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1.
BMJ Case Rep ; 17(7)2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38955386

RESUMO

Coinfection of Pseudomonas and Aspergillus has not been previously reported in patients with chronic obstructive pulmonary disease (COPD). A middle-aged, thinly built woman (Body Mass Index: 18.1 kg/m²) who smokes bidi (a type of tobacco) and has a history of exposure to open log fires for cooking, has been suffering from COPD for the last 4 years. She has been taking inhaled betamethasone and tiotropium. Additionally, she had uncontrolled diabetes for a few months. She presented with fever, productive cough, shortness of breath and chest pain for 5 days. She required non-invasive ventilation support for type-2 respiratory failure. Chest X-ray and CT confirmed pneumonia, cavities and abscesses in both lungs. Repeated sputum and bronchoalveolar lavage confirmed coinfections with Pseudomonas aeruginosa and Aspergillus fumigatus, respectively. Along with supportive therapy, she was treated with tablet levofloxacin and injection amikacin for 6 weeks based on culture sensitivity reports, and capsule itraconazole for 6 months. She recovered completely to her baseline COPD and diabetes status. This case study confirms that coinfections can occur in COPD and diabetes, highlighting the need for clinicians to be vigilant for the possibility of such symbiotic coinfections.


Assuntos
Aspergillus fumigatus , Coinfecção , Infecções por Pseudomonas , Pseudomonas aeruginosa , Doença Pulmonar Obstrutiva Crônica , Humanos , Doença Pulmonar Obstrutiva Crônica/complicações , Feminino , Infecções por Pseudomonas/complicações , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/diagnóstico , Pessoa de Meia-Idade , Pseudomonas aeruginosa/isolamento & purificação , Aspergillus fumigatus/isolamento & purificação , Antibacterianos/uso terapêutico , Antibacterianos/administração & dosagem , Diabetes Mellitus Tipo 2/complicações , Aspergilose Pulmonar/complicações , Aspergilose Pulmonar/tratamento farmacológico , Aspergilose Pulmonar/diagnóstico , Antifúngicos/uso terapêutico , Antifúngicos/administração & dosagem , Aspergilose/complicações , Aspergilose/tratamento farmacológico , Aspergilose/diagnóstico
2.
Zhonghua Jie He He Hu Xi Za Zhi ; 47(7): 663-667, 2024 Jul 12.
Artigo em Chinês | MEDLINE | ID: mdl-38955753

RESUMO

Pulmonary aspergillosis is a serious pulmonary fungal infectious disease. It is difficult to manage and has limited treatment options. Existing anti-aspergillus medications have high rates of treatment failure and increased drug resistance, making it difficult to meet the clinical requirements. Therefore, the development of new, effective treatment programs is critical. According to research, interferons play an important role in the body's immune response to bacterial and viral infectious diseases. Inadequate interferon expression or dysfunction can put the body at risk for certain infectious diseases. Interferon has been used in clinical trials to prevent or treat infectious diseases. In recent years, researchers have focused on the immunological role of interferon in Aspergillus infections and its potential for clinical application. This review summarized the most recent advances in the immunoregulatory mechanisms of interferon and its clinical application in Aspergillus infections.


Assuntos
Interferons , Humanos , Aspergillus , Aspergilose/imunologia , Aspergilose Pulmonar/imunologia , Aspergilose Pulmonar/tratamento farmacológico
3.
Mycopathologia ; 189(4): 61, 2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38958798

RESUMO

The genus Aspergillus consists of a vast number of medically and environmentally relevant species. Aspergillus species classified in series Versicolores are ubiquitous in the environment and include the opportunistic pathogen Aspergillus sydowii, which is associated with onychomycosis and superficial skin infections. Despite frequent clinical reports of A. sydowii and related series Versicolores species, antifungal susceptibility data are scarce, hampering optimal treatment choices and subsequent patient outcomes. Here, we employed antifungal susceptibility testing (AFST) based on microbroth dilution on a set of 155 series Versicolores strains using the common antifungals amphotericin B, itraconazole, voriconazole, posaconazole, isavuconazole and micafungin with the addition of luliconazole and olorofim. All strains were identified using partial calmodulin gene sequencing, with 145 being A. sydowii, seven A. creber and three A. versicolor, using the latest taxonomic insights. Overall, tested antifungals were potent against the entire strain collection. In comparison to A. fumigatus, azole and amphotericin B MICs were slightly elevated for some strains. AFST with luliconazole and olorofim, here reported for the first time, displayed the highest in vitro activity, making these antifungals interesting alternative drugs but clinical studies are warranted for future therapeutic use.


