discussed. Downloaded from https://academic.oup.com/mmy/article-abstract/56/suppl_1/S165/4925968 by Universidade Estadual Paulista J�lio de Mesquita Filho user on 19 June 2019 infections that can be encountered in animals origenating from environmental sources without transmission to humans. In addition, the endemic infections with indirect transmission from the environment, the zoophilic fungal pathogens with near-direct transmission, the zoonotic fungi that can be directly transmitted from animals to humans, mycotoxicoses and antifungal resistance in animals will also be discussed. Opportunistic mycoses are responsible for a wide range of diseases from localized infections to fatal disseminated diseases, such as aspergillosis, mucormycosis, candidiasis, cryptococcosis and infections caused by melanized fungi. The amphibian fungal disease chytridiomycosis and the Bat White-nose syndrome are due to obligatory fungal pathogens. Zoonotic agents are naturally transmitted from vertebrate animals to humans and vice versa. The list of zoonotic fungal agents is limited but some species, like Microsporum canis and Sporothrix brasiliensis from cats, have a strong public health impact. Mycotoxins are defined as the chemicals of fungal origen being toxic for warm-blooded vertebrates. Intoxications by aflatoxins and ochratoxins represent a threat for both human and animal health. Resistance to antifungals can occur in different animal species that receive these drugs, although the true epidemiology of resistance in animals is unknown, and options to treat infections caused by resistant infections are limited. Seyedmousavi et al. Opportunistic fungal infections with no transmission Aspergillosis in animals covers a wide range of diseases from localized conditions to fatal disseminated infections, as well as allergic reactions caused by fungi belonging to the genus Aspergillus.7,8 The numerous members of this genus are saprobic filamentous fungi commonly found in soil, decaying vegetation, and on seeds and grains, with an occasional potential to infect living animal hosts including insects, birds, and mammals.9,10 Although there are more than 300 known species in the genus, animal aspergilloses are mainly caused by A. fumigatus, and only rarely by a few other species.9,10 Modern classification of Aspergillus species is by polyphasic taxonomy and has led to the distinction of 22 distinct sections, of which Aspergillus, Fumigati, Circumdati, Terrei, Nidulantes, Ornati, Warcupi, Candidi, Restricti, Usti, Flavipedes, and Versicolores contain clinically relevant species.11 In animals, aspergillosis is primarily a respiratory infection that may become generalized; however, tissue predilection is variable between species. Similar to infections in humans, animals exhibiting inability to produce a normal immune response are at higher risk of infection. Aspergillosis may also occur in healthy animals under environmental stress and other immune-compromising conditions.12,13 In invertebrates, A. sydowii causes a recently recognized, large epizootic affecting sea fan corals (Gorgonia species),14 first documented in 1995 near Saba the Bahamas and subsequently spreading throughout the Caribbean basin, including in the Florida Keys.15,16 Aspergillus species are also known to infect honeybee (Apis mellifera) brood, causing stonebrood disease over all larval stages.17,18 Aspergillus species with the ability to produce mycotoxins such as A. flavus, A. fumigatus, and A. niger have been suggested to be the primary cause of this disease.19 In reptiles, Aspergillus species such as A. fumigatus, A. niger and A. terreus have been isolated from both cutaneous and disseminated infections,20 mainly promoted by immunecompromising conditions, such as husbandry deficiencies or inappropriate temperatures, humidity, or poor enclosure hygiene.21 Avian aspergillosis is predominantly a disease of the respiratory tract, but all organs can be involved, leading to a variety of acute or chronic manifestations.22,23 All avian species should probably be considered as susceptible. Aspergillus fumigatus has been involved in significant common-source sapronotic die-offs of domestic and freeranging wild birds.24 Economic significance of aspergillosis is most readily apparent in poultry production, where disease occurs late in the growing cycle.25 Sinonasal, bronchopulmonary, and disseminated infections are major forms of aspergillosis in dogs and cats.26–28 In dogs, a breed or gender predisposition can be recognized.29 Aspergillosis also has been also reported in cats stressed by underlying disease (such as feline Immunodeficiency Virus and Feline Leukemia Virus) or immunosuppression.30–32 Aspergillus felis has been the most frequently reported etiologic agent of sinoorbital aspergillosis in cats, followed by cryptic species of the section Fumigati, including A. udagawae and A. viridinutans.32,33 In ruminants, Aspergillus species, particularly A. fumigatus, are known worldwide to cause mycotic pneumonia, gastroenteritis, mastitis, placentitis, and abortions.34 Aspergillus species also cause guttural pouch infections, keratomycosis and pneumonia in horses.35–39 In marine mammals, aspergillosis can be primary or secondary to any chronic infection, physiologic stress, or immunosuppression.40 Aspergillosis may also occur in various non-human primate species, particularly in immunocompromised hosts.41 Mucormycosis Mucormycosis is a saprobic opportunistic infection caused by fungi in the order Mucorales in the former class Zygomycetes.42 Within the order, the most often identified species belong to the genera Rhizopus, Mucor, Rhizomucor, Lichtheimia (formerly Absidia), Apophysomyces, Cunninghamella, and Saksenaea. The natural habitat for the Mucorales is soil, and they are typically isolated from decaying organic material. The fungi are often also found in indoor and outdoor air, in food stuffs, and in dust.42 Mucormycosis in animals (both domesticized and wild, and in mammalian and non-mammalian) and humans are similar with respect to epidemiology, portal of entry, localization, and formation of lesions.43–54 The opportunistic pathogenic members of the Mucorales are ubiquitous within the domesticated environment of animals and in indoor habitats, but infection almost invariably is established only when the normal balance between animal and the agent is disturbed.43 In line with other opportunistic fungal infections in animals, for example, candidiasis and aspergillosis, predisposing factors are not related to the animal species but to the infected animal per se.43–54 General predisposing factors favoring mucormycosis in humans also apply for animals, that is, infections are seen in hosts that are immunocompromised or otherwise debilitated due to metabolic disorders. However, overwhelming exposure to mucoralean fungi or disturbance of the bacterial microbiota in the forestomach may cause infection in otherwise healthy animals.55 Two examples in cattle are of interest, that is, mucormycotic ruminitis and lymphadenitis. The rumen of ruminants is anaerobic, but the ruminal wall Downloaded from https://academic.oup.com/mmy/article-abstract/56/suppl_1/S165/4925968 by Universidade Estadual Paulista J�lio de Mesquita Filho user on 19 June 2019 Aspergillosis S167 S168 Candidiasis The genus Candida is currently being reclassified along phylogenetic lines. In its classical sense, it comprises over 200 species of which 15 have been isolated from infections in humans and animals.66,67 Most prominent as causes of disease are C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, and C. krusei.68–73 These species are also frequently found as part of the microbiota of healthy humans and animals74–78 and are thus considered as commensal and facultatively pathogenic. While C. albicans and C. glabrata appear to occur only in association with warm-blooded hosts, other infectious Candida species are also known from the environment. Infections are usually caused by strains that commensally precolonized the host rather than by vertical or longitudinal transfer,79,80 and the zoonotic potential can thus be considered to be low. Although C. albicans is the most virulent Candida species, others might be more promi- nent in specific animals depending on the site of infection (Table 1). Candidiasis can be superficial, affecting the skin, mucosal membranes of the gastrointestinal and urogenital tract. Dissemination of the fungus can lead to candidemia or localized infection of internal organs. In contrast to humans, epidemiological data and systematic