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Aspergillus no contexto “One Health”: Epidemiologia molecular, resistência a azóis e novos compostos com atividade antifúngica frente a isolados clínicos de humanos e de aves aquáticas
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Advisor(s)
Abstract(s)
O contexto "One health" considera a saúde em três pilares: saúde animal, saúde
humana e saúde do ecossistema. Nesta abordagem, evidencia-se o papel das
mudanças ambientais na emergência de doenças crônicas e infecciosas, e, como forte
aliada no desenvolvimento de estratégias de prevenção de doenças. Fungos do
gênero Aspergillus se enquadram substancialmente nesta abordagem, tendo em vista
sua ubiquidade, bem como sua importância como potenciais patógenos animais e
humanos. Além da resistência intrínseca apresentada por algumas espécies, a
emergência da resistência a azóis adquirida por isolados de Aspergillus fumigatus
sensu stricto é uma preocupação da comunidade científica a nível global. Este
trabalho teve como objetivo a avaliação da epidemiologia molecular de isolados
clínicos de Aspergillus de aves e humanos do sul do Rio Grande do Sul, Brasil, e
avaliar perfil de suscetibilidade e mecanismos de resistência aos azóis. Como
resultados, realizamos uma ampla revisão de literatura no contexto One Health, com
enfoque no papel da aves como indicador ambiental e na dispersão de cepas de
Aspergillus; descrevemos pela primeira vez a aspergilose em albatrozes durante a
reabilitação; e descrevemos casos de aspergilose em aves aquáticas de vida livre.
Também obtivemos importantes resultados in vitro sobre a atividade antifúngica do
composto disseleneto de difenila sozinho e em combinação com antifúngicos
clássicos. Em relação a pesquisa de resistências aos azóis em A. fumigatus, não
foram detectadas mutações relacionadas ao contexto ambiental da emergência da
resistência nessa espécie fúngica na região estudada no Brasil. Além disso, a
pesquisa de diversidade genética demonstrou elevada diversidade nos isolados
estudados, pelo que se conclui que a técnica utilizada é de grande valia para o
acompanhamento clínico dos pacientes, além de permitir confirmar que o ambiente
de recuperação de animais é uma potencial fonte de infecção para aves (no caso
estudado, pinguins) durante reabilitação. A detecção de um mesmo genótipo em
estirpe de A. fumigatus isolado em um paciente humano e um pinguim de vida livre
demonstraram a importância de uma abordagem One Health do Aspergillus e da
aspergilose, uma vez que uma mesma estirpe possui potencial de
colonização/infecção tanto em animais como em humanos. Por fim, como resultado
da parceria internacional estabelecida durante o desenvolvimento desse trabalho,
tivemos o primeiro reporte da mutação de resistência TR34/L98H em ambiente indoor
em Portugal, e o resultado da vigilância em Aspergillus realizada por um laboratório
de referência em Portugal, no qual encontrou-se grande prevalência de espécies
crípticas de Aspergillus em isolados clínicos e ambientais, além de resistência panazol
em estirpes de A. fumigatus, confirmando-se os mecanismos moleculares
envolvidos com a resistência antifúngica no gene cyp51A. Os resultados obtidos neste
trabalho mostram a importância da abordagem multidisciplinar do Aspergillus e da aspergilose, e a necessidade de ampliar a vigilância de Aspergillus no contexto One
Health, com objetivo de entender melhor os mecanismos envolvidos na dispersão de
estirpes, e na adoção de medidas mais efetivas de monitoramento da emergência da
resistência, bem como para adoção de estratégias de controle do crescimento desse
problema global.