Assuntos
Antifúngicos , Aspergilose , Aspergillus , Microbiologia Ambiental , Testes de Sensibilidade Microbiana , Antifúngicos/farmacologia , Aspergillus/efeitos dos fármacos , Aspergillus/classificação , Aspergillus/isolamento & purificação , Humanos , Aspergilose/microbiologia , Aspergilose/tratamento farmacológico , Calmodulina/genética , Análise de Sequência de DNA , Acetamidas , Piperazinas , Pirimidinas , Pirróis
4.
Afr Health Sci ; 24(1): 69-75, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38962337

RESUMO

Background: Otomycosis is common in environments with hot, humid weather, and it may be challenging to manage. Objectives: To profile common clinical presentations, the pathogenic fungi, the treatment modalities with responses, and explore clinical factors associated with having positive fungal culture in Otomycosis. Methods: Retrospective review of patients with Otomycosis. Demographic and clinical parameters, otoscopic findings and mycological study results were recorded. The treatment modalities used and treatment response were summarized. Comparative statistical analyses of associated factors to positive fungal culture were performed with Chi square test, and Student's t-test, using SPSS version 22.0. Results: Total of 71 patients with M: F=1:1.8, mean age 38.5±19.8 years. Average duration of symptoms was 5.4 ±4.6 weeks; common presenting complaint was itchy ear (33.8%). Majority of patients (85.9%) had unilateral ear involvement, 50.0% applied ototopic medications before presentation, 8.5% had multiple co-morbidities. 20 patients had positive fungal culture results; common fungal isolate was Aspergillus niger 9 (45.0%).Clinical factors associated with positive culture of fungus were age, non-previous use of ototopic drugs, and presence of co-morbidity. The most common treatment was local ear debridement and use of topical antifungal creams. Majority (91.5%) of the patients responded with resolution of fungal infection. Complications rate was 8.4%. Conclusions: Otomycosis commonly present with itchy ears, the pathogenic fungi commonly being Aspergillus species. The factors associated with positive fungal culture were age, non-usage of ototopic agents and presence of co-morbidity. Treatment modality used was local debridement and topical antifungal agents, which produced favourable response in most patients.


Assuntos
Antifúngicos , Otomicose , Centros de Atenção Terciária , Humanos , Otomicose/tratamento farmacológico , Otomicose/epidemiologia , Otomicose/microbiologia , Feminino , Adulto , Masculino , Estudos Retrospectivos , Pessoa de Meia-Idade , Antifúngicos/uso terapêutico , Nigéria/epidemiologia , Adulto Jovem , Idoso , Adolescente , Aspergillus niger/isolamento & purificação , Desbridamento/métodos , Aspergilose/tratamento farmacológico , Aspergilose/epidemiologia , Criança
5.
Invest Ophthalmol Vis Sci ; 65(8): 4, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38953845

RESUMO

Purpose: The purpose of this study was to investigate the role and mechanism of microtubule-associated protein light chain-3 (LC3)-associated phagocytosis (LAP) in the immune response to Aspergillus fumigatus (A. fumigatus) keratitis. Methods: The formation of single-membrane phagosomes was visualized in the corneas of healthy or A. fumigatus-infected humans and C57BL/6 mice using transmission electron microscopy (TEM). Rubicon siRNA (si-Rubicon) was used to block Rubicon expression. RAW 264.7 cells or mice corneas were infected with A. fumigatus with or without pretreatment of si-Rubicon and scrambled siRNA. RAW 264.7 cells were pretreated with Dectin-1 antibody or Dectin-1 overexpressed plasmid and then stimulated with A. fumigatus. Flow cytometry was used to label macrophages in normal and infected corneas of mice. In mice with A. fumigatus keratitis, the severity of the disease was assessed using clinical scores. We used lentiviral technology to transfer GV348-Ubi-GFP-LC3-II-SV40-Puro Lentivirus into the mouse cornea. The GFP-LC3 fusion protein was visualized in corneal slices using a fluorescence microscope. We detected the mRNA and protein expressions of the inflammatory factors IL-6, IL-1ß, and IL-10 using real-time PCR (RT-PCR) and ELISA. We detected the expression of LAP-related proteins Rubicon, ATG-7, Beclin-1, and LC3-II using Western blot or immunofluorescence. Results: Accumulation of single-membrane phagosomes within macrophages was observed in the corneas of patients and mice with A. fumigatus keratitis using TEM. Flow cytometry (FCM) analysis results show that the number of macrophages in the cornea of mice significantly increases after infection with A. fumigatus. LAP-related proteins were significantly elevated in the corneas of mice and RAW 264.7 cells after infection with A. fumigatus. The si-Rubicon treatment elevated the clinical score of mice. In A. fumigatus keratitis mice, the si-Rubicon treated group showed significantly higher expression of IL-6 and IL-1ß and lower expression of IL-10 and LC3-II compared to the control group. In RAW 264.7 cells, treatment with the Dectin-1 overexpressed plasmid upregulated the expression of LAP-related proteins, a process that was significantly inhibited by the Dectin-1 antibody. Conclusions: LAP participates in the anti-inflammatory immune process of fungal keratitis (FK) and exerts an anti-inflammatory effect. LAP is regulated through the Dectin-1 signaling pathway in A. fumigatus keratitis.