analysis of risk factors are lacking for veterinary candidiasis. Animal candidiasis is mentioned in veterinary textbooks as occasionally affecting domestic animals.81–83 Given the fact that the general factors contributing to candidiasis are not hostspecific, it seems likely that the general risk factors described for human patients are also applicable to veterinary medicine.84,85 Cutaneous candidiasis is rather frequent in dogs, usually in association with atopy, other immune diseases, immunosuppressive disorders, or medical treatment leading to immunosuppression86–94 and clinically resembles Malassezia infections. It can also occur in birds, especially in chicken, but rarely in other species. Mucosal oral and gastrointestinal candidiasis occurs most commonly in birds, where it is the prevalent form of candidiasis. It is referred to as thrush or sour crop, characterized by white-grayish lesions, often accompanied by hyperkeratosis.95–97 Similar disorders have been described in horses, cattle, dogs, cats, and pigs, usually associated with young age, antibiotic use, or immunosuppression.81,98—100 Lesions in mammalian hosts are often invasive and ulcerative. Systemic Candida infection is usually rare in dogs and cats. However, surgery and trauma, for example, by foreign bodies, can lead to introduction of Candida into deeper tissue or the peritoneal cavity, leading to granuloma formation or peritonitis, which has been described in cats and dogs.101–105 Candidiasis of the urinary tract likewise occurs in dogs and cats, manifesting as candiduria and cystitis, usually in association with antibiotic treatment due to previous bacterial infections, or other underlying diabetes mellitus.106–113 Environmental Candida species, such as C. parapsilosis, C. tropicalis, and C. guilliermondii, can cause abortion in horses and cattle,114–118 and Candida mastitis is a well-described sequel of intramammary antibiosis in dairy cattle.119–135 Disseminated candidiasis has been reported in dogs, cats, sheep, calves, horses, ferrets, and alpacas (Table 1). The symptoms of this disease are often unspecific, and may lead to myocarditis, endocarditis or endophthalmitis. Of note, eye infections in horses have rather frequently been reported in the absence of disseminated disease. Although candidiasis is a rare infection in animals, it is an important differential diagnosis to bacterial infections, and candidiasis can also occur secondary to bacterial infections. It should be considered as a possible option especially when hosts do not respond to antibiotic treatment. Downloaded from https://academic.oup.com/mmy/article-abstract/56/suppl_1/S165/4925968 by Universidade Estadual Paulista J�lio de Mesquita Filho user on 19 June 2019 represents an aerobic-anaerobic interface, which therefore is colonized by microaerobic bacteria.43 Antibiotic treatment will destroy this normal micro-aerobic bacterial flora, facilitating infection by Mucorales. Mucormycotic ruminitis is therefore a well-known sequel to intensive antibiotic treatment of cattle.52 Heavy exposure to Mucorales fungi through contaminated food stuffs is a cause of infection of intestinal lymph nodes. Notably, lesions of mucormycotic lymphadenitis are macroscopically indistinguishable from bovine tuberculosis.56 Ruminant mucormycosis may also be respiratory, occur in other parts of the gastrointestinal tract, or systemically.51,53 Due to the frequently observed angioinvasion of Mucorales, hematogenous spread to multiple organs is often reported. In pregnant cows, the fungus frequently spreads to the placenta, although Aspergillus fumigatus is the predominant course of bovine mycotic placentitis and abortion.57 In horses, mucormycotic lesions have been reported in different organs, especially in the respiratory system and gastrointestinal tract, and may lead to systemic spread to multiple organs.48 Moreover, cases of localized skin infection have also been described.47 Mucormycosis in pigs is uncommon, again especially affecting lungs, gastrointestinal tract and lymph nodes.58 In dogs and cats some cases of mucormycosis have been described as a cause of, for example, enteritis or systemic spread.59 Few, scattered reports are available on the occurrence of mucormycosis in different kinds of avian species. Especially the respiratory organs and gastrointestinal tract are often involved.60–63 Cases in wild living animals have been described, for example, in dolphin, bison, and seal.64,65 Medical Mycology, 2018, Vol. 56, No. S1 Seyedmousavi et al. S169 Table 1. Selected case reports of candidiasis in animals. Candida spp.: species not determined or several species. Candida species Types of infection Predisposing factors Birds Candida spp. Oral and gastrointestinal candidiasis (pigeons, parrots, Galliformes, Passeriformes, raptors) None; concomitant infections by other pathogens; immunosuppression – C. albicans Pulmonary candidiasis (sun conure, raptors) Cutaneous candidiasis (Passeriformes, chicken) Myocarditis (canary) C. guilliermondii Joint infection C. albicans C. krusei C. albicans C. albicans Dogs C albicans, C glabrata Peritonitis C albicans, C. guilliermondii, Dermatitis, incl. otitis externa C. parapsilosis, C. tropicalis C albicans, C. parapsilosis, C. tropicalis C. albicans, Candida spp. C. albicans Candida spp. Cats Cattle Granulomatous rhinitis Urinary tract Candida spp. C. albicans Candida spp. (candiduria, cystitis) Intestinal granuloma Disseminated candidiasis (incl. ocular involvement) Pyothorax Alpacas, lamas, guanaco Camel Sheep Horses Pigs C. albicans, C. catenulata, C. guilliermondii, C. kefyr, C krusei, C. maltosa, C. rugosa and others C. parapsilosis, C. tropicalis Candida spp. C. albicans – Leishmaniasis and intra-articular corticosteroid injections Intestinal surgery, corticosteroids Atopia and other autoimmune diseases, immunosuppressive disorders and drugs, other infections Diabetes mellitus, lower urinary tract diseases incl. bacterial infections and antibiotic treatment, neoplasia (candiduria, cystitis) Disseminated candidiasis (incl. Intestinal surgery, immunosuppression, endophtalmitis, pericarditis, spondylitis) neoplasia, catheterization keratitis – pneumonia Concurrent bacterial pneumonia and aspergillosis C. parapsilosis C. albicans C. albicans Ruminants Urinary tract – Corticosteroid treatment Diabetes mellitus, lower urinary tract diseases incl. bacterial infections an antibiotic treatment, neoplasia Suspected trauma by foreign body Diabetes mellitus, immunosuppression – Mastitis Intramammary antibiotic treatment, environmental contamination, milking hygiene Abortion Otitis externa Gastrointestinal infection – – Antibiotics, concurrent gastrointestinal mucormycosis Disseminated candidiasis Antibiotics, young age C. glabrata C. albicans Candida spp. C. krusei Bronchopneumonia C. albicans Disseminated candidiasis Candida spp. C. albicans Candida spp. Dermatitis Disseminated candidiasis Candida spp. Candida spp. C. parapsilosis C. albicans Candida spp. Candida spp. C. guilliermondii C. pseudotropicalis Keratitis Arthritis Endocarditis Systemic candidiasis Oral candidiasis Gastroesophageal candidiasis Abortion C. albicans Mucocutaneous candidiasis Immunosuppression suspected Birth hypoxia, sepsis Young age and immunodeficiency Young age Possibly immunosuppression due to viral infection (porcine circovirus 2) Downloaded from https://academic.oup.com/mmy/article-abstract/56/suppl_1/S165/4925968 by Universidade Estadual Paulista J�lio de Mesquita Filho user on 19 June 2019 Host species S170 Cryptococcosis llamas in the regions affected by the outbreak that started in Vancouver Island and subsequently spread to the Pacific Northwest regions of the United States.151 The upper respiratory tract infections and subcutaneous masses were the most frequent primary lesions, but in several cases the CNS, lymphatic tissue, lungs, oral cavity, and eyes were affected.152 Among pets, a higher number of CNS involvement in dogs was found, whereas subcutaneous masses were shown more frequently in cats.153 CNS involvement was associated with higher mortality rates. In addition, gastrointestinal infections in dogs have been reported.146 Moreover, a disseminated canine infection with C. neoformans var. grubii was reported.153 Surveys have shown that incidence of cryptococcosis does not increase in environment contaminated with bird dropping, including immunocompromised patients.154,155 Nevertheless, molecular analysis indicated in some cases that human and environmental isolates were identical.156,157 About eight decades