<named-content content-type="genus-species">Aspergillus fumigatus</named-content> Transcription Factors Involved in the Caspofungin Paradoxical Effect
ABSTRACT Aspergillus fumigatus is the leading cause of pulmonary fungal diseases. Azoles have been used for many years as the main antifungal agents to treat and prevent invasive aspergillosis. However, in the last 10 years there have been several reports of azole resistance in A. fumigatus and new...
Guardado en:
| Autores principales: | , , , , , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
American Society for Microbiology
2020
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/d469d9ee2a384733b3c52ec484cd42d1 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:d469d9ee2a384733b3c52ec484cd42d1 |
|---|---|
| record_format |
dspace |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Aspergillus fumigatus calcium caspofungin cell wall transcription factors mitochondria Microbiology QR1-502 |
| spellingShingle |
Aspergillus fumigatus calcium caspofungin cell wall transcription factors mitochondria Microbiology QR1-502 Clara Valero Ana Cristina Colabardini Jéssica Chiaratto Lakhansing Pardeshi Patrícia Alves de Castro Jaire Alves Ferreira Filho Lilian Pereira Silva Marina Campos Rocha Iran Malavazi Jonas Henrique Costa Taícia Fill Mário Henrique Barros Sarah Sze Wah Wong Vishukumar Aimanianda Koon Ho Wong Gustavo H. Goldman <named-content content-type="genus-species">Aspergillus fumigatus</named-content> Transcription Factors Involved in the Caspofungin Paradoxical Effect |
| description |
ABSTRACT Aspergillus fumigatus is the leading cause of pulmonary fungal diseases. Azoles have been used for many years as the main antifungal agents to treat and prevent invasive aspergillosis. However, in the last 10 years there have been several reports of azole resistance in A. fumigatus and new strategies are needed to combat invasive aspergillosis. Caspofungin is effective against other human-pathogenic fungal species, but it is fungistatic only against A. fumigatus. Resistance to caspofungin in A. fumigatus has been linked to mutations in the fksA gene that encodes the target enzyme of the drug β-1,3-glucan synthase. However, tolerance of high caspofungin concentrations, a phenomenon known as the caspofungin paradoxical effect (CPE), is also important for subsequent adaptation and drug resistance evolution. Here, we identified and characterized the transcription factors involved in the response to CPE by screening an A. fumigatus library of 484 null transcription factors (TFs) in CPE drug concentrations. We identified 11 TFs that had reduced CPE and that encoded proteins involved in the basal modulation of the RNA polymerase II initiation sites, calcium metabolism, and cell wall remodeling. One of these TFs, FhdA, was important for mitochondrial respiratory function and iron metabolism. The ΔfhdA mutant showed decreased growth when exposed to Congo red or to high temperature. Transcriptome sequencing (RNA-seq) analysis and further experimental validation indicated that the ΔfhdA mutant showed diminished respiratory capacity, probably affecting several pathways related to the caspofungin tolerance and resistance. Our results provide the foundation to understand signaling pathways that are important for caspofungin tolerance and resistance. IMPORTANCE Aspergillus fumigatus, one of the most important human-pathogenic fungal species, is able to cause aspergillosis, a heterogeneous group of diseases that presents a wide range of clinical manifestations. Invasive pulmonary aspergillosis is the most serious pathology in terms of patient outcome and treatment, with a high mortality rate ranging from 50% to 95% primarily affecting immunocompromised patients. Azoles have been used for many years as the main antifungal agents to treat and prevent invasive aspergillosis. However, there were several reports of evolution of clinical azole resistance in the last decade. Caspofungin, a noncompetitive β-1,3-glucan synthase inhibitor, has been used against A. fumigatus, but it is fungistatic and is recommended as second-line therapy for invasive aspergillosis. More information about caspofungin tolerance and resistance is necessary in order to refine antifungal strategies that target the fungal cell wall. Here, we screened a transcription factor (TF) deletion library for TFs that can mediate caspofungin tolerance and resistance. We have identified 11 TFs that are important for caspofungin sensitivity and/or for the caspofungin paradoxical effect (CPE). These TFs encode proteins involved in the basal modulation of the RNA polymerase II initiation sites, calcium metabolism or cell wall remodeling, and mitochondrial respiratory function. The study of those genes regulated by TFs identified in this work will provide a better understanding of the signaling pathways that are important for caspofungin tolerance and resistance. |