Assuntos
Aspergilose , Aspergillus fumigatus , Infecções Oculares Fúngicas , Ceratite , Camundongos Endogâmicos C57BL , Proteínas Associadas aos Microtúbulos , Fagocitose , Animais , Camundongos , Aspergilose/microbiologia , Aspergilose/metabolismo , Aspergilose/imunologia , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Ceratite/microbiologia , Ceratite/metabolismo , Infecções Oculares Fúngicas/microbiologia , Infecções Oculares Fúngicas/metabolismo , Modelos Animais de Doenças , Macrófagos/metabolismo , Macrófagos/imunologia , Feminino , Citometria de Fluxo , Microscopia Eletrônica de Transmissão , Masculino , Córnea/metabolismo , Córnea/microbiologia , Córnea/patologia
6.
Clin Nucl Med ; 49(8): 750-753, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38967507

RESUMO

ABSTRACT: We report a case of recurrent nasopharyngeal carcinoma postnasopharyngectomy, presenting with headaches. MRI revealed abnormal signals of the clivus with enhancement, and FDG PET/CT indicated intense uptake in the nasopharynx, clivus, and left neck lymph nodes. Bone SPECT/CT showed bony erosion and uptake in bilateral skull base areas. Biopsy confirmed aspergillosis. Despite the challenges in distinguishing tumor invasion from Aspergillus infection on MRI, bone SPECT/CT, and FDG PET/CT, the short postsurgery period and extensive uptake suggested skull base osteomyelitis.


Assuntos
Aspergilose , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Base do Crânio , Humanos , Carcinoma Nasofaríngeo/diagnóstico por imagem , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/diagnóstico por imagem , Diagnóstico Diferencial , Base do Crânio/diagnóstico por imagem , Base do Crânio/patologia , Aspergilose/diagnóstico por imagem , Masculino , Recidiva Local de Neoplasia/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Pessoa de Meia-Idade , Carcinoma/diagnóstico por imagem , Imageamento por Ressonância Magnética , Recidiva
7.
Mycoses ; 67(7): e13764, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38970226

RESUMO

BACKGROUND: The performance of serum galactomannan (GM) for the diagnosis of invasive aspergillosis (IA) has been studied mainly in adults. Paediatric data are scarce and based on small and heterogeneous cohorts. OBJECTIVE: To evaluate the performance of serum GM for the diagnosis of IA in a paediatric oncologic population at high risk of IA and to clarify the impact of antifungal prophylaxis on this test. METHODS: We performed a retrospective study from January 2014 to December 2020 in the paediatric oncologic haematologic department of the University Hospital of Bordeaux. The diagnosis of IA was made using the recommendations of the EORTC and the MSGERC. RESULTS: Among the 329 periods at high risk of IA in 222 patients, the prevalence of IA was 1.8% (3 proven and 3 probable IA). In the total population, the sensitivity, and the positive predictive value (PPV) were respectively 50% and 17.6%. Under antifungal prophylaxis, the sensitivity and PPV dropped, respectively, to 33.3% and 14.3%. In this group, the post-test probability of IA was 2% for a negative serum GM and only 14%. CONCLUSION: In this large cohort of children at high risk of IA, the incidence of IA is low and the diagnostic performance of GM is poor, especially in the case of mould-active prophylaxis. Screening should be targeted rather than systematic and should be reserved for patients at highest risk for IA without mould-active prophylaxis. Combination with other tests such as Aspergillus PCR would increase the accuracy of GM in screening setting.


Assuntos
Antifúngicos , Galactose , Mananas , Humanos , Mananas/sangue , Galactose/análogos & derivados , Estudos Retrospectivos , Criança , Masculino , Feminino , Antifúngicos/uso terapêutico , Pré-Escolar , Adolescente , Lactente , Aspergilose Pulmonar Invasiva/diagnóstico , Aspergilose Pulmonar Invasiva/prevenção & controle , Aspergilose/diagnóstico , Aspergilose/prevenção & controle , Aspergilose/sangue , Sensibilidade e Especificidade , Valor Preditivo dos Testes
9.
Turk J Ophthalmol ; 54(3): 175-179, 2024 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-38860516