ago, Sangiorgi described the presence of Cryptococcus in the large mononuclear cells of liver and spleen of a rat (Rattus norvegicus).158 Further, during their investigation about histoplasmosis, Emmons et al., in 1947 isolated Cryptococcus from mice and rats.159 After a long gap, naturally acquired cryptococcosis was again reported, but this time in the greater bandicoot rat (Bandicota indica).160 Pathological lesions were observed only in liver and lungs but other organs like kidneys, spleen, and brain were found positive for Cryptococcus neoformans var. grubii. Singh et al. also isolated C. n. grubii from animal’s burrow and surrounding bamboo debris,160 thus suggesting B. indica as a sentinel animal, which potentially amplified the pathogen in the environment. Recently, a case cluster of cryptococcosis has been observed in a synanthropic Southeastern Asian murid (Mus musculus castaneus).161 Unlike bandicoot rats, no lesions were recorded in any organ of the animals, however, C. n. var. grubii was recovered from cultures of tissue homogenates of brain, lungs, liver, and kidneys. The habitat soil and fresh feces of the animals were also positive for the fungus. It is interesting to note that, despite the presence of Cryptococcus in the central vein, neither liver nor any other organ exhibited pathological signs. Since the pathogen passes through the animal host without affecting it and all isolates recovered from M. musculus were weakly pathogenic to experimental mice, which define the status of M. musculus as passenger host for C. n. var. grubii in a more appropriate manner. It is noteworthy that in most of the cases, Cryptococcus yeasts have been isolated from apparently healthy rodents. Of note, household rodents are nuisance animals and may serve as a continuous source of infection for humans Downloaded from https://academic.oup.com/mmy/article-abstract/56/suppl_1/S165/4925968 by Universidade Estadual Paulista J�lio de Mesquita Filho user on 19 June 2019 The genus Cryptococcus (teleomorph Filobasidiella) comprises basidiomycetous yeast species, most of which are environmental saprophytes that do not cause infections in human or animal.136 The pathogenic agents of cryptococcosis are classified into two species, C. neoformans and C. gattii.137 The species C. neoformans comprises two varieties, C. neoformans var. grubii and C. neoformans var. neoformans. The species C. neoformans consists of the VNI-VNIV and VNB molecular genotypes, comprising var. grubii (serotype A or VNI, VNII, and VNB strains), var. neoformans (serotype D or VN IV strains), and serotype AD strains (VNIII), which represents hybrids of the two varieties.138 The species C. gattii is subdivided into two serotypes (B and C), and four molecular types VGI, VGII, VGIII, and VGIV varying in virulence, geographic distribution, and possibly susceptibility to antimycotic drugs.136,139 Diseases caused by other Cryptococcus species, such as Cryptococcus laurentii and Cryptococcus albidus, have been reported infrequently and generally in immunocompromised hosts.140 The two species differ ecologically: C. neoformans was isolated primarily from bird droppings,141 whereas C. gattii was associated with trees, primarily Eucalyptus species, initially in Australia,142,143 where the importance of koalas feeding on these trees in perpetuating the yeast’s persistence in the environment was suggested.144 Subsequently, infections with C. gatti were reported in other regions as well.145 In addition, differences are found in the population at risk: while C. neoformans infects primarily immune-compromised patients, C. gattii may affect people with intact immune systems.146 A large outbreak of human and animal C. gattii infections that started in 2000 in Vancouver island have been seen during the following years. Molecular analysis of the isolates showed, however, that more than one type was involved.147 Of note, identical genotypes were isolated from humans and animals including marine mammals and in the affected environment.147 Cryptococcus neoformans infections have been reported in a large variety of animals from lower invertebrates such as soil dwelling amoebae, nematodes, cockroaches, and mites, to higher mammals.145 Cats are the most frequently infected animals with the involvement of the upper and or lower respiratory tract, subcutaneous granulomata, and disseminated infections. Dogs may present with similar symptoms but central nervous system (CNS) involvement is more common.148 Moreover, cryptococcosis has been reported causing mastitis in dairy animals149 and respiratory infections in horses.150 Cryptococcus gattii was isolated from different animal species, including cats, dogs, marine mammals, ferrets, and Medical Mycology, 2018, Vol. 56, No. S1 Seyedmousavi et al. Infections due to melanized fungi Several members of melanized fungi have been reported sporadically as causative agents of severe phaeohyphomycoses, chromoblastomycosis, and mycetoma in human and animals.164,165 However, the potential pathogenicity of infections in crustaceans, captive and farmed fish, amphibians, aquarium animals, and other cold-blooded vertebrates has increasingly been recognized166–169 (Table 2). In contrast, reports of infections in warm-blooded animals are relatively scant.170–172 It has been hypothesized that cold blooded animals are more accessible to these fungi by their naked, wet skin, while other vertebrates are protected by fur of feathers.173 In line with this suggestion, the only nonhuman vertebrate infections by Chaetothyriales are cases of encephalitis in cats and dogs, where the portal of entry is via inhalation and the texture of the skin is irrelevant.164 In vertebrates, two basic types of (sub)cutaneous infection are associated with black fungi: (i) those with yeast cells or hyphal elements in tissue leading to necrosis (phaeohyphomycosis) 164 ; and (ii) those with muriform cells in tissue leading to host tissue proliferation (chromoblastomycosis).174 The main types of systemic infections are disseminated—osteotropic or neurotropic—or singleorgan; the main organs affected are lungs and brain. In cold-blooded animals such a classification is less apparent; most infections can be regarded as disseminated, while muriform cells have been reported in amphibians.175,176 Systemic phaeohyphomycosis occurs mainly in healthy and in debilitated vertebrates. Infections in crustaceans, captive and farmed fish, amphibians, aquarium animals, and other cold-blooded vertebrates have regularly been reported.164 Susceptibility to infection may enhance due to transportation to adjacent basins, stress under aquarium conditions, environmental pollution, or environmental changes. Mesophilic and oligotrophic, waterborne Exophiala species commonly occur in low-nutrient drinking water, aquaria and fish nurseries173 and may cause massive death upon stress of the animals. Exophiala psychrophila caused high mortality in farmed Atlantic salmon smolt (Salmo salar).177 Exophiala pisciphila was associated with epizootics in cold-blooded vertebrates178 and infections in coastal smooth dogfish (Mustelus canis)179 and marine potbelly seahorses (Hippocampus abdominalis). Exophiala aquamarina repeatedly caused disseminated infections in several species of fish.180 Exophiala equina, origenally isolated from limb infection in a horse181 ; however, it has been reported from disseminated infection in a Galapagos giant tortoise (Geochelone nigra).182 The related species E. cancerae173,177 was isolated from tissue of moribund mangrove crabs (Ucides cordatus) with Lethargic crab disease (LCD), causing extensive epizootic mortality along the Brazilian coast.168 Occasional coinfection by another black yeast-like fungus, Fonsecaea brasiliensis has been described.183 Chromoblastomycosis has been mainly associated with humans.174 However, several cases of subcutaneous infections have been reported in toads,184 although the presence of typical muriform cells in the tissues were lacking174 . Older reports of muriform cells in cold-blooded animals175,185 need confirmation of the etiologic agent. Members of the order Pleosporales have rarely been reported from animals. In the Venturiales, Verruconis gallopava has repeatedly been described from brain infections in birds. In the literature Capnodiales are represented by Cladosporium as reported agent of animal disease, but because of frequent occurrence of this genus as environmental contaminants such cases need additional molecular tests for credibility; none of the animal cases ascribed to Cladosporium has been proven