| format |
article |
| author |
Clara Valero Ana Cristina Colabardini Jéssica Chiaratto Lakhansing Pardeshi Patrícia Alves de Castro Jaire Alves Ferreira Filho Lilian Pereira Silva Marina Campos Rocha Iran Malavazi Jonas Henrique Costa Taícia Fill Mário Henrique Barros Sarah Sze Wah Wong Vishukumar Aimanianda Koon Ho Wong Gustavo H. Goldman |
| author_facet |
Clara Valero Ana Cristina Colabardini Jéssica Chiaratto Lakhansing Pardeshi Patrícia Alves de Castro Jaire Alves Ferreira Filho Lilian Pereira Silva Marina Campos Rocha Iran Malavazi Jonas Henrique Costa Taícia Fill Mário Henrique Barros Sarah Sze Wah Wong Vishukumar Aimanianda Koon Ho Wong Gustavo H. Goldman |
| author_sort |
Clara Valero |
| title |
<named-content content-type="genus-species">Aspergillus fumigatus</named-content> Transcription Factors Involved in the Caspofungin Paradoxical Effect |
| title_short |
<named-content content-type="genus-species">Aspergillus fumigatus</named-content> Transcription Factors Involved in the Caspofungin Paradoxical Effect |
| title_full |
<named-content content-type="genus-species">Aspergillus fumigatus</named-content> Transcription Factors Involved in the Caspofungin Paradoxical Effect |
| title_fullStr |
<named-content content-type="genus-species">Aspergillus fumigatus</named-content> Transcription Factors Involved in the Caspofungin Paradoxical Effect |
| title_full_unstemmed |
<named-content content-type="genus-species">Aspergillus fumigatus</named-content> Transcription Factors Involved in the Caspofungin Paradoxical Effect |
| title_sort |
<named-content content-type="genus-species">aspergillus fumigatus</named-content> transcription factors involved in the caspofungin paradoxical effect |
| publisher |
American Society for Microbiology |
| publishDate |
2020 |
| url |
https://doaj.org/article/d469d9ee2a384733b3c52ec484cd42d1 |
| work_keys_str_mv |
AT claravalero namedcontentcontenttypegenusspeciesaspergillusfumigatusnamedcontenttranscriptionfactorsinvolvedinthecaspofunginparadoxicaleffect AT anacristinacolabardini namedcontentcontenttypegenusspeciesaspergillusfumigatusnamedcontenttranscriptionfactorsinvolvedinthecaspofunginparadoxicaleffect AT jessicachiaratto namedcontentcontenttypegenusspeciesaspergillusfumigatusnamedcontenttranscriptionfactorsinvolvedinthecaspofunginparadoxicaleffect AT lakhansingpardeshi namedcontentcontenttypegenusspeciesaspergillusfumigatusnamedcontenttranscriptionfactorsinvolvedinthecaspofunginparadoxicaleffect AT patriciaalvesdecastro namedcontentcontenttypegenusspeciesaspergillusfumigatusnamedcontenttranscriptionfactorsinvolvedinthecaspofunginparadoxicaleffect AT jairealvesferreirafilho namedcontentcontenttypegenusspeciesaspergillusfumigatusnamedcontenttranscriptionfactorsinvolvedinthecaspofunginparadoxicaleffect AT lilianpereirasilva namedcontentcontenttypegenusspeciesaspergillusfumigatusnamedcontenttranscriptionfactorsinvolvedinthecaspofunginparadoxicaleffect AT marinacamposrocha namedcontentcontenttypegenusspeciesaspergillusfumigatusnamedcontenttranscriptionfactorsinvolvedinthecaspofunginparadoxicaleffect AT iranmalavazi namedcontentcontenttypegenusspeciesaspergillusfumigatusnamedcontenttranscriptionfactorsinvolvedinthecaspofunginparadoxicaleffect AT jonashenriquecosta namedcontentcontenttypegenusspeciesaspergillusfumigatusnamedcontenttranscriptionfactorsinvolvedinthecaspofunginparadoxicaleffect AT taiciafill namedcontentcontenttypegenusspeciesaspergillusfumigatusnamedcontenttranscriptionfactorsinvolvedinthecaspofunginparadoxicaleffect AT mariohenriquebarros namedcontentcontenttypegenusspeciesaspergillusfumigatusnamedcontenttranscriptionfactorsinvolvedinthecaspofunginparadoxicaleffect AT sarahszewahwong namedcontentcontenttypegenusspeciesaspergillusfumigatusnamedcontenttranscriptionfactorsinvolvedinthecaspofunginparadoxicaleffect AT vishukumaraimanianda namedcontentcontenttypegenusspeciesaspergillusfumigatusnamedcontenttranscriptionfactorsinvolvedinthecaspofunginparadoxicaleffect AT koonhowong namedcontentcontenttypegenusspeciesaspergillusfumigatusnamedcontenttranscriptionfactorsinvolvedinthecaspofunginparadoxicaleffect AT gustavohgoldman namedcontentcontenttypegenusspeciesaspergillusfumigatusnamedcontenttranscriptionfactorsinvolvedinthecaspofunginparadoxicaleffect |