RESUMO

A 78-year-old man with a history of lung cancer, chemotherapy, radiotherapy, and coronavirus disease 2019 infection experienced visual deterioration of two-weeks' duration in his right eye. There was multifocal, yellowish-white retinitis foci, vascular engorgement, and scattered intraretinal hemorrhages extending from posterior pole to retinal periphery in the right eye, whereas the left eye was normal. Intravitreal vancomycin, ceftazidime, clindamycin, and dexamethasone were given for endogenous endophthalmitis initially. Vitreous culture confirmed the presence of Aspergillus lentulus, and he was treated with intravitreal amphotericin-B and voriconazole injections together with systemic amphotericin-B, voriconazole, posaconazole, and micafungin therapy. During follow-up, vitreoretinal surgery was performed because of rhegmatogenous retinal detachment, and he received one additional cycle of chemotherapy due to recurrence of the cancer. Although the retina was attached, enucleation was eventually required due to painful red eye. Atypical squamous cells beneath the neurosensory retina suggesting metastasis were noted on histopathological examination. Timely ocular examination is crucial for any immunocompromised patient having ocular symptoms. High level of suspicion for a fungal etiology is a must in these patients.


Assuntos
Aspergilose , Aspergillus , Endoftalmite , Infecções Oculares Fúngicas , Hospedeiro Imunocomprometido , Neoplasias Pulmonares , Humanos , Endoftalmite/diagnóstico , Endoftalmite/microbiologia , Masculino , Idoso , Infecções Oculares Fúngicas/diagnóstico , Infecções Oculares Fúngicas/microbiologia , Neoplasias Pulmonares/diagnóstico , Aspergilose/diagnóstico , Aspergilose/microbiologia , Aspergillus/isolamento & purificação , Antifúngicos/uso terapêutico , COVID-19/complicações , Corpo Vítreo/microbiologia , Injeções Intravítreas , SARS-CoV-2
10.
PLoS Pathog ; 20(6): e1012315, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38889192

RESUMO

Invasive aspergillosis causes significant morbidity and mortality in immunocompromised patients. Natural killer (NK) cells are pivotal for antifungal defense. Thus far, CD56 is the only known pathogen recognition receptor on NK cells triggering potent antifungal activity against Aspergillus fumigatus. However, the underlying cellular mechanisms and the fungal ligand of CD56 have remained unknown. Using purified cell wall components, biochemical treatments, and ger mutants with altered cell wall composition, we herein found that CD56 interacts with the A. fumigatus cell wall carbohydrate galactosaminogalactan (GAG). This interaction induced NK-cell activation, degranulation, and secretion of immune-enhancing chemokines and cytotoxic effectors. Supernatants from GAG-stimulated NK cells elicited antifungal activity and enhanced antifungal effector responses of polymorphonuclear cells. In conclusion, we identified A. fumigatus GAG as a ligand of CD56 on human primary NK cells, stimulating potent antifungal effector responses and activating other immune cells.


Assuntos
Aspergilose , Aspergillus fumigatus , Antígeno CD56 , Células Matadoras Naturais , Humanos , Aspergillus fumigatus/imunologia , Células Matadoras Naturais/imunologia , Antígeno CD56/metabolismo , Antígeno CD56/imunologia , Aspergilose/imunologia , Aspergilose/microbiologia , Ativação Linfocitária/imunologia , Polissacarídeos/metabolismo , Polissacarídeos/imunologia , Parede Celular/imunologia , Parede Celular/metabolismo
11.
BMC Infect Dis ; 24(1): 581, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38867163

RESUMO

BACKGROUND: Several antifungal agents are available for primary therapy in patients with invasive aspergillosis (IA). Although a few studies have compared the effectiveness of different antifungal agents in treating IA, there has yet to be a definitive agreement on the best choice. Herein, we perform a network meta-analysis comparing the efficacy of different antifungal agents in IA. METHODS: We searched PubMed, Embase, and the Cochrane Central Register of Controlled Clinical Trials databases to find studies (both randomized controlled trials [RCTs] and observational) that reported on treatment outcomes with antifungal agents for patients with IA. The study quality was assessed using the revised tool for risk of bias and the Newcastle Ottawa scale, respectively. We performed a network meta-analysis (NMA) to summarize the evidence on antifungal agents' efficacy (favourable response and mortality). RESULTS: We found 12 studies (2428 patients) investigating 11 antifungal agents in the primary therapy of IA. There were 5 RCTs and 7 observational studies. When treated with monotherapy, isavuconazole was associated with the best probability of favourable response (SUCRA, 77.9%; mean rank, 3.2) and the best reduction mortality against IA (SUCRA, 69.1%; mean rank, 4.1), followed by voriconazole and posaconazole. When treated with combination therapy, Liposomal amphotericin B plus caspofungin was the therapy associated with the best probability of favourable response (SUCRA, 84.1%; mean rank, 2.6) and the best reduction mortality (SUCRA, 88.2%; mean rank, 2.2) against IA. CONCLUSION: These findings suggest that isavuconazole, voriconazole, and posaconazole may be the best antifungal agents as the primary therapy for IA. Liposomal amphotericin B plus caspofungin could be an alternative option.