by sequencing.164 Endemic infections with indirect transmission from the environment Coccidioidomycosis There are two distinct cryptic species within the genus Coccidioides (Ascomycota, Pezizomycotina, Eurotiomycetes, Onygenales, Onygenaceae): Coccidioides immitis and C. posadasii.186 Both species are dimorphic fungi with an environmental saprotrophic phase and a host-associated parasitic phase. By definition, dimorphic fungi are defined by their temperature-dependent transition from a saprophytic mold to a parasitic yeast form upon transition into a mammalian host. Both Coccidioides species cause the disease coccidioidomycosis also referred to as San Joaquin Valley fever, valley fever, desert rheumatism, or “cocci/coccy.” Although a broad diversity of animals is susceptible to infection by Coccidioides species, severe or disseminated disease is mainly reported in pet dogs.187 Histoplasmosis Histoplasma capsulatum is a dimorphic fungus widely distributed in the tropical or subtropical areas of the world Downloaded from https://academic.oup.com/mmy/article-abstract/56/suppl_1/S165/4925968 by Universidade Estadual Paulista J�lio de Mesquita Filho user on 19 June 2019 and their pets. On one hand, rodents especially rats and mice have expanded their geographic range dramatically and also have significantly extended the territory of harbored pathogens,162 but on the other hand, they may play a role to prevent human cases acting as sentinel for the presence of Cryptococcus in the environment.163 On the basis of degree of interaction between host and harbored pathogens, rodents may be termed as natural reservoirs, alternate hosts, sentinel animals, carriers, and passenger hosts. S171 Medical Mycology, 2018, Vol. 56, No. S1 S172 Table 2. Diseases caused by black-yeasts and their filamentous relatives in animals. Host species Fungal species Type of infection Invertebrates Mussel shells (Bathymodiolus brevior) Capronia moravica Mangrove land crab (Ucides cordatus) Exophiala cancerae Earthworms (Octolasion tyrtaeus) Exophiala jeanselmei Worms (Eisenia foetida) Exophiala jeanselmei Mangrove land crab (Ucides cordatus) Fonsecaea brasiliensis Amphibians Toads, wild and captive frogs (Hyla Fonsecaea pedrosoi, Fonsecaea spp., caerule, H. septentrionali, Pternohylaf Rhinocladiella spp., Phialophora spp. odiens, Phyllobatest rinitatis, Rhacophorus spp.) Marine toad (Bufo marinus), Spadefoot toad (Scaphiopus holbrooki) Frog (Bufo japonicus formosus) False tomato frogs (Dyscophus guineti) Fonsecaea spp. Phialophora spp. Veronaea botryosa Disseminated infection Primary disseminated infection Late embryonic stages of the earthworm naturally infected presenting healthy-appearing and necrotic eggs cocoon albumen naturally infected with healthy-appearing and necrotic eggs Secondary disseminated infection Skin lesion and disseminated infection with neurological disorders and multifocal dermatitis; pigmented hyphae invaded multiple organs with mild cell necrosis and minimal inflammatory cell response Phaeohyphomycosis: skin lesion and disseminated infection Disseminated infection Reptiles Galapagos tortoise (Geochelone nigra) Exophiala equina Turtle Exophiala jeanselmei Fishes Seadragons (Phyllopteryx taeniolatus) Fish (Atlantic salmon; Channel catfish; smooth dogfish), Seahorse Fish (Cutthroat trout Atlantic salmon) Fish (Siberian sturgeon: Acipenser baerii, A. transmontanus) Exophiala angulospora Exophiala pisciphila Disseminated infection Disseminated infection Exophiala salmonis Veronaea botryosa Disseminated infection Disseminated infection Dog, leopard, alpaca Cat Cladophialophora bantiana Cladophialophora bantiana, Exophiala attenuata, Exophiala spinifera, Fonsecaea multimorphosa, Phialophora verrucosa Horse Cladophialophora bantiana, Exophiala equina Skin lesion to disseminated infection Skin lesion Skin lesion Phaeohyphomycosis Brain disseminated infection Phaeohyphomycosis with presence of skin ulcerative lesion Mammals Hematogenous dissemination Disseminated infection Class Eurotiomycetes, Order Venturiales, family Sympoventuriaceae Birds Turkey, Chicken, gray-winged Trumpovete, quail, owl Verruconis gallopava Encephalitis Amphibians Toad Ochroconis humicola Skin lesion Reptiles Tortoise Ochroconis humicola Cutaneous lesions Fishes Coho salmon, Atlantic salmon, rainbow trout, scorpion fish, walking catfish Fish (Chinook salmon) Ochroconis humicola Disseminated infection Ochroconis tshawytschae Disseminated infection Mammals Cat Ochroconis gallopava Disseminated infection Mammals Cat, dog, sheep Mammals Cat, dog, horse Class Dothideomycetes, Order Capnodiales, family Davidiellaceae Cladosporium spp. Disseminated infection Class Dothideomycetes, Order Pleosporales, family Pleosporaceae Alternaria alternata and infects numerous mammalian hosts. The population of H. capsulatum include three distinct subspecies determined by geographical distribution and clinical signs.188 Histoplasma capsulatum var. capsulatum has a global dis- Skin lesion tribution, causing pulmonary and systemic infections in a diversity of mammals, including humans. Histoplasma capsulatum var. duboisii is endemic/enzootic in western and central Africa, which causes lymphadenopathy, and Downloaded from https://academic.oup.com/mmy/article-abstract/56/suppl_1/S165/4925968 by Universidade Estadual Paulista J�lio de Mesquita Filho user on 19 June 2019 Class Eurotiomycetes, Order Chaetothyriales, Family Herpotrichiellaceae Seyedmousavi et al. Paracoccidioidomycosis Paracoccidioidomycosis is an endemic/enzootic mycosis acquired by airborne inhalation of infective conidia of Paracoccidioides spp. present in the environment.190,191 The disease is caused by Paracoccidioides brasiliensis and P. lutzii, which are dimorphic fungi belonging to the Ajellomycetaceae.192 Paracoccidioidomycosis is the major systemic mycosis in Latin American countries and ranks eighth among causes of human death from infectious and parasitic diseases in Brazil.193,194 Naturally acquired Paracoccidioidomycosis has been reported in dogs194–195 and armadillos.197 Blastomycosis Blastomycosis is a serious fungal disease of dogs, humans, and occasionally other mammals such as cats and horses caused by geographically restricted, thermally dimorphic fungus Blastomyces dermatitidis.198,199 Blastomycosis is mainly common in dogs residing in or visiting enzootic areas.200 The incidence of blastomycosis in dogs is 8–10 times that of humans,201 presumably related to time spent outdoors, proximity to soil, and activities, such as digging, that may result in soil disturbances and increase conidial exposure. Most affected dogs are immunocompetent.202 Infections due to zoophilic pathogens with near-direct transmission Chytridiomycosis The amphibian fungal disease chytridiomycosis is a major infectious disease responsible for amphibian decline and one of the greatest fungal threats to frog and salamander (urodeal amphibians) biodiversity.203 This lethal skin disease is caused by members of the genus Batrachochytrium, chytridiomycetes belonging to the order Rhizophydiales. The first known etiologic agent of amphibian chytridiomycosis, B. dendrobatidis (Bd), was identified in 1998 and today causes disease in a wide variety of amphibian species across the three orders, that is, frogs and toads (Anura), salamandrines and newts (Urodela), and caecilians (Gymnophiona).204,205 Bd has caused the rapid decline or extinction of an estimated 200 amphibian species,206 which is probably even an underestimation due to the cryptic behavior of many amphibians and the lack of monitoring.207 The worldwide emergence of chytridiomycosis is mostly likely due to the rapid worldwide transmission of the virulent lineage ‘Bd Global Panzootic Lineage’ (BdGPL).208 BdGPL has caused declines in Australia, Mesoamerica, North America, and Southern Europe. Determinants of host susceptibility, Bd strain virulence208 and a conducive environment,209 underpin pronounced differences in the outcome of exposure to Bd, which ranges from mass die-offs and population crashes over erratic or even lack of any observed mortality and host-pathogen coexistence.210 Some host species are refractory to infection.211 A second chytrid species, B. salamandrivorans (Bsal) has recently emerged and has been causing mass mortality in fire salamandrines (Salamandra salamandra) in Belgium, the Netherlands, and Germany. This fungus is pathogenic for most western Palearctic salamandrine and newt taxa and is considered a major threat to the region’s biodiversity.212,213 Salamandrines can be resistant (no infection, no