| _version_ |
1718427121864409088 |
| spelling |
oai:doaj.org-article:d469d9ee2a384733b3c52ec484cd42d12021-11-15T15:56:46Z<named-content content-type="genus-species">Aspergillus fumigatus</named-content> Transcription Factors Involved in the Caspofungin Paradoxical Effect10.1128/mBio.00816-202150-7511https://doaj.org/article/d469d9ee2a384733b3c52ec484cd42d12020-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00816-20https://doaj.org/toc/2150-7511ABSTRACT Aspergillus fumigatus is the leading cause of pulmonary fungal diseases. Azoles have been used for many years as the main antifungal agents to treat and prevent invasive aspergillosis. However, in the last 10 years there have been several reports of azole resistance in A. fumigatus and new strategies are needed to combat invasive aspergillosis. Caspofungin is effective against other human-pathogenic fungal species, but it is fungistatic only against A. fumigatus. Resistance to caspofungin in A. fumigatus has been linked to mutations in the fksA gene that encodes the target enzyme of the drug β-1,3-glucan synthase. However, tolerance of high caspofungin concentrations, a phenomenon known as the caspofungin paradoxical effect (CPE), is also important for subsequent adaptation and drug resistance evolution. Here, we identified and characterized the transcription factors involved in the response to CPE by screening an A. fumigatus library of 484 null transcription factors (TFs) in CPE drug concentrations. We identified 11 TFs that had reduced CPE and that encoded proteins involved in the basal modulation of the RNA polymerase II initiation sites, calcium metabolism, and cell wall remodeling. One of these TFs, FhdA, was important for mitochondrial respiratory function and iron metabolism. The ΔfhdA mutant showed decreased growth when exposed to Congo red or to high temperature. Transcriptome sequencing (RNA-seq) analysis and further experimental validation indicated that the ΔfhdA mutant showed diminished respiratory capacity, probably affecting several pathways related to the caspofungin tolerance and resistance. Our results provide the foundation to understand signaling pathways that are important for caspofungin tolerance and resistance. IMPORTANCE Aspergillus fumigatus, one of the most important human-pathogenic fungal species, is able to cause aspergillosis, a heterogeneous group of diseases that presents a wide range of clinical manifestations. Invasive pulmonary aspergillosis is the most serious pathology in terms of patient outcome and treatment, with a high mortality rate ranging from 50% to 95% primarily affecting immunocompromised patients. Azoles have been used for many years as the main antifungal agents to treat and prevent invasive aspergillosis. However, there were several reports of evolution of clinical azole resistance in the last decade. Caspofungin, a noncompetitive β-1,3-glucan synthase inhibitor, has been used against A. fumigatus, but it is fungistatic and is recommended as second-line therapy for invasive aspergillosis. More information about caspofungin tolerance and resistance is necessary in order to refine antifungal strategies that target the fungal cell wall. Here, we screened a transcription factor (TF) deletion library for TFs that can mediate caspofungin tolerance and resistance. We have identified 11 TFs that are important for caspofungin sensitivity and/or for the caspofungin paradoxical effect (CPE). These TFs encode proteins involved in the basal modulation of the RNA polymerase II initiation sites, calcium metabolism or cell wall remodeling, and mitochondrial respiratory function. The study of those genes regulated by TFs identified in this work will provide a better understanding of the signaling pathways that are important for caspofungin tolerance and resistance.Clara ValeroAna Cristina ColabardiniJéssica ChiarattoLakhansing PardeshiPatrícia Alves de CastroJaire Alves Ferreira FilhoLilian Pereira SilvaMarina Campos RochaIran MalavaziJonas Henrique CostaTaícia FillMário Henrique BarrosSarah Sze Wah WongVishukumar AimaniandaKoon Ho WongGustavo H. GoldmanAmerican Society for MicrobiologyarticleAspergillus fumigatuscalciumcaspofungincell walltranscription factorsmitochondriaMicrobiologyQR1-502ENmBio, Vol 11, Iss 3 (2020) |