Assuntos
Antifúngicos , Aspergilose , Metanálise em Rede , Antifúngicos/uso terapêutico , Humanos , Aspergilose/tratamento farmacológico , Aspergilose/microbiologia , Resultado do Tratamento , Caspofungina/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Infecções Fúngicas Invasivas/tratamento farmacológico , Triazóis/uso terapêutico , Anfotericina B/uso terapêutico , Voriconazol/uso terapêutico , Nitrilas , Piridinas
12.
Commun Biol ; 7(1): 704, 2024 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-38851817

RESUMO

Aspergillus fumigatus represents a public health problem due to the high mortality rate in immunosuppressed patients and the emergence of antifungal-resistant isolates. Protein acetylation is a crucial post-translational modification that controls gene expression and biological processes. The strategic manipulation of enzymes involved in protein acetylation has emerged as a promising therapeutic approach for addressing fungal infections. Sirtuins, NAD+-dependent lysine deacetylases, regulate protein acetylation and gene expression in eukaryotes. However, their role in the human pathogenic fungus A. fumigatus remains unclear. This study constructs six single knockout strains of A. fumigatus and a strain lacking all predicted sirtuins (SIRTKO). The mutant strains are viable under laboratory conditions, indicating that sirtuins are not essential genes. Phenotypic assays suggest sirtuins' involvement in cell wall integrity, secondary metabolite production, thermotolerance, and virulence. Deletion of sirE attenuates virulence in murine and Galleria mellonella infection models. The absence of SirE alters the acetylation status of proteins, including histones and non-histones, and triggers significant changes in the expression of genes associated with secondary metabolism, cell wall biosynthesis, and virulence factors. These findings encourage testing sirtuin inhibitors as potential therapeutic strategies to combat A. fumigatus infections or in combination therapy with available antifungals.


Assuntos
Aspergilose , Aspergillus fumigatus , Sirtuínas , Aspergillus fumigatus/patogenicidade , Aspergillus fumigatus/genética , Aspergillus fumigatus/enzimologia , Sirtuínas/genética , Sirtuínas/metabolismo , Virulência , Animais , Camundongos , Aspergilose/microbiologia , Aspergilose/tratamento farmacológico , Acetilação , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Regulação Fúngica da Expressão Gênica , Fatores de Virulência/genética , Fatores de Virulência/metabolismo , Mariposas/microbiologia
13.
J Med Microbiol ; 73(6)2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38836745

RESUMO

Introduction. The fungal pathogen Aspergillus fumigatus can induce prolonged colonization of the lungs of susceptible patients, resulting in conditions such as allergic bronchopulmonary aspergillosis and chronic pulmonary aspergillosis.Hypothesis. Analysis of the A. fumigatus secretome released during sub-lethal infection of G. mellonella larvae may give an insight into products released during prolonged human colonisation.Methodology. Galleria mellonella larvae were infected with A. fumigatus, and the metabolism of host carbohydrate and proteins and production of fungal virulence factors were analysed. Label-free qualitative proteomic analysis was performed to identify fungal proteins in larvae at 96 hours post-infection and also to identify changes in the Galleria proteome as a result of infection.Results. Infected larvae demonstrated increasing concentrations of gliotoxin and siderophore and displayed reduced amounts of haemolymph carbohydrate and protein. Fungal proteins (399) were detected by qualitative proteomic analysis in cell-free haemolymph at 96 hours and could be categorized into seven groups, including virulence (n = 25), stress response (n = 34), DNA repair and replication (n = 39), translation (n = 22), metabolism (n = 42), released intracellular (n = 28) and cellular development and cell cycle (n = 53). Analysis of the Gallerial proteome at 96 hours post-infection revealed changes in the abundance of proteins associated with immune function, metabolism, cellular structure, insect development, transcription/translation and detoxification.Conclusion. Characterizing the impact of the fungal secretome on the host may provide an insight into how A. fumigatus damages tissue and suppresses the immune response during long-term pulmonary colonization.