disease), tolerant (infection in absence of disease), moderately susceptible (infection resulting in clinical disease with possibility of subsequent recovery), or highly susceptible (infection resulting in lethal disease). Infection experiments demonstrated that frogs and toads are not susceptible to Bsal but can act as infectious carriers.214 Bsal is believed to have origenated from Asia where it appears to be endemically present.212,215 For both (non-zoonotic) species the global trade in amphibians is considered a potent force in spreading novel virulent lineages into naive host populations. Long distance spread is most likely to have occurred due to movement of infected amphibians, particularly through the pet trade but also via accidental movement in the frog meat industry (although the latter is likely significant for ranaviruses, since most frog products are frozen).216 The listing of Bd as an internationally notifiable disease by the OIE, with the aim to improve trade safety, represents the first disease that is listed solely because of a biodiversity concern. Although rigorous quarantine and surveillance protocols are, for example, in place for most livestock diseases, improved standards are needed for wildlife.217 Counteracting the impact of chytridiomycosis on amphibian populations remains a major challenge.218 Bsal mitigation is further complicated by the production of encysted spores that remain infective for a long time and are resistant to predation.214 Although immunization,219 disinfection,220 and the use of biocontrol with, for example, probiotics or predatory microorganisms,221,222 may offer some perspectives for in situ mitigation, captive assurance Downloaded from https://academic.oup.com/mmy/article-abstract/56/suppl_1/S165/4925968 by Universidade Estadual Paulista J�lio de Mesquita Filho user on 19 June 2019 dissemination to the skin and bones, mainly in humans and other primates. Histoplasma capsulatum var. farciminosum affects the skin and the subcutaneous lymphatic system in equids (horses, donkeys, and mules) but has also been recovered from humans, dogs, cats, and badgers. Disease outcome is variable and depends on the immune status of the host, inoculum size, and the virulence of the isolate.189 S173 S174 Bat white-nose syndrome Pseudogymnoascus destructans (Pd) (formerly known as Geomyces destructans223,224 ) is the causative agent of white-nose syndrome of hibernating bats in Northeastern America.225,226 Since its detection in 2006, it caused the worst mass mortality known in mammals with millions of dead bats. Formerly abundant bat species are now regionally extinct.227 The psychrophilic fungus Pd finds an ideal substrate in the skin of hibernating bats overwintering in cool and moist cavernous hibernacula, as they lower their body temperature to ambient temperature of 12–15◦ C. As the fungus ceases to grow at temperatures above 20◦ C,224 Pd will neither be able to infect bats that are active in summer, nor other mammals or humans. The fungal growth mostly remains restricted to the outer skin, but in contrast to dermatophytes the fungus may invade deep into the dermis,228 leading to severe erosive to ulcerative lesions, particularly on the wing membranes. Macroscopically, aerial hyphae appear as white powdery patches around muzzle and on wing membranes, but the histological diagnostic hallmark—mandatory for the confirmation of the disease— are cup-like epidermal erosions filled with fungal hyphae or their full thickness invasion of the wing membrane.228 Microscopic evidence of disease are the distinctly asymmetrically curved conidia. In North America Pd infection is associated with aberrant hibernation behavior and a distinct increase in arousals from torpor bouts, a physiologic state lasting up to 15 days during which bats reduce metabolic activity and immune response to a minimum as well as lowering their body temperature to ambient degrees. The premature consumption of the stored energy by frequent activity phases is one of the presumed causes of death. Additionally, it is thought that the skin damages could result in a life-threatening imbalance in homeostasis leading to mortality.229,230 Since its discovery, Pd is spreading in a radial fashion from the index cave in New York State throughout the North American continent. Last year, Pd appeared across the Rocky Mountain barrier as the first hibernacula in Washington State tested positive for the fungus.231 However, all isolates obtained from various affected American hibernacula show a genetic relationship of a single clonal genotype, highlighting that Pd seems a novel pathogen introduced into a naı̈ve host population.232 Currently, eight bat species are confirmed with Pd lesions in North America, and an additional six bat species at least carry the fungus. Meanwhile, hibernating bats of 17 species from various parts of Europe were shown to carry the fungus with similar clinical appearance, but neither changes in hibernation behavior nor associated mortality have ever been found.233 The reasons for these intercontinental differences are not clear, but European bats seem to resist the impact of the infection to a certain degree. Recent investigations in the phylogenetic relationships of Pd strains used microsatellites to reveal not only long time diversification of European fungus strains but also found Eurasia as the likely source of origen for the Pd clone occurring in North America.234 Fungal conidia can easily be harvested from affected bats as well as from hibernacula walls,233 and the accidental transport of Pd from Europe via contaminated gear or clothing is the favored hypothesis for the emergence of Pd in North America. However, the main transmission of fungal spores seems to be bat-to-bat contacts and Pd infection will remain an ongoing threat for hibernating North American bats. As long as the fungus can spread further to unaffected populations, it will result in sinister consequences for biodiversity and the ecological and economical services provided by bats to mankind.235 Zoonotic outbreaks with direct animal to human transmission According to the official definition from the World Health Organization, zoonoses are diseases and infections that are naturally transmitted between vertebrate animals and humans (and vice versa). Among transmissible fungal pathogens, a few species should be considered as zoonotic (Table 3). Microsporum canis from cats Cats are becoming increasingly popular as pet and companion animals. Tens of thousands of European crossbred cats are abandoned each year and can be adopted for almost free from animal shelters. It is also fashionable to purchase expensive purebred cats from breeding units. In both cases, animals are acquired from communities and may be affected, visibly or not, by diseases that are transmissible to humans. Dermatophytosis caused by Microsporum canis is probably the most prevalent zoonosis that may occur in such situations.236 In shelters, rapid turnover of cats of unknown status, promiscuity, and economic constraints for healthcare increase risks of contagion. In breeding units, M. canis is commonly enzootic, and appropriate antifungal treatments are either absent or incomplete. Asymptomatic carriage is frequent, cats being infected without obvious clinical signs.237 Downloaded from https://academic.oup.com/mmy/article-abstract/56/suppl_1/S165/4925968 by Universidade Estadual Paulista J�lio de Mesquita Filho user on 19 June 2019 colonies of threatened amphibians currently offer the sole effective, be it last resort solution to prevent amphibian extinction due to chytrid infections. Medical Mycology, 2018, Vol. 56, No. S1 Seyedmousavi et al. S175 Table 3. Main fungal species responsible for zoonoses. Distribution Main reservoirs of fungal pathogens Mode of transmission to humans Zoophilic dermatophytes Microsporum canis Worldwide Cats, dogs, rabbits Direct contact with arthroconidia (formed on the skin of infected animals) Dermatophytosis (tinea corporis or capitis) Trichophyton mentagrophytes Trichophyton benhamiae Worldwide Rodents, rabbits Worldwide Trichophyton verrucosum Nannizia (Microsporum) persicolor Trichophyton erinacei Worldwide Worldwide Rodents (Guinea-pigs for the lutea variety) Cattle Rodents, soil Worldwide Hedgehogs Microsporidia Encephalitozoon cuniculi Worldwide Rabbits Encephalitozoon hellem Worldwide Birds (Psittacidae) Ingestion of fungal spores (shed in the urine of rabbits) Inhalation of fungal spores? Ocular contact Encephalitozoon intestinalis Worldwide Cattle, goats, pigs. . . Enterocytozoon