The "One health" context considers health on three pillars: animal health, human health and ecosystem health. In this approach, the role of environmental changes in the emergence of chronic and infectious diseases is highlighted, and as a strong ally in the development of disease prevention strategies. Fungi of the Aspergillus genus fit substantially in this approach, in view of their ubiquity, as well as their importance as potential animal and human pathogens. In addition to the intrinsic resistance presented by some species, the emergence of azole resistance acquired by isolates of Aspergillus fumigatus sensu stricto is a concern of the scientific community at a global level. This study aimed to evaluate the molecular epidemiology of clinical isolates of Aspergillus from birds and humans from the south of Rio Grande do Sul, Brazil, and to evaluate the susceptibility profile and mechanisms of azole resistance. As a result, we carried out a wide literature review in the context of One Health, focusing on the role of birds as an environmental indicator and on the dispersion of Aspergillus strains; we first described aspergillosis in albatrosses during rehabilitation; and we describe cases of aspergillosis in free-living aquatic birds. We also obtained important in vitro results on the antifungal activity of the diphenyl diselenide compound alone and in combination with classic antifungals. Regarding the search for azole resistance in A. fumigatus, no mutations related to the environmental context of the emergence of resistance in this fungal species in the region studied in Brazil were detected. In addition, genetic diversity research has shown high diversity in the isolates studied, so it is concluded that the technique used is of great value for the clinical monitoring of patients, in addition to confirming that the animal recovery environment is a potential source of infection for birds (in this case, penguins) during rehabilitation. The detection of the same genotype in A. fumigatus strain isolated in a human patient and a freeliving penguin demonstrated the importance of an Aspergillus and aspergillosis One Health approach, since the same strain has both a potential for colonization / infection in animals as in humans. Finally, as a result of the international partnership established during the development of this work, we had the first report of the resistance mutation TR34 / L98H in an indoor environment in Portugal, and the result of surveillance in Aspergillus carried out by a reference laboratory in Portugal, in which a high prevalence of cryptic species of Aspergillus was found in clinical and environmental isolates, in addition to pan-azole resistance in A. fumigatus strains, confirming the molecular mechanisms involved with antifungal resistance in the cyp51A gene. The results obtained in this work show the importance of the multidisciplinary approach of Aspergillus and aspergillosis, and the need to expand the surveillance of Aspergillus in the context of One Health, in order to better understand the mechanisms involved in the dispersion of strains, and in the adoption of more effective measures to monitoring the emergence of resistance, as well as the adoption of strategies to control the growth of this global problem.
The "One health" context considers health on three pillars: animal health, human health and ecosystem health. In this approach, the role of environmental changes in the emergence of chronic and infectious diseases is highlighted, and as a strong ally in the development of disease prevention strategies. Fungi of the Aspergillus genus fit substantially in this approach, in view of their ubiquity, as well as their importance as potential animal and human pathogens. In addition to the intrinsic resistance presented by some species, the emergence of azole resistance acquired by isolates of Aspergillus fumigatus sensu stricto is a concern of the scientific community at a global level. This study aimed to evaluate the molecular epidemiology of clinical isolates of Aspergillus from birds and humans from the south of Rio Grande do Sul, Brazil, and to evaluate the susceptibility profile and mechanisms of azole resistance. As a result, we carried out a wide literature review in the context of One Health, focusing on the role of birds as an environmental indicator and on the dispersion of Aspergillus strains; we first described aspergillosis in albatrosses during rehabilitation; and we describe cases of aspergillosis in free-living aquatic birds. We also obtained important in vitro results on the antifungal activity of the diphenyl diselenide compound alone and in combination with classic antifungals. Regarding the search for azole resistance in A. fumigatus, no mutations related to the environmental context of the emergence of resistance in this fungal species in the region studied in Brazil were detected. In addition, genetic diversity research has shown high diversity in the isolates studied, so it is concluded that the technique used is of great value for the clinical monitoring of patients, in addition to confirming that the animal recovery environment is a potential source of infection for birds (in this case, penguins) during rehabilitation. The detection of the same genotype in A. fumigatus strain isolated in a human patient and a freeliving penguin demonstrated the importance of an Aspergillus and aspergillosis One Health approach, since the same strain has both a potential for colonization / infection in animals as in humans. Finally, as a result of the international partnership established during the development of this work, we had the first report of the resistance mutation TR34 / L98H in an indoor environment in Portugal, and the result of surveillance in Aspergillus carried out by a reference laboratory in Portugal, in which a high prevalence of cryptic species of Aspergillus was found in clinical and environmental isolates, in addition to pan-azole resistance in A. fumigatus strains, confirming the molecular mechanisms involved with antifungal resistance in the cyp51A gene. The results obtained in this work show the importance of the multidisciplinary approach of Aspergillus and aspergillosis, and the need to expand the surveillance of Aspergillus in the context of One Health, in order to better understand the mechanisms involved in the dispersion of strains, and in the adoption of more effective measures to monitoring the emergence of resistance, as well as the adoption of strategies to control the growth of this global problem.
Description
Tese de doutoramento em Microbiologia e Parasitologia - Micologia, Instituto de Biologia, Universidade Federal de Pelotas, 2020
Orientação: Melissa Orzechowski Xavier; Co-orientação: Raquel Filipa Pinheiro Sabino (INSA)
Tese defendida a 4 de novembro de 2020
Orientação: Melissa Orzechowski Xavier; Co-orientação: Raquel Filipa Pinheiro Sabino (INSA)
Tese defendida a 4 de novembro de 2020
Keywords
Aspergillus Aspergillus fumigatus Identificação Molecular Susceptibilidade Antifúngica Genotipagem Microssatélites One health Infecções Sistémicas e Zoonoses Cryptic Species Bena Sequencing Microdilution Birds Humans