Assuntos
Aspergillus fumigatus , Proteínas Fúngicas , Larva , Mariposas , Animais , Aspergillus fumigatus/metabolismo , Larva/microbiologia , Mariposas/microbiologia , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/genética , Secretoma/metabolismo , Proteômica , Fatores de Virulência/metabolismo , Proteoma/análise , Hemolinfa/microbiologia , Hemolinfa/metabolismo , Virulência , Aspergilose/microbiologia , Aspergilose/metabolismo
14.
Nat Commun ; 15(1): 4984, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38862481

RESUMO

More than 10 million people suffer from lung diseases caused by the pathogenic fungus Aspergillus fumigatus. Azole antifungals represent first-line therapeutics for most of these infections but resistance is rising, therefore the identification of antifungal targets whose inhibition synergises with the azoles could improve therapeutic outcomes. Here, we generate a library of 111 genetically barcoded null mutants of Aspergillus fumigatus in genes encoding protein kinases, and show that loss of function of kinase YakA results in hypersensitivity to the azoles and reduced pathogenicity. YakA is an orthologue of Candida albicans Yak1, a TOR signalling pathway kinase involved in modulation of stress responsive transcriptional regulators. We show that YakA has been repurposed in A. fumigatus to regulate blocking of the septal pore upon exposure to stress. Loss of YakA function reduces the ability of A. fumigatus to penetrate solid media and to grow in mouse lung tissue. We also show that 1-ethoxycarbonyl-beta-carboline (1-ECBC), a compound previously shown to inhibit C. albicans Yak1, prevents stress-mediated septal spore blocking and synergises with the azoles to inhibit A. fumigatus growth.


Assuntos
Antifúngicos , Aspergillus fumigatus , Quinases Dyrk , Proteínas Fúngicas , Proteínas Serina-Treonina Quinases , Proteínas Tirosina Quinases , Aspergillus fumigatus/genética , Aspergillus fumigatus/efeitos dos fármacos , Aspergillus fumigatus/enzimologia , Animais , Antifúngicos/farmacologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/antagonistas & inibidores , Camundongos , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , Azóis/farmacologia , Aspergilose/microbiologia , Aspergilose/tratamento farmacológico , Pulmão/microbiologia , Esporos Fúngicos/efeitos dos fármacos , Esporos Fúngicos/genética , Feminino
15.
Arch Microbiol ; 206(7): 305, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38878211

RESUMO

Aspergillus fumigatus is a ubiquitous filamentous fungus commonly found in the environment. It is also an opportunistic human pathogen known to cause a range of respiratory infections, such as invasive aspergillosis, particularly in immunocompromised individuals. Azole antifungal agents are widely used for the treatment and prophylaxis of Aspergillus infections due to their efficacy and tolerability. However, the emergence of azole resistance in A. fumigatus has become a major concern in recent years due to their association with increased treatment failures and mortality rates. The development of azole resistance in A. fumigatus can occur through both acquired and intrinsic mechanisms. Acquired resistance typically arises from mutations in the target enzyme, lanosterol 14-α-demethylase (Cyp51A), reduces the affinity of azole antifungal agents for the enzyme, rendering them less effective, while intrinsic resistance refers to a natural resistance of certain A. fumigatus isolates to azole antifungals due to inherent genetic characteristics. The current review aims to provide a comprehensive overview of azole antifungal resistance in A. fumigatus, discusses underlying resistance mechanisms, including alterations in the target enzyme, Cyp51A, and the involvement of efflux pumps in drug efflux. Impact of azole fungicide uses in the environment and the spread of resistant strains is also explored.


Assuntos
Antifúngicos , Aspergilose , Aspergillus fumigatus , Azóis , Farmacorresistência Fúngica , Proteínas Fúngicas , Aspergillus fumigatus/efeitos dos fármacos , Aspergillus fumigatus/genética , Azóis/farmacologia , Farmacorresistência Fúngica/genética , Antifúngicos/farmacologia , Humanos , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Aspergilose/microbiologia , Aspergilose/tratamento farmacológico , Testes de Sensibilidade Microbiana , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Mutação
16.
Mycopathologia ; 189(4): 49, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38864956

RESUMO

Aspergillosis encompasses a wide range of clinical conditions based on the interaction between Aspergillus and the host. It ranges from colonization to invasive aspergillosis. The human lung provides an entry door for Aspergillus. Aspergillus has virulence characteristics such as conidia, rapid growth at body temperature, and the production of specific proteins, carbohydrates, and secondary metabolites that allow A. fumigatus to infiltrate the lung's alveoli and cause invasive aspergillosis. Alveolar epithelial cells play an important role in both fungus clearance and immune cell recruitment via cytokine release. Although the innate immune system quickly clears conidia in immunocompetent hosts, A. fumigatus has evolved multiple virulence factors in order to escape immune response such as ROS detoxifying enzymes, the rodlet layer, DHN-melanin and toxins. Bacterial co-infections or interactions can alter the immune response, impact Aspergillus growth and virulence, enhance biofilm formation, confound diagnosis, and reduce treatment efficacy. The gut microbiome's makeup influences pulmonary immune responses generated by A. fumigatus infection and vice versa. The real-time PCR for Aspergillus DNA detection might be a particularly useful tool to diagnose pulmonary aspergillosis. Metagenomics analyses allow quick and easy detection and identification of a great variety of fungi in different clinical samples, although optimization is still required particularly for the use of NGS techniques. This review will analyze the current state of aspergillosis in light of recent discoveries in the microbiota and mycobiota.