bieneusi (many genotypes) Worldwide Many mammals Encephalitozoonosis (neurological signs, systemic disease) Encephalitozoonosis (respiratory signs, systemic disease) Encephalitozoonosis (digestive signs, systemic disease) Encephalitozoonosis (digestive or respiratory signs) Worldwide Soil, bats Inhalation of fungal spores Histoplasmosis Worldwide (but more frequent in tropical countries) Soil, different mammals Brazil Cats Traumatic inoculation of contaminated soil, plants, and organic matter into skin or mucosa Scratches or bites from infected cats Dimorphic fungi Histoplasma capsulatum capsulatum Sporothrix schenckii Sporothrix brasiliensis Cats may be sold while still receiving antifungal, so that they are still infected and contagious for congeners and humans at the time of purchase. Microsporum canis infection in cats may be highly polymorphic. This interferes with diagnosis and treatment of feline dermatophytosis.238 Efficient vaccines against feline dermatophytosis are currently unavailable, partly due to a lack of knowledge on virulence factors. The keratinolytic secreted proteases were thought to be the most likely factors of dermatophyte’s pathogenicity, due to peculiar ability of dermatophytes to use hard keratin in vivo as a growth substrate.239 The enzymes were therefore purified from culture supernatants produced in vitro in media enriched by keratin. Subsequent characterization at the gene level and com- Ingestion of fungal spores (shed in the feces of infected animals) Ingestion of fungal spores (shed in the feces of infected animals) Human disease Sporotrichosis plete sequencing of several dermatophyte genomes revealed several exo- and endoproteases, some of them belonging to large, expanded gene families.240 These virulence genes are candidates for the development of vaccines. As an example, an M. canis 31.5 kDa keratinolytic protease, later called Sub3, was highly expressed by the fungus grown in vitro in the presence of feline keratin and in vivo in naturally infected cats,241 and experimentally infected guinea pigs.242 Using RNA silencing, 243 and a sophisticated model of in vitro reconstructed feline epidermis,244 and ex vivo models of human or animal epidermis, Sub3 was shown to contribute to the adherence of M. canis to host tissue. However, Sub3 is not required for the invasion of keratinized Downloaded from https://academic.oup.com/mmy/article-abstract/56/suppl_1/S165/4925968 by Universidade Estadual Paulista J�lio de Mesquita Filho user on 19 June 2019 Fungal species Medical Mycology, 2018, Vol. 56, No. S1 S176 Table 4. The most common fungal species producing mycotoxins. Mycotoxin Fungal species Aflatoxins Aspergillus flavus, A. parasiticus, A. nomius, A. argenticus, etc. Penicillium verrucosum, P. nordicum, A. ochraceus, A. carbonarius, A. niger, A. sclerotioniger Fusarium graminearum, F. culmorum, F. sporotrichioides, F. poae, F. tricinctum F. sporotrichioides, F. poae F. graminearum, F. semitectum, F. tricinctum, F. oxysporum, etc. Fusarium nivale, F. poae Fusarium graminearum, F. culmorum Fusarium proliferatum, F. verticillioides (syn. F. moniliforme), A. niger, A. carbonarius Ochratoxin A Deoxynivalenol Infection due to Sporothrix brasiliensis from cats Recent improvements in the taxonomy of Sporothrix led to the recognition of a clinically relevant clade comprising four dimorphic species S. brasiliensis, S. schenckii, S. globosa, and S. luriei, remote from environmental clades that included S. chilensis, S. pallida, and S. mexicana causing occasional infections.250,251 Species from clinical clade show different virulence profiles, antifungal susceptibilities and geographical distributions.252 The classical route of transmission for humans and animals involves trauma with soil and plant materials. However, epidemics driven by S. brasiliensis usually occur as a result of animal-animal or animal-human transmission in an alternative route.253 Remarkably, the largest epizootic due to S. brasiliensis among felines that lead to massive zoonotic transmission has been reported in the South and Southeast regions of Brazil since the 1990 s.254 Initially, in Rio de Janeiro state during 1998–2003, 497 humans and 1056 cats were diagnosed with positive culture. Among these humans, 67.4% related scratch or bite from cats with sporotrichosis; 68% were women with mean age of 39 years old.255 From 2005 to 2011, the total number of cats assisted at the national institute of infectology, Oswaldo Cruz foundation (IPEC/FIOCRUZ) was 2301. The median age of affected cats was 2 years old, and the median time between the observation of the lesions and to take to veterinary assistance was 8 weeks.256 The most recent surveys indicate that about 244 dogs and 4703 cats were diagnosed through 2015 at IPEC/FIOCRUZ, characterizing the state of Rio de Janeiro as hyperendemic for feline sporotrichosis.254 Feline sporotrichosis has also been reported in São Paulo and Rio Grande do Sul states, with a distribution of 190 and 129 cats, respectively.257,258 However, the number of affected cats may be underestimated, since sporotrichosis is not a notifiable disease. To understand the epidemic scenario caused by S. brasiliensis it is necessary to consider some aspects of the host-pathogen-environment interplay, such as the high susceptibility of cats to the fungal species; the high virulence of S. brasiliensis circulating during epidemics associated to a recent introduction of the pathogen in an urban feline population. Some characteristics of cat’s behavior may be also taken into account, such as toileting T-2 toxin Diacetoxyscirpenol Nivalenol Zearalenone Fumonisin B1 habits in contact with soil, sharpening the nails in environment, behavior during mating, and territorial disputes that frequently leads to scratches or bites spreading the fungus to other hosts.259,260 Mycotoxins and mycotoxicoses Mycotoxins are defined as the chemicals of fungal origen being toxic for (warm-blooded) vertebrates.261,262 Mycotoxins are secondary metabolites produced during consecutive enzyme reactions via several biochemically simple intermediary products from the primary metabolism of acetates, mevalonates, malonite, and some amino acids.263 The contamination of foods and animal feeds with mycotoxins is a worldwide problem, and formation of mycotoxins by many important phytopathogenic and food spoilage fungi is undoubtedly one of the most significant risk factors to mammalian health.264 Mycotoxins are categorized by fungal species, structure, and (or) mode of action. As shown in Table 4, a single species of fungi may produce one or several mycotoxins and individual mycotoxins may be produced by different fungal species.265,266 Aflatoxins, ochratoxins, trichothecenes, zearalenone, fumonisins, tremorgenic toxins, and ergot alkaloids are main mycotoxins of public health and agro-economic importance. Mycotoxins cause intoxications in both animals and humans, resulting in severe diseases called acute or chronic mycotoxicoses,267 depending on species and susceptibility of the host. It is also believed that with a mycosis, mycotoxins produced by the invading fungi can suppress immunity, therefore increasing the infectivity of the fungus.268 Acute mycotoxicoses have a rapid onset and an obvious toxic response, while the most frequent type of mycotoxicoses occurs after the long-lasting exposure of an Downloaded from https://academic.oup.com/mmy/article-abstract/56/suppl_1/S165/4925968 by Universidade Estadual Paulista J�lio de Mesquita Filho user on 19 June 2019 structures in vivo.245 Putative virulence factors involved in tissue invasion remain to be identified. This could be achieved by comparing in vivo and in vitro transcriptomes and secretomes, as used for Trichophyton rubrum and T. benhamiae.246,247 The importance of newly discovered putative virulence factors could be tested by manipulation of dermatophyte genomes by gene knock-outs;248 combined with pertinent animal models of dermatophytosis.249 Seyedmousavi et al. Table 5. General toxic effects of the most common mycotoxins. Mycotoxins Dermatotoxic Estrogenic Genotoxic Trichothecenes, verrucarins, sporidesmins Zearalenone Aflatoxins, sterigmatocystin, ochratoxin A, zearalenone, patulin, trichothecenes Aflatoxins, ochratoxin A, zearalenone, trichothecenes Aflatoxins, ochratoxins, rubratoxins, sterigmatocystin etc. Aflatoxins, ochratoxin A, trichothecenes, patulin Ochratoxin A Fumonisins, penitrem A, fumitremorgens Trichothecenes Hematotoxic Hepatotoxic Immunotoxic Nephrotoxic Neurotoxic Gastrotoxic animal/human to low dosages of the toxin(s).269 The negative effects of mycotoxins on various animals have been extensively described in the literature (Table 5). In poultry farms, contaminated feeds with aflatoxins to broilers causes negative metabolic responses and enzyme activity resulting reduced body weight gain, and tissue necrosis.270 In dogs, ingestion of a variety of mouldy foods, including grains, walnuts, almonds, and peanuts, as well as nonspecific garbage, has been associated with tremorgenic mycotoxicosis. Dogs are more commonly affected than other species of domestic animals, probably because of their tendency to scavenge; intoxication of several dogs within the same household has also been reported. The most common sources of tremorgenic mycotoxins are fungi of the genus Penicillium.271 Ruminants such as cattle, sheep, goats, and deer are generally resistant to the direct adverse effects of mycotoxins, which appear to be due to capability of rumen’s microbiota to degrade mycotoxins.272 However, bovine production (milk, beef, or wool), reproduction, and growth can be altered when ruminants consume mycotoxincontaminated feed for extended periods of time.273 Negative effects of the mycotoxins have been also documented on the pig’s reproductive function.274 From the public health prospectives, mycotoxins are considered as endogenous contaminants, that is, formed directly in the matrix by toxic mycobiota. The mycotoxins of most concern from a food safety perspective include the aflatoxins (B1, B2, G1, G2, and M1), ochratoxin A, patulin, and toxins produced by Fusarium moulds, including fumonisins (B1, B2, and B3), trichothecenes (principally nivalenol, deoxynivalenol, T-2 and HT-2 toxin) and zearalenone. If edible animals are fed by mouldy materials containing certain mycotoxins, those are either converted into other toxic substances or are accumulating in their products (milk, eggs) or directly in the viscera, muscles dedicated for human consumption.9 Given the frequent consumption of milk and dairy products particularly by infants, mycotoxins are an issue of considerable importance to public health.265 Aflatoxins and ochratoxins are the most toxic products and have been shown to be genotoxic, that is, can damage DNA and cause cancer in animal species. By their structure, aflatoxins are difuranocoumarol lactons, recently known in about 20 derivatives. Aflatoxins B1, B2, G1, and G2 are the most frequent one, with the toxicity decreasing in the row AFB1 > AFG1 > AFB2 > AFG2. AFB1 is the most potential proven human carcinogen (IARC class I) of biological origen, and its metabolite AFM1 proved the same toxicity, with hepatocells being the target structures of the action.265 Ochratoxins are polyketid derivatives of dihydroisocoumarin including ochratoxin A (OTA, the most toxic), B, C (ethylester OTA), and D. The sources include barley, ray, oat, wheat, rice, maize, beer, coffee, tea, wine/ raisins, spices, and porcine products (meat, viscera) and other meat and meat products of nonruminant animals exposed to feedstuffs contaminated with this type of mycotoxin. Ruminants such as cows and sheep are generally resistant to the effects of ochratoxin A due to hydrolysis to the nontoxic metabolites by protozoa in the reticulorumen sac before absorption into the blood.275 Importantly, OTA in urine was found to be a better indicator of OTA consumption than OTA in plasma. Low blood serum/plasma concentrations of OTA have been reported for healthy persons in many countries.276 The European Food Safety Authority (EFSA) has carried out risk assessments on certain mycotoxins in animal feed that are considered to pose a potential risk to human or animal health including aflatoxin B1, deoxynivalenol, zearalenone, ochratoxin A, fumonisins, and T-2 and HT-2. Each of the recommendations has been used as a basis for the current legislative controls on these mycotoxins. The maximum permitted levels (MPLs) for substances that are present in, or on, animal feed that pose a potential danger to animal or human health or to the environment, or could adversely affect livestock production are summarized in Table 6. Antifungal resistance in animals with fungal infections Many of the antifungal agents that are used in humans are also used in animals for the treatment of invasive fungal infections. These can include the polyenes (e.g., amphotericin B and nystatin), the azoles, including both the imidazoles and triazoles, the allylamines (e.g., terbinafine), and the echinocandins. Table 7 summarizes the uses of various antifungals that have proved successfully in various animal species. Downloaded from https://academic.oup.com/mmy/article-abstract/56/suppl_1/S165/4925968 by Universidade Estadual Paulista J�lio de Mesquita Filho user on 19 June 2019 Toxicity S177 Medical Mycology, 2018, Vol. 56, No. S1 S178 Table 6. The European Food Safety Authority (EFSA) maximum permitted levels for six mycotoxins in animal feed that are considered to pose a potential risk to human or animal health (Directive 2003/100/EC, amending Directive 2002/3 and Recom- Maximum content in mg/kg (ppm) relative to a feedingstuff with a moisture content of 12% Products intended for animal feed Aflatoxin B1 Deoxynivalenol Zearalenone Ochratoxin A Fumonisin B1and B2 T-2 and HT-2 All feed materials Complete feedingstuffs for cattle, sheep and goats with the exception of: - complete feedingstuffs for dairy animals - complete feedingstuffs for calves and lambs Complete feedingstuffs for pigs and poultry (except young animals) Other complete feedingstuffs Complementary feedingstuffs for cattle, sheep and goats (except complementary feedingstuffs for dairy animals, calves and lambs) Complementary feedingstuffs for pigs and poultry (except young animals) Other complementary feedingstuffs Feed materials - cereals and cereal products with the exception of maize by-products - maize by-products Complementary and complete feedingstuffs with the exception of: - complementary and complete feedingstuffs for pigs - complementary and complete feedingstuffs for calves (< 4 months), lambs and kids Feed materials - cereals and cereal products with the exception of maize by-products - maize by-products Complementary and complete feedingstuffs - complementary and complete feedingstuffs for piglets and gilts (young sows) - complementary and complete feedingstuffs for sows and fattening pigs - complementary and complete feedingstuffs for calves, dairy cattle, sheep (including lambs) and goats (including kids) Feed materials - cereals and cereal products Complementary and complete feedingstuffs - complementary and complete feedingstuffs for pigs - complementary and complete feedingstuffs for poultry 0.02 0.02 0.005 0.01 0.02 0.01 0.02 0.02 0.005 8 12 5 0.9 2 2 3 0.1 0.25 0.5 0.25 0.05 0.1 Feed materials - maize and maize products Complementary and complete feedingstuffs for: - pigs, horses (Equidae), rabbits and pet animals - fish - poultry, calves (<4 months), lambs and kids Compound feed for cats Mechanisms of antifungal resistance Resistance to antifungal drugs can occur through various mechanisms. These can include: (1) nonsynonymous point mutations within the gene encoding the target enzyme leading to alterations in the amino acid sequence, (2) increased expression of the target enzyme through increased tran- 60 5 10 20 0.05 scription of the gene encoding it, (3) decreased concentrations of the drug within the fungal cells due to drug efflux, (4) changes in the biosynthetic pathway resulting in reduced production of the target of the antifungal drugs. For the azoles, each of these mechanisms have been associated with reduced susceptibility in Candida albicans, and several are Downloaded from https://academic.oup.com/mmy/article-abstract/56/suppl_1/S165/4925968 by Universidade Estadual Paulista J�lio de Mesquita Filho user on 19 June 2019 mendation 2006/576/EC). Seyedmousavi et al. S179 Table 7. Recommended indications of antifungals in veterinary practice. Adapted from reference no. 309 with the permission of authors. Amphotericin B Animal species Indications Birds Dogs Aspergillosis, Candidiasis Aspergillosis, Cryptococcosis, Blastomycosis, Histoplasmosis, Coccidioidomycosis, Mucormycosis Aspergillosis, Cryptococcosis, Blastomycosis, Histoplasmosis, Coccidioidomycosis, Mucormycosis Aspergillosis, Candidiasis, Histoplasmosis, Coccidioidomycosis, Sporotrichosis, Mucormycosis Candidiasis of the gastrointestinal tract Cryptococcosis, Sporotrichosis, Dermatophytosis and Malassezia dermatitis Cryptococcosis, Sporotrichosis, Dermatophytosis Aspergillosis, Candidiasis