Assuntos
Aspergilose , Micobioma , Humanos , Aspergilose/microbiologia , Aspergilose/diagnóstico , Aspergilose/imunologia , Aspergillus fumigatus/patogenicidade , Aspergillus fumigatus/genética , Aspergillus fumigatus/imunologia , Aspergillus/genética , Aspergillus/patogenicidade , Fatores de Virulência/genética , Microbiota , Virulência , Metagenômica , Interações Hospedeiro-Patógeno/imunologia
17.
Mycopathologia ; 189(4): 57, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38878212

RESUMO

A 67 year-old male was admitted in the ICU because of multi-organ failure due to sepsis secondary to Fournier's gangrene. He had sustained radical prostatectomy in the last 48 hours. Peritoneal fluid and fatty tissue biopsies grew Aspergillus Fumigatus without concomitant pulmonary involvement. Postoperative acquisition via exogenous and endogenous routes is discussed, as this nosocomial entity is very rarely reported apart from peritoneal dialysis, especially in non-immunosuppressed patients.


Assuntos
Aspergilose , Aspergillus fumigatus , Peritonite , Complicações Pós-Operatórias , Humanos , Masculino , Aspergillus fumigatus/isolamento & purificação , Idoso , Peritonite/microbiologia , Peritonite/patologia , Peritonite/etiologia , Aspergilose/microbiologia , Aspergilose/diagnóstico , Aspergilose/patologia , Aspergilose/etiologia , Complicações Pós-Operatórias/microbiologia , Complicações Pós-Operatórias/etiologia , Prostatectomia/efeitos adversos
18.
Mycopathologia ; 189(4): 50, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38864903

RESUMO

Aspergillus fumigatus is a saprophytic fungal pathogen that causes opportunistic infections in animals and humans. Azole resistance has been reported globally in human A. fumigatus isolates, but the prevalence of resistance in isolates from animals is largely unknown. A retrospective resistance surveillance study was performed using a collection of clinical A. fumigatus isolates from various animal species collected between 2015 and 2020. Agar-based azole resistance screening of all isolates was followed by in vitro antifungal susceptibility testing and cyp51A gene sequencing of the azole-resistant isolates. Over the 5 year period 16 (11.3%) of 142 A. fumigatus culture-positive animals harbored an azole-resistant isolate. Resistant isolates were found in birds (15%; 2/13), cats (21%; 6/28), dogs (8%; 6/75) and free-ranging harbor porpoise (33%; 2/6). Azole-resistance was cyp51A mediated in all isolates: 81.3% (T-67G/)TR34/L98H, 12.5% TR46/Y121F/T289A. In one azole-resistant A. fumigatus isolate a combination of C(-70)T/F46Y/C(intron7)T/C(intron66)T/M172V/E427K single-nucleotide polymorphisms in the cyp51A gene was found. Of the animals with an azole-resistant isolate and known azole exposure status 71.4% (10/14) were azole naive. Azole resistance in A. fumigatus isolates from animals in the Netherlands is present and predominantly cyp51A TR-mediated, supporting an environmental route of resistance selection. Our data supports the need to include veterinary isolates in resistance surveillance programs. Veterinarians should consider azole resistance as a reason for therapy failure when treating aspergillosis and consider resistance testing of relevant isolates.


Assuntos
Antifúngicos , Aspergilose , Aspergillus fumigatus , Azóis , Farmacorresistência Fúngica , Testes de Sensibilidade Microbiana , Aspergillus fumigatus/efeitos dos fármacos , Aspergillus fumigatus/genética , Aspergillus fumigatus/isolamento & purificação , Animais , Azóis/farmacologia , Farmacorresistência Fúngica/genética , Aspergilose/microbiologia , Aspergilose/veterinária , Antifúngicos/farmacologia , Países Baixos/epidemiologia , Estudos Retrospectivos , Proteínas Fúngicas/genética , Aves/microbiologia , Gatos , Cães , Sistema Enzimático do Citocromo P-450
19.
Med Mycol ; 62(6)2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-38935907