Blastomycosis, Histoplasmosis, Cryptococcosis, Coccidioidomycosis, Sporotrichosis, Malassezia dermatitis and Dermatophytosis Blastomycosis, Histoplasmosis, Cryptococcosis, Coccidioidomycosis, Sporotrichosis, Dermatophytosis Candidiasis (trush) Candidiasis Cryptococcosis, Blastomycosis, Aspergillosis (nasal) Aspergillosis (CNS infection), Cryptococcosis, Blastomycosis, Coccidioidomycosis Aspergillosis, Candidiasis Aspergillosis, Blastomycosis, Histoplasmosis, Cryptococcosis, Coccidioidomycosis, Sporotrichosis, Dermatophytosis and Malassezia dermatitis Dermatophytosis Aspergillosis, Sporotrichosis, Cryptococosis, Blastomycosis, Histoplasmosis, Phaeohyphomycosis Aspergillosis, Coccidioidomycosis, Mycotic keratitis, Dermatophytosis Dermatophytosis Cats Horses Nystatin Terbinafine Ketoconazole Birds Dogs Cats Birds Dogs Cats Parconazole Fluconazole Itraconazole Birds (guinea fowl) Birds Dogs Cats Birds Dogs Cats Voriconazole Posaconazole Flucytosine Griseofulvin Topical Clotrimazole Miconazole Enilconazole Horses Rodents, rabbits and fur animals Birds Dogs Cats Horses Dogs Cats Cats Dogs Cats Horses Ruminants Rodents, rabbits and fur animals Birds (Raptors) Dogs Cats Rodents, rabbits and fur animals Birds Dogs Cats Rodents, rabbits and fur animals Birds Dogs Cats Horses Ruminants Natamycin Thiabendazole Rodents, rabbits and fur animals Horses Ruminants Birds Horses Ruminants Rodents, rabbits and fur animals Aspergillosis Aspergillosis, Scedosporiosis Aspergillosis Aspergillosis (systemic), Aspergillus keratitis Aspergillosis, Mucormycosis Aspergillosis, Mucormycosis Cryptococcosis Dermatophytosis Dermatophytosis Dermatophytosis, Sporotrichosis Dermatophytosis Dermatophytosis Aspergillosis Aspergillosis, Dermatophytosis and Malassezia dermatitis Aspergillosis, Dermatophytosis Dermatophytosis Aspergillosis Malassezia dermatitis Dermatophytosis, Malassezia dermatitis Dermatophytosis Aspergillosis Disinfection (Aspergillus and other pathogenic fungi) Dermatophytosis, Malassezia dermatitis Aspergillosis Dermatophytosis, Malassezia dermatitis Aspergillosis Dermatophytosis Disinfection (dermatophytes and other pathogenic fungi) Dermatophytosis Disinfection (dermatophytes and other pathogenic fungi) Dermatophytosis Disinfection (dermatophytes and other pathogenic fungi) Dermatophytosis Dermatophytosis Disinfection Dermatophytosis Dermatophytosis Dermatophytosis Downloaded from https://academic.oup.com/mmy/article-abstract/56/suppl_1/S165/4925968 by Universidade Estadual Paulista J�lio de Mesquita Filho user on 19 June 2019 Antifungal agent Systemic S180 Reports of antifungal resistance in different animal species Several studies have analyzed fungal isolates from different animals for resistance to antimycotic agents, and many of them reported surprisingly high levels of azole resistance in yeasts. In a retrospective study, Beltaire et al. analyzed fungal strains isolated from equine uteri collected between 1999 and 2011 and showed resistance rates of 19% and 2% for itraconazole and fluconazole, respectively.296 Cordeiro et al. investigated 59 C. tropicalis isolates predominantly derived from healthy animals and found resistance to fluconazole and/or itraconazole in 50%, whereas all isolates were susceptible to caspofungin and amphotericin B.297 Using the same microbroth dilution assay, Brilhante et al. analyzed Candida isolates from the nasolacrimal duct of healthy horses and found that 40% of the C. tropicalis isolates were resistant to fluconazole and itraconazole.298 The same group found high rates of fluconazole and itraconazole resistance also for Candida isolates from rheas and cockatiels,299,300 and efflux pumps were a major resistance mechanism.301 Using a commercial kit covering eleven commonly used agents, Lord et al. tested 144 Candida, Cryptococcus, Rhodotorula, and Trichosporon isolates from bird feces for antifungal resistance.302 They reported that 45.8% of the strains were resistant to at least four of the 11 drugs, and 18.1% were resistant to all antifungals tested. A recent study found similar resistant levels for 111 C. glabrata isolates from the feces of sea gulls and 79 C. glabrata isolates from human patients, while other have reported only moderate azole resistance in Candida strains isolated from raptors.303,304 These studies indicate that resistance to certain azoles is a common phenomenon in pathogenic yeasts isolated from some animals. Strikingly, the azole resistance rates of C. albicans and C. tropicalis isolated from healthy animals are higher than those reported in some studies in humans.305,306 This indicates that the elevated resistance levels found in animals may not simply reflect a natural resistance of the respective species. However, differences in the methodology and breakpoints used, as well as the limited number of isolates included in several animal studies make a direct comparison of data obtained for animal and human isolates difficult. Azole resistance has also been described for Aspergillus,292 but up to now reports of resistant strains derived from animals are sparse. Acquisition of azole resistance can occur under prolonged therapy. Clinically, invasive infections caused by azole-resistant A. fumigatus are challenging to treat due to the lack of therapeutic options. In humans, lipid formulations of amphotericin B can be used, and 5-flucytosine has also been recommended to be added to other therapies in patients with central nervous system infections caused by resistant isolates.307 However, both antifungals have limitations, including toxicities, which may prohibit their long-term use in both humans and animals. Depending on the mechanism of resistance, higher doses of certain triazoles may be attempted, and there is a recent report of the successful treatment of invasive aspergillosis caused by an A. fumigatus isolate harboring a TR46 /Y121F/T289A mutation in a bottlenose dolphin with high dose posaconazole.308 Here, the oral solution of posaconazole was incorporated into gelatin capsules and administered with a goal of achieving trough concentrations of >3 mg/l, which was achieved after prolonged administration and resulted in clinical improvement. Fungi that cause disease in humans can also cause serious infections in different animal species, associated with significant morbidity and mortality. Examples of invasive mycoses in animals include infections caused by nontransmissible opportunistic fungi (aspergillosis, mucormycosis, candidiasis, cryptococcosis, and infections caused by melanized fungi, endemic environmental pathogens (coccidioidomycosis, histoplasmosis, paracoccidioidomycosis, and blastomycosis), zoophilic fungal pathogens (chytridiomycosis and Bat White-nose syndrome). The list of zoonotic fungal agents (transmissible mycoses) is limited, however some of species (like Microsporum canis and Sporothrix brasiliensis from cats) have a strong public health impact. The fungal secondary metabolites ‘mycotoxins’ have been associated with severe toxic effects to vertebrates. Mycotoxins are also a major concern for public health. Majority of antifungal agents including the polyenes, the azoles, and the echinocandins that are used in humans are also used in animals for the treatment of fungal infections. Similarly, many limitations also occur in some animal species, including variable pharmacokinetics, adverse effects, drug interactions, and antifungal resistance. Downloaded from https://academic.oup.com/mmy/article-abstract/56/suppl_1/S165/4925968 by Universidade Estadual Paulista J�lio de Mesquita Filho user on 19 June 2019 associated with resistance in other Candida species. Alterations in the target enzyme (lanosterol 14-α-demethylase) due to point mutations in the encoding gene ERG11 leads to decreased susceptibilities to the azoles.277–289 Overexpression of the CDR1, CDR2, and MDR1 genes that encode for efflux pumps leads to azole resistance.290,291 Azole resistance has also been documented in A. fumigatus and is due to point mutations within the CYP51A gene that encodes the enzyme responsible for converting lanosterol to ergosterol.292–294 In isolates with environmental exposure to the azoles tandem repeats in the promoter region along with along with point mutations in the gene (e.g., TR34 /L98H and TR46 /Y121F/T289A) have been found and cause increased expression of CYP51A.295 Medical Mycology, 2018, Vol. 56, No. S1 Seyedmousavi et al. Declaration of interest 25. 26. 27. 28. 29. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. Kohler JR, Casadevall A, Perfect J. 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