RESUMO

Recognizing the growing global burden of fungal infections, the World Health Organization established a process to develop a priority list of fungal pathogens (FPPL). In this systematic review, we aimed to evaluate the epidemiology and impact of invasive infections caused by Aspergillus fumigatus to inform the first FPPL. The pre-specified criteria of mortality, inpatient care, complications and sequelae, antifungal susceptibility, risk factors, preventability, annual incidence, global distribution, and emergence were used to search for relevant articles between 1 January 2016 and 10 June 2021. Overall, 49 studies were eligible for inclusion. Azole antifungal susceptibility varied according to geographical regions. Voriconazole susceptibility rates of 22.2% were reported from the Netherlands, whereas in Brazil, Korea, India, China, and the UK, voriconazole susceptibility rates were 76%, 94.7%, 96.9%, 98.6%, and 99.7%, respectively. Cross-resistance was common with 85%, 92.8%, and 100% of voriconazole-resistant A. fumigatus isolates also resistant to itraconazole, posaconazole, and isavuconazole, respectively. The incidence of invasive aspergillosis (IA) in patients with acute leukemia was estimated at 5.84/100 patients. Six-week mortality rates in IA cases ranged from 31% to 36%. Azole resistance and hematological malignancy were poor prognostic factors. Twelve-week mortality rates were significantly higher in voriconazole-resistant than in voriconazole-susceptible IA cases (12/22 [54.5%] vs. 27/88 [30.7%]; P = .035), and hematology patients with IA had significantly higher mortality rates compared with solid-malignancy cases who had IA (65/217 [30%] vs. 14/78 [18%]; P = .04). Carefully designed surveillance studies linking laboratory and clinical data are required to better inform future FPPL.


Assuntos
Antifúngicos , Aspergilose , Aspergillus fumigatus , Farmacorresistência Fúngica , Organização Mundial da Saúde , Humanos , Aspergillus fumigatus/efeitos dos fármacos , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Aspergilose/epidemiologia , Aspergilose/microbiologia , Aspergilose/mortalidade , Voriconazol/farmacologia , Voriconazol/uso terapêutico , Incidência , Testes de Sensibilidade Microbiana , Infecções Fúngicas Invasivas/epidemiologia , Infecções Fúngicas Invasivas/microbiologia , Infecções Fúngicas Invasivas/mortalidade , Infecções Fúngicas Invasivas/tratamento farmacológico , Fatores de Risco
20.
J Med Case Rep ; 18(1): 261, 2024 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-38797854

RESUMO

BACKGROUND: All-trans retinoic acid (ATRA) is an indispensable part of the treatment of acute promyelocytic leukemia (APL). Although, mild cutaneous toxicities like mucocutaneous xerosis, rash, and pruritus are well reported, ATRA associated severe dermatological toxicities are extremely rare. ATRA is primary metabolized by cytochrome P450 (CYP450) enzyme system, and triazole antifungals are notorious for their strong inhibitory effect on CYP450. CASE PRESENTATION: Three Asian APL patients experienced rare ATRA-induced severe dermatological toxicities: exfoliative dermatitis (ED) in cases 1 and 2, and necrotic scrotal ulceration in case 3. Both case 1 (33-year-old female), and case 2 (28-year-old male) landed in emergency department with dehydration, generalized skin erythema and xerosis during their induction chemotherapy. Both of these patients also developed invasive aspergillosis and required concomitant triazole antifungals during their chemotherapy. For ED, intravenous fluids and broad-spectrum antibiotics were started along with application of local emollients to prevent transdermal water loss. Although their general condition improved but skin exfoliation continued with complete desquamation of palms and soles. Dermatology was consulted, and clinical diagnosis of ED was established. Discontinuation of ATRA resulted in complete resolution of ED. Case 3 (15-year-old boy) reported two blackish mildly tender scrotal lesions during induction chemotherapy. He also had mucocutaneous candidiasis at presentation and was kept on triazole antifungal. Local bacterial & fungal cultures, and serological testing for herpes simplex virus were reported negative. Despite adequate local care and optimal antibiotic support, his lesions persisted, and improved only after temporary discontinuation of ATRA. After a thorough literature review and considering the temporal association of cutaneous toxicities with triazole antifungals, we speculate that the concomitant use of triazole antifungals inhibited the hepatic metabolism of ATRA, resulting in higher serum ATRA concentration, and markedly accentuated cutaneous toxicities in our patients. CONCLUSION: By highlighting this crucial pharmacokinetic interaction, we want to caution the fellow oncologists to be mindful of the inhibitory effect of triazole antifungals on CYP450. We propose using a non-myelosuppressive combination of ATRA and arsenic trioxide for management of APL hence, obliterating the need of prophylactic antifungals. However, in the event of invasive fungal infection (IFI), we suggest using alternative class of antifungals.


Assuntos
Antifúngicos , Leucemia Promielocítica Aguda , Tretinoína , Triazóis , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Masculino , Antifúngicos/efeitos adversos , Antifúngicos/uso terapêutico , Feminino , Tretinoína/efeitos adversos , Adulto , Triazóis/efeitos adversos , Triazóis/uso terapêutico , Antineoplásicos/efeitos adversos , Aspergilose/tratamento farmacológico , Toxidermias